| Section 4.2:
The following wording has been deleted:
“In clinical studies the duration of effect was variable. In the patients who responded to treatment (those who experienced an improvement in TWSTRS greater than 20% over baseline) the following duration of effect was observed: at least 4 weeks (40% of patients); at least 8 weeks (30%), at least 12 weeks (16%); 16 weeks or longer (14%).”
And replaced by:
“In long term clinical studies, the average dosing frequency was approximately every 12 weeks, however this may vary between subjects and a proportion of patients maintained a significant improvement relative to baseline for 16 weeks or longer. The dosing frequency should therefore be adapted based on the clinical assessment of an individual patient.”
Section 4.4:
The following wording has been deleted:
“Following repeated administration of NeuroBloc, development of an immune response can occur due to production of neutralising antibodies to Botulinum Toxin Type B. Tolerance, thought to be due to the development of an immune response, may occur uncommonly.”
And replaced by:
“As with many biological/biotechnology proteins used as therapeutic agents, repeated administration of NeuroBloc may be associated with development of antibodies to Botulinum Toxin Type B in some patients. Immunogenicity data from three long term clinical studies indicate that approximately one third of patients develop antibodies, as determined by the mouse neutralisation / mouse protection assay dependent on duration of exposure (See Section 5.1).
An investigation into the consequence of seroconversion showed that the presence of antibodies was not synonymous with a loss of clinical response, and did not have an impact on the overall safety profile. However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation / mouse protection assay is uncertain.”
Section 5.1:
The following paragraph has been added after the paragraph ending “…sprouting of the nerve ending.”
“A series of clinical studies have been conducted to evaluate the efficacy and safety of NeuroBloc in the treatment of cervical dystonia. These studies have demonstrated the activity of NeuroBloc in both treatment-naïve patients, and patients who have previously received treatment with Botulinum Toxin Type A, including those that were considered clinically resistant to Botulinum Toxin Type A.”
The following wording has been deleted from the paragraph beginning “Two Phase III…” and this paragraph has been combined with the next paragraph:
“On enrolment all patients had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) -Total scores of 20 or greater with at least two muscles involved, no neck contractures or other causes of decreased neck range of motion, and no history of any other neuromuscular disorder. The TWSTRS is comprised of three sub-scales which examine severity, pain and disability.”
The following highlighted wording has been added:
“The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale TWSTRS-Total score (range of possible scores is 0-87) at Week 4.”
The following text has been deleted:
“Exploratory analyses of these studies suggested that the majority of patients who showed a beneficial response by the fourth week had returned to their baseline status between 12 to 16 weeks after their injection.”
The following wording has been deleted:
“A further exploratory analysis of duration of effect employed data from a Phase II study in addition to the Phase III data described. In the patients who responded to treatment (those who experienced an improvement in TWSTRS greater than 20% over baseline) the following duration of effect was observed at doses of 5000 and 10,000 U.
Table 2:
Duration of Effect in Responders
|
Dose
|
Duration Of Effect (% Responders)
|
|
4 Weeks
|
8 Weeks
|
12 Weeks
|
16 Weeks
|
|
5000 U
|
43
|
22
|
16
|
19
|
|
10,000 U
|
38
|
34
|
16
|
11
|
|
Overall
|
40
|
30
|
16
|
14
|
In open-label studies, doses up to 15,000 U were given to patients at intervals of not less than 12 weeks. The proportion of patients who responded to these injections was similar to that in the key controlled studies.
A Phase IV randomised, multicentre, double-blind study was conducted to compare the efficacy of NeuroBloc (10,000 U) to Botulinum Toxin Type A (150 U) in patients with cervical dystonia who have never previously received a botulinum toxin product. Final analysis was carried out on a total of 93 enrolled botulinum naive patients (46 in the NeuroBloc group) following a single injection, into 2 of 4 predetermined muscles. Baseline assessments, including TWSTRS and VAS pain evaluation by patient and investigator, were repeated at 4, 8 and 12 weeks after treatment.
The primary efficacy analysis demonstrates the noninferiority of NeuroBloc to Type A toxin as shown by the TWSTRS total score at session 1, week 4, for the PP population. Excluding site 121, the mean scores for NeuroBloc and Type A toxin were 32.7 (SD 11.61) and 36.0 (SD 11.71) respectively with a 95% CI of 29.3, 36.2 and 32.6, 39.4 respectively. The upper limit of the 1-sided CI in the LS mean difference (NeuroBloc - type A toxin) in the TWSTRS total score at week 4 of session 1 for the PP population (excluding site 121) was 0.6 which is well within the predefined criterion for noninferiority of 4 points in the mean difference between groups adjusted for baseline for the TWSTRS. These findings led to an identical conclusion when site 121 was included.
The robustness of this analysis was confirmed by additional analyses that calculated the 1-sided 97.5% CI, analyses using the unadjusted scores, and analyses using the ITT and interim CSR PP populations. In this regard the noninferiority of NeuroBloc compared to Botulinum Toxin Type A is also supported by a responder analysis using the ITT population, which showed that a similar percentages of subjects showed any improvement in the TWSTRS score at Week 4 of Session 1 (86% NeuroBloc and 85% Botox), as did subjects who experienced at least a 20% decrease from baseline in the TWSTRS score at Week 4 of Session 1 (51% NeuroBloc, 47% Botox).
A Phase IV open label study has been conducted to evaluate the safety, immunogenicity and effect of repeated doses of NeuroBloc in subjects with cervical dystonia (CD) who were previously treated with Botulinum Toxin Type A. The primary objectives of the open label study were to evaluate the safety, immunogenicity and effect of repeat doses of NeuroBloc in subjects with CD who were already resistant to Botulinum Toxin Type A compared to subjects who were responsive to Botulinum Toxin Type A. . A total of 130 subjects were enrolled, comprising 67 Type A resistant and 63 type A responsive. Subjects were given a starting dose of 10,000 Units of NeuroBloc at their first treatment, then subsequent doses modified at increments of 2,500 or 5,000 units to a maximum of 25,000 units with a dosage interval of at least 12 weeks.
Eight of the 67 Type A resistant subjects (11.9%) had developed neutralising antibodies to Botulinum Toxin Type B within completion of 4 treatment cycles of NeuroBloc and 15 out of 67 subjects (22.4%) had developed neutralising antibodies at the time of interim study analysis. The earliest development of neutralising antibodies was seen in 2 out of 67 subjects (3%) 6-9 months after the start of NeuroBloc treatment.
NeuroBloc treatment was associated with a low incidence of development of neutralising antibodies to Botulinum Toxin Type B during the first year of treatment. The presence of antibodies does not necessarily mean resistance to treatment as the number of patients truly resistant is likely to be much lower than the results indicate. Therefore patients resistant to Botulinum Toxin Type A may benefit from treatment with NeuroBloc and continue to experience this benefit over a long time period.”
And replaced by:
“A further randomised, multicentre, double-blind study was conducted to compare the efficacy of NeuroBloc (10,000 U) to Botulinum Toxin Type A (150 U) in patients with cervical dystonia who have never previously received a botulinum toxin product. The primary efficacy assessment was the TWSTRS Total score, and secondary efficacy assessments included VAS assessment of change evaluated by patient and investigator, conducted at 4, 8 and 12 weeks after treatment. The study met the pre-defined criteria for non-inferiority of NeuroBloc compared to Botulinum Toxin Type A, both in terms of mean TWSTRS total score at week 4 after first and second treatment sessions, and in terms of duration of effect.
The non-inferiority of NeuroBloc compared to Botulinum Toxin Type A was further supported by a responder analysis where similar percentages of subjects showed improvement in the TWSTRS score at Week 4 of Session 1 (86% NeuroBloc and 85% Botox), and a similar proportion of subjects experienced at least a 20% decrease from baseline in the TWSTRS score at Week 4 of Session 1 (51% NeuroBloc, 47% Botox).
Further clinical studies and open label follow-up have shown that subjects can continue to respond to NeuroBloc for prolonged periods of time, with some subjects receiving more than 14 treatment sessions over a period of more than 3.5 years. In addition to improved function as demonstrated by a reduction in TWSTRS-total score, treatment with NeuroBloc was associated with a significant reduction in TWSTRS-Pain and pain VAS scores at each treatment session at weeks 4, 8 and 12 relative to baseline. In these studies, the average dosing frequency was approximately every 12 weeks.
The immunogenicity of NeuroBloc has been evaluated in two clinical studies and an open-label extension study. The presence of antibodies in these studies was assessed using the mouse protection assay (also known as the Mouse Neutralization Assay, MNA).
Immunogenicity data from three long term clinical studies indicate that approximately one third of patients develop antibodies, as determined by the mouse neutralisation / mouse protection assay dependent on duration of exposure. Specifically, these studies showed approximately 19-25% seroconverted within 18 months of initiation of treatment, increasing to approximately 33-44% with up to 45 months of treatment. An investigation into the consequence of seroconversion showed that the presence of antibodies was not synonymous with a loss of clinical response, and did not have an impact on the overall safety profile. However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation / mouse protection assay is uncertain.
The extent and time course of seroconversion were similar in patients with prior toxin A exposure and those who were toxin A naïve, and between toxin A resistant and toxin A responsive patients.”
Section 10:
The date of revision of text has been amended to 27 July 2009
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