Abstract
Objective: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD).
Background: Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients.
Methods: The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A–resistant patients with CD. After resistance to therapy was confirmed with the frontalis–type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16.
Results: A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p < 0.0001, 0.0001, and 0.001). A Kaplan–Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group.
Conclusions: Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks.
Cervical dystonia (CD) is the most common form of focal dystonia treated in a medical practice.1 It is characterized by abnormal, involuntary muscle contractions of the cervical and/or shoulder muscles that may be sustained or intermittent, and the contractions result in abnormal head postures that may be fixed or associated with repetitive, rhythmic, jerky movements.2-4 Tremor and musculoskeletal pain frequently accompany the abnormal movements and postures.4,5 Disability from CD may interfere markedly with the ability to lead a normal life.6,7 Oral pharmacologic treatments, including anticholinergics, muscle relaxants, and anticonvulsants, are generally inadequate, and peripheral surgical treatment is irreversible.8-10
The intramuscular injection of botulinum toxin type A (BoNT/A) into affected muscles is used as therapy for the treatment of CD.4,11-15 After repeated use, however, some patients receiving high doses, as are often required in CD, develop secondary resistance to type A therapy, possibly related to the development of neutralizing antibodies.16-19 The incidence of clinical resistance to type A treatment in CD has been estimated to be as a high as 6.5%.19-22 Patients who have become resistant secondarily to type A toxin, and who have failed pharmacotherapy, have limited options for effective symptom relief (e.g., phenol injections, rhizotomy, brain surgery).8,19-22
Mediated through a three-step process, BoNTs inhibit the release of acetylcholine (ACh) by interfering with the fusion protein complex responsible for vesicular docking on the inner surface of the cellular membrane.23 Each toxin molecule is composed of a light and heavy chain. The first step is extracellular binding of the toxin’s heavy chain to specific acceptors on motor nerve terminals. This is followed by toxin internalization and release of the light chain into the cytosol of the nerve terminal. The light chain is a zinc-dependent endopeptidase that cleaves one component of the fusion protein complex (the third step), and therefore inhibits release of ACh from nerve terminals into the neuromuscular junction, resulting in muscle weakness. Although the clinical manifestations of the neurotoxin serotypes are generally similar (e.g., muscle weakness), their target intraneuronal proteins are serotype specific: BoNT/A cleaves synapse-associated protein-25 and BoNT/B cleaves vesicle-associated membrane protein (also known as synaptobrevin).24,25 Furthermore, types A and B toxins are also distinct antigenically,24,26,27 and neutralizing antibodies to BoNT/A do not protect against type B toxin effects28,29 in in vivo studies and vice versa.
In a double-blind, placebo-controlled study of 122 patients with CD treated with BoNT/B (formulated as NeuroBloc), the drug was observed to be safe, well tolerated, and efficacious.30 Efficacy was demonstrated by improvements in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and in visual analog scales designed to assess global benefit and pain assessment. The subset analysis of type A-resistant patients demonstrated a response similar to those who were type A toxin responsive.30
The randomized, multicenter (seven centers), double-blind, placebo-controlled trial presented here evaluates the safety and efficacy of BoNT/B in the treatment of CD patients who are type A toxin resistant (secondary nonresponders).
Methods.
Inclusion/exclusion criteria.
All participants signed an institutional review board-approved informed consent form. During screening, patients were considered eligible for enrollment if they had CD for at least 1 year that involved two or more of the following muscles: levator scapulae, scalene complex, semispinalis capitis, splenius capitis, sternocleidomastoid, or trapezius. For this trial, clinically resistant patients must have met one of the following two criteria:
-
Resistance criteria 1: Previously the patient had a clinically meaningful response to type A toxin treatment (“clinically meaningful”in the opinion of the investigator), but failed to respond to the last two adequate treatment sessions with type A toxin (“adequate treatment”was defined as a treatment session of adequate dose, technique, and an injection into correct CD muscles to produce an anticipated, clinically meaningful response) and, at one of these last two treatment sessions, a greater (increased) dose of type A toxin was used relative to the previously effective dose.
-
Resistance criteria 2: Previously the patient had a clinically meaningful response to type A toxin treatment, but had failed to respond to the last adequate treatment session with type A toxin and the patient had either a positive type A mouse neutralization test or “the patient had demonstrated type A resistance by a failure to respond to an appropriate dose of type A toxin injected into a selected CD muscle (e.g., “failure to respond to an appropriate dose” was defined as failure of the injected muscle to demonstrate appropriate acute denervation by electromyographic or clinical muscle atrophy when a higher [increased] dose of type A toxin was injected into that muscle than had previously produced an effect).
After meeting one of the two type A resistance criteria, the patient also needed to have an appropriate frontalis–type A test (F-TAT) result before being considered for study enrollment. The F-TAT consisted of the injection of 15 U type A toxin, administered as two doses of 7.5 U each, into the right frontalis muscle.8,31 Patients were considered to be type A resistant if they could wrinkle their right frontalis muscle 2 weeks after the F-TAT injection.
After resistance to type A toxin was established, the following additional criteria were required at baseline: a TWSTRS-Total score of 20, a TWSTRS-Severity score of 10, a TWSTRS-Disability score of 3, and a TWSTRS-Pain score of ≥1. Patients enrolled were at least 18 years of age, weighed at least 46 kg, and had physical and neurologic examinations and laboratory evaluations at baseline that were acceptable clinically, in the opinion of the investigator, for entry into the study.
Patients were excluded if they had received a BoNT injection in the last 4 months for their CD, had previously participated in a BoNT/B trial, had neck contractures or cervical spine disease such that a notable decrease in passive range of motion of the neck was present, had pure retrocollis or anterocollis, used drugs irregularly that could interfere with the evaluation of the safety and efficacy measures (e.g., narcotics, muscle relaxants, or benzodiazepines), had an acute or chronic medical condition or known drug hypersensitivity to the study drug formulation, had a history of myotomy or denervation surgery of the neck and/or shoulder region, received tetanus toxoid in the last 4 months, or used another investigational drug or device within 30 days of entry into this study. Also excluded were patients with a history of clinically significant, persistent neurologic or neuromuscular disorder; with a cardiovascular, renal, hepatic, gastrointestinal, dermatologic, major psychiatric or hematologic illness; or were women of child-bearing potential who were pregnant or breast-feeding.
Study design.
See figure 1 for study flow chart.
Figure 1. Flow chart of the NeuroBloc randomized trial in the treatment of patients with type A–resistant cervical dystonia. *Adverse events included neck pain, headache, urticaria, eye pain, asthenia, and nausea. TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale.
Personnel.
To maintain the blinding of the principal investigator (PI), two investigators (the PI and an administrative investigator [AI]) were required at each study site. The PI performed all screening assessments, identified muscles for injection, and performed the injection, in addition to acquiring all TWSTRS scores and the PI Global Assessment of Change. The AI or a designee (but not the PI) performed all other activities for each visit (including adverse event [AE] collection and assessment). Patients were instructed not to divulge any AE information to the PI.
Efficacy assessments.
The TWSTRS-Total score (range, 0 to 87) was the primary efficacy measure.32,33 It is composed of three subscales—Severity (range, 0 to 35), Disability (range, 0 to 32), and Pain (range, 0 to 20)—and was completed at each visit. Three visual analog scale assessments were also used to assess efficacy: Patient Global Assessment of Change, PI Global Assessment of Change, and Patient Analog Pain Assessment.
Safety assessments.
AE data and vital signs were collected at each visit during the study. An AE was defined as any undesirable event that occurred to a participant during the course of the study or within a reasonable time after study termination, regardless of whether the event was considered to be related to the study drug. AEs were recorded and assessed for severity and their relationship to the study drug. Blood and urine samples were collected at screening, week 4, and at termination.
Treatment and study activities.
Eligible patients were assigned randomly to one of two treatment groups: placebo or BoNT/B (10,000 U). Master randomization tables were generated by an independent organization (Pharmaceutical Research Associates, Charlottesville, VA), and the investigators, patients, and sponsor were blinded to drug assignment until after the database was locked and analyzed.
The screening visit was divided into two parts. During part 1 of the screening visit, which was conducted no more than 21 days before study drug injection, an institutional review board-approved informed consent form was signed and dated. Study entrance requirements were then reviewed, and the F-TAT injection was administered. Approximately 2 weeks later, screening visit part 2 was conducted, and the following were obtained/performed: medical history, physical and neurologic examination (including vital signs), laboratory tests, pregnancy test, and serum sample for BoNT/B antibody determination. Efficacy assessments were performed by the PI at the treatment visit (day 1) and at weeks 2, 4, 8, 12, and 16 (termination). During each visit the patient global and pain assessments were completed independently by the patient, and vital signs, AEs, and concomitant medications were recorded and assessed. Additionally, a phone call was made to the patient at week 1 to assess safety.
Test material formulation and dose selection.
The study drug, provided by Athena Neurosciences, Inc. (San Francisco, CA), was packaged in liquid form in 3.5-mL vials. Each vial contained 5,000 U of NeuroBloc (BoNT/B) or placebo (same solution without toxin) in a 1.0-mL sterile solution, buffered to a pH of 5.6 and stored in a refrigerator. The study drug was assigned randomly to each patient. A total of 2.0 mL of the study drug was injected into two to four involved CD muscles by the PI during the day 1 visit with or without the use of electromyography. Based on the PI’s judgment, the proportionate volume per muscle could then be divided and injected into one to five sites within that selected muscle, with each injection site receiving from 0.1 to 1.0 mL of the study drug. Each patient participated in only one dosing session.
Statistical analyses.
The intent-to-treat dataset was used for all analyses and consisted of data for every efficacy variable at every visit for all patients who were randomized to treatment. If a patient had missing data for an efficacy variable at any visit, the value of that variable from the previous visit was carried forward. The level of significance for the main effects (i.e., center and treatment) was set at α = 0.05, and the level of significance for interactions was set at α = 0.10. The analyses consisted of a single, primary efficacy analysis and multiple supporting analyses performed by using SAS (version 6.12; SAS Statistical Institute, Inc., Cary, NC).34,35
The primary efficacy analysis compared the TWSTRS-Total scores at week 4 between the treatment groups by using an analysis of covariance (ANCOVA). An analysis of variance (ANOVA) of the Patient Global Assessment of Change at week 4 was defined as the supportive secondary efficacy analysis. Other secondary efficacy analyses were an ANOVA of the PI Global Assessment of Change at week 4 and ANCOVAs of the TWSTRS-Total scores at weeks 8 and 12. Tertiary efficacy analyses consisted of ANCOVAs of the Patient Analog Pain Assessments at week 4, TWSTRS subscale scores at week 4, and TWSTRS-Total scores at week 16.
Effects in the preliminary models for the ANCOVAs were baseline score, center, treatment, and the baseline-by-treatment and center-by-treatment interactions; effects in the preliminary models for the ANOVAs were center, treatment, and the center-by-treatment interaction. Reduced ANCOVAs were performed as the prospectively defined primary analysis, with baseline, center, and treatment in the model, but with both interactions removed.
For the primary (TWSTRS-Total at week 4) and secondary (TWSTRS-Total at weeks 8 and 12) efficacy outcome variables when interactions were noted, three analyses are presented: the prospectively defined ANCOVA without interactions (primary analysis), a test of treatment effect at the baseline mean in the preliminary ANCOVA with interactions included (supportive analysis), and an ANOVA without the baseline score included (supportive analysis). For the tertiary outcome efficacy variables when interactions were noted, only the prospectively defined ANCOVA results are presented.
The estimated difference between the two treatment groups for each variable with a 95% CI for that difference was calculated (figure 2). The estimated difference is based on adjusted least squares means from the prospectively defined ANCOVA or ANOVA. The numbers were adjusted so that positive numbers indicate a difference in favor of NeuroBloc treatment, and negative numbers indicate a difference in favor of placebo.
Figure 2. Comparisons of 10,000 U versus placebo, 95% CIs, and levels of significance for efficacy variables for botulinum toxin type B treatment in type A–resistant cervical dystonia patients. A, primary efficacy; B, secondary efficacy variables; C, tertiary efficacy variables. The statistical analysis was performed as an intention-to-treat dataset. TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale.
An exploratory Kaplan–Meier survival analysis36 was performed to assess the duration of treatment effect. The event of interest was the time to return to the baseline value as measured by the TWSTRS-Total. This time was defined as the number of days until the TWSTRS-Total score equaled or exceeded the baseline value, and was based on all assessments at or greater than week 4. The median time until return to baseline was then estimated for each treatment group. Using the log-rank statistic,37 the two distributions were compared.
Results.
Patient disposition and population.
A total of 77 patients were enrolled: 38 received placebo and 39 received 10,000 U of NeuroBloc. One patient (placebo group) discontinued the study prematurely because of AEs (urticaria, headache, asthenia, nausea, eye pain, and neck pain secondary to CD). Table 1 summarizes the demographic and baseline data for age, gender, height, and weight by treatment group. There were no significant differences among the groups for demographic characteristics. All of the patients in the study were white, and thus race was not tested.
Demographic and baseline characteristics
Efficacy results.
TWSTRS-Total scores.
Table 2 summarizes TWSTRS-Total scores by visit, and figure 2 summarizes the pairwise comparisons, p values, and 95% CIs for selected efficacy outcome variables.
Summary of mean ± SD and p values for study variables
Primary efficacy outcome variable.
The mean TWSTRS-Total scores at baseline were 51.2 (placebo) and 52.8 (10,000 U; see table 2), with the mean improvements (decreases) from baseline to week 4 of 2.0 (placebo) and 11.1 (10,000-U group). In the preliminary model for the analysis of the TWSTRS-Total scores at week 4, significant center-by-treatment and baseline-by-treatment interactions were noted. Although the improvement in TWSTRS-Total scores from baseline to week 4 was higher on average for patients treated with BoNT/B than for placebo patients at all sites, the difference between the two treatment groups was smaller at two sites than the others. Also, the change from baseline in TWSTRS-Total scores for placebo patients did not tend to depend on their baseline score, but the change from baseline for BoNT/B-treated patients tended to increase as their baseline scores increased (as anticipated, patients with more severe baseline disease tended to demonstrate a greater improvement in the active group). The TWSTRS-Total scores at week 4 between the two groups were different in the prospectively defined ANCOVA with both the interactions removed (estimated difference, 8.7; 95% CI, 12.2, 5.2; p = 0.0001; see table 2 and figure 2).
For the primary efficacy outcome variable, two other supportive analyses were performed to assess the baseline-by-treatment interaction. First, the test of treatment at the mean baseline TWSTRS-Total score in the preliminary ANCOVA was performed and was found to be different (p = 0.0001). Second, a supporting ANOVA was performed to analyze the data using a model from which the baseline covariate and the baseline-by-treatment interaction were removed. The TWSTRS-Total scores at week 4 between the two groups remained different (p = 0.0042). Therefore, these three analyses (prospectively defined ANCOVA, mean baseline ANCOVA, and ANOVA) all demonstrated the superiority of BoNT/B over placebo.
Supportive and other secondary efficacy outcome variables.
For the prospectively defined supportive secondary outcome efficacy measure, mean values for the Patient Global Assessment of Change at week 4 were 39.5 (placebo) and 60.2 (10,000 U; see table 2) with a difference noted between the two treatment groups (estimated difference, 20.1; 95% CI, 11.2, 29.1; p = 0.0001; see table 2 and figure 2).
Three other secondary efficacy outcome variables were defined prospectively and found to be significant. Mean values for the PI Global Assessment of Change at week 4 were 47.9 (placebo) and 60.6 (10,000 U; see table 2), with a difference noted between the two treatment groups (estimated difference, 12.7; 95% CI, 7.4, 18.1; p = 0.0001; see table 2 and figure 2). The mean values for the TWSTRS-Total scores at week 8 were 49.6 (placebo) and 44.1 (10,000 U; see table 2), with mean improvements from baseline to week 8 of 1.7 (placebo) and 8.8 (10,000 U). The TWSTRS-Total scores at week 8 between the two treatment groups were different in the reduced ANCOVA with both the interactions removed (estimated difference, 6.8; 95% CI, 10.2, 3.4; p = 0.0002; see figure 2). The test of treatment at the mean baseline TWSTRS-Total score in the preliminary ANCOVA (baseline to week 8) and the test of treatment in the supporting ANOVA (at week 8) were also different (p = 0.0006 and p = 0.0362, respectively). Mean values for the TWSTRS-Total scores at week 12 were 50.5 (placebo) and 46.8 (10,000 U; see table 2), with mean improvements from baseline to week 12 of 0.8 (placebo) and 6.0 (10,000 U). The TWSTRS-Total scores at week 12 between the two treatment groups were different in the reduced ANCOVA with both the interactions removed (estimated difference, 4.8; 95% CI, 8.5, 1.0; p = 0.0129; see figure 2). The test of treatment at the mean baseline TWSTRS-Total score in the preliminary ANCOVA was also different (p = 0.0113). However, for the less sensitive ANOVA, the difference at week 12 between the groups was not significant.
Tertiary efficacy outcome variables.
For the tertiary efficacy outcome variables, the results of the prospectively defined ANCOVA are presented here. Mean values for the Patient Analog Pain Assessment at baseline were 33.6 (placebo) and 41.4 (10,000 U), and mean values at week 4 were 37.3 (placebo) and 57.7 (10,000 U; see table 2). The statistical comparison between the two groups demonstrated a difference (estimated difference, 15.9; 95% CI, 6.7, 25.2; p = 0.0010; see figure 2). For the TWSTRS subscale scores (Severity, Disability, and Pain), the following was noted. Mean values for the TWSTRS-Severity subscale scores at week 4 were 21.0 (placebo) and 18.9 (10,000 U; see table 2), and mean improvements from baseline to week 4 were 1.2 (placebo) and 3.7 (10,000 U). The statistical comparison between the two treatment groups demonstrated a difference (estimated difference, 2.4; 95% CI, 3.9, 1.0; p = 0.0011; see figure 2). Mean values for the TWSTRS-Disability subscale scores at week 4 were 16.1 (placebo) and 14.5 (10,000 U; see table 2), and mean improvements in the TWSTRS-Disability subscale scores from baseline to week 4 were 0.8 (placebo) and 3.8 (10,000 U). The statistical comparison between the two treatment groups demonstrated a difference (estimated difference, 2.5; 95% CI, 4.1, 1.0; p = 0.0019; see figure 2). Mean values for the TWSTRS-Pain subscale scores at week 4 were 12.1 (placebo) and 8.4 (10,000 U; see table 2), and mean improvements in TWSTRS-Pain subscale scores from baseline to week 4 were 0.1 (placebo) and 3.6 (10,000 U). The statistical comparison between the groups demonstrated a difference (estimated difference, 3.5; 95% CI, 5.0, 2.1; p = 0.0001; see figure 2).
The mean values for the TWSTRS-Total scores at week 16 were 50.9 (placebo) and 49.6 (10,000 U; see table 2). Mean improvements in TWSTRS-Total scores from baseline to week 16 were 0.3 (placebo) and 3.2 (10,000 U). The difference in TWSTRS-Total scores at week 16 between the two groups was not significant.
Duration of treatment effect.
Figure 3 displays the Kaplan–Meier survival curve with the estimated median time until the return to baseline for the placebo and the 10,000-U groups. The time to event was 59 and 112 days for the placebo and BoNT/B groups respectively. Based on the log-rank statistic, the two distributions were different with a p value of 0.004.
Figure 3. Kaplan–Meier survival analysis of the number of days to return to baseline by botulinum toxin type A-resistant patients after treatment with botulinum toxin type B or placebo. Log-rank statistic, p = 0.004, with a median time to event in the 10,000-U group of 112 days (estimated, 12 to 16 weeks). PBO = placebo; 10,000 = 10,000 U botulinum toxin type B.
Adverse events.
Thirty-two patients (84%) in the placebo group and 39 patients (100%) in the 10,000-U group reported at least one AE. The numbers and percentages of patients who reported AEs, which occurred in at least 10% of patients, are summarized in table 3.
Number and percent of patients who reported the adverse events that occurred in ≥10% of all study patients, by adverse event and treatment group
Thirteen of 77 patients (2 in the placebo group and 11 in the 10,000-U group) reported dysphagia. Of the 13 reported cases of dysphagia, 0 were severe, 6 were moderate (1 in placebo and 5 in 10,000 U), and 7 were mild (1 in placebo and 6 in 10,000 U). The duration of dysphagia ranged from 1 to 53 days. For the six moderate cases of dysphagia reported, the durations of dysphagia were 2, 11 (placebo), 16, 16, 28, and 33 days. For the seven mild cases of dysphagia reported, the durations were 1 (placebo), 1, 5, 21, 38, 50, and 53 days.
Five patients reported five serious adverse events (SAEs) that were distributed evenly among the groups (two placebo and three active), and none of the SAEs was considered to be related to the study drug. Reports of SAEs were skin carcinoma and abscess in the placebo group, and gastrointestinal carcinoma, chest pain (thought to be gastrointestinal in origin), and coronary artery disease/angina pectoris in the 10,000-U group.
Other safety assessments.
None of the results of clinical laboratory evaluations or the patients’ vital signs were significant clinically relative to treatment with BoNT/B.
Discussion.
Chemodenervation with BoNT revolutionized the therapeutic approach to patients with CD. Although the frequency of secondary resistance to therapy is low, patients who have become resistant secondarily to type A toxin treatment have limited options for effective symptom relief.8,19-22 The results of this study demonstrate the safety and efficacy of BoNT/B treatment at a dose of 10,000 U in patients with CD who are type A toxin resistant. The safety and efficacy of BoNT/B in CD patients who are still type A responsive are reported.30,38
In our study, results for patients treated with BoNT/B were better than those for placebo patients, and the differences were significant for all of the following prospectively defined efficacy outcome variables: TWSTRS-Total at week 4 (primary efficacy variable, p = 0.0001), Patient Global Assessment at week 4 (supportive secondary efficacy variable, p = 0.0001), PI Global Assessment at week 4 (secondary efficacy variable, p = 0.0001), and the TWSTRS-Total at weeks 8 and 12 (secondary efficacy variables, p = 0.0002 and p = 0.0129 respectively).
Additional support for the efficacy of BoNT/B was demonstrated by the significant differences between the placebo and 10,000-U groups at week 4 for the following tertiary efficacy variables: Patient Analog Pain Assessment, and the TWSTRS-Severity, -Disability, and -Pain subscales.
Using a Kaplan–Meier survival analysis to estimate the duration of BoNT/B treatment effect, statistical differences (p = 0.004) were noted between the 10,000-U and the placebo groups, with an overall estimated duration of treatment effect for BoNT/B of 12 to 16 weeks.
As observed in other placebo-controlled studies of BoNT/B,30 the clinically relevant AEs of dry mouth and dysphagia were also noted in this study. The dysphagia was self-limited and tolerable in this study population at this dose. No study drug-related, SAE was reported.
Our data are strong and compelling evidence for the safety and efficacy of BoNT/B (NeuroBloc) at a dose of 10,000 U in the treatment of type A toxin-resistant patients with CD. This study supports our prior exploration of the efficacy of BoNT/B (Neuro-Bloc) in type A–responsive and -resistant patients,30 and complements our study demonstrating the robust efficacy of this formulation in type A-responsive patients.38
In the current series of studies in type A-responsive38 and type A-resistant patients, we have shown improvements in pain, disability, and severity of CD for patients who were treated with BoNT/B when compared with patients who were treated with placebo. Additionally, a Kaplan–Meier survival analysis supports a 12 to 16-week duration of treatment effect for BoNT/B in these patient populations. In this randomized, multicenter, controlled study, the muscles for injection, number of sites for injection, and dosage per dosing session were limited by the protocol. Greater clinical improvement would be anticipated in the clinical setting in which flexible individualization of dosing for each patient would be practiced.
BoNT/B in this liquid preparation (NeuroBloc) is refrigerated, does not require reconstitution, and offers type A-resistant patients a new therapeutic option.
Acknowledgments
Supported by a grant from Athena Neurosciences, Inc., a wholly owned subsidiary of Elan Corporation, plc.
Acknowledgment
The authors acknowledge the following administrative investigators who contributed substantially to the success of this study: Drs. Katrina Gwinn, John Caviness, Fabio Danisi, Eric Pappert, Eric Molho, William Ondo, Cheryl Waters, and Lauren Seeberger.
Disclosure. A.W-.H., J.D.W., and M.K. are full-time employees of Athena Neurosciences Inc., and receive salary and other compensation therefor. They have no significant interest in Athena Neurosciences Inc. or its parent, Elan Corporation, plc. They certify that they have no affiliation with any other organization or entity with a direct financial interest in the subject matter or material discussed in this article.
Footnotes
-
See also page 1439
References
Disputes & Debates: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.