BOTOX - BOTOX - CT 12193 - English version

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Description

Introduction BOTOX 50 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 831-4 0) BOTOX 100 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 562 088-8 3) BOTOX 200 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 832-0 1) Posted on Jul 18 2012 Active substance (DCI) botulinum toxin type A Progrès thérapeutique modéré dans l’incontinence urinaire par hyperactivité détrusorienne neurologique chez certains patients BOTOX a l’AMM dans l’hyperactivité détrusorienne conduisant à une incontinence urinaire non contrôlée par un traitement anticholinergique, chez les patients blessés médullaires ou atteints de sclérose en plaques et utilisant l’autosondage comme mode mictionnel.C’est un traitement de deuxième intention qui apporte un progrès thérapeutique modéré dans la prise en charge des patients.On ne dispose pas de données cliniques sur la réduction des complications liées à la rétention rénale et l’intérêt de BOTOX n’est pas établi lors d’administrations réitérées. ATC Code M03AX01 Laboratory / Manufacturer ALLERGAN FRANCE SAS BOTOX 50 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 831-4 0) BOTOX 100 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 562 088-8 3) BOTOX 200 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 832-0 1) Posted on Jul 18 2012

Sujets

• Pédiatrie
• Maladie auto-immune
• Handicap

Informations

• Publié par: haute-autorite-sante-maladies-urologiques
• Publié le: 18 juillet 2012
• Nombre de lectures: 14
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

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    The legally binding text is the original French version  

TRANSPARENCY COMMITTEE   OPINION   18 July 2012       BOTOX 50 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 831-4 0)   BOTOX 100 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 562 088-8 3)   BOTOX 200 ALLERGAN UNITS, powder for solution for injection Powder in vial (type I glass) supplied with a stopper (rubber) and a ring (aluminium), B/1 (CIP code: 34009 370 832-0 1)     Applicant: ALLERGAN FRANCE SAS     botulinum toxin type A ATC code: M03AX01 (Muscle relaxants, peripherally acting agents)   List I – Medicinal product reserved for hospital use.   Date of Marketing Authorisation: 22 August 2011 for the extension of the indication. (National registration procedure; BOTOX forms part of a risk management plan)     Reason for request: Inclusion on the list of medicines approved for hospital use in the extension of the indication: “ of urinary incontinence with neurogenic detrusor overactivitythe management due to spinal cord injury or multiple sclerosis, who are not adequately managed with anticholinergics and who are catheterising”.                   Medical, Economic and Public Health Assessment Division

 

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1.

CHARACTERISTICS OF THE MEDICINAL PRODUCT

    1.1. Active ingredient   Botulinum toxin type A. 1       1.2. Indication   New indication forming the subject of this opinion: “Adults: the management of urinary incontinence with neurogenic detrusor overactivity not adequately managed with anticholinergics in: - spinal cord injury patients, - patients with multiple sclerosis who are catheterising.”    “Adults and children 12 years and above: - Ocular motility disorders: squint, recent ocular motility paralysis, and recent thyrotoxic myopathy.  - Blepharospasm. - Hemifacial spasm. - Spasmodic torticollis. - Severe hyperhidrosis of the axillae, which does not respond to topical treatment leading to significant psychological and social issues.   Adults and children aged 2 years and over: - Topical symptomatic treatment of spasticity (muscle hyperactivity) of the upper and/or lower limbs.”     1.3. Dosage and method of administration   "General recommendations: […] Botulinum toxin units are not interchangeable f rom one product to another. Doses are expressed in ALLERGAN 2 units are different from other botulinum toxin preparations. […]   Dosage: […] Patients should be informed that intermittent c atheterising to empty their bladder will be required. They should be willing and able or have a member of their family capable of performing it for them. […] Intravesical instillation of diluted anaesthetic solution can be administered with or without sedation, or a general anaesthetic may be given before the injection, depending on local medical practices. If a local anaesthetic intravesical instillation is performed, the bladder should be drained and rinsed with sterile saline before continuing with the injection procedure.[…] The recommended dose is 200 units of BOTOX across 30 sites of the detrusor muscle given as 1 ml injections (or approximately 6.7 units). […] The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 ml each (total volume 30 ml) should be spaced approximately 1 cm apart.

                                             1 Botulinum toxin is produced from Clostridium botulinum. It has a curare-mimetic action: it inhibits the release of acetylcholine at presynaptic nerve endings of the motor end plate, also preventing contraction of the muscle fibre. Its action is transitory and reversible. After injection into the detrusor, it inhibits the efferent message controlling the motor activity of the detrusor. 2 An ALLERGAN UNIT corresponds to the lethal dose (LD50) of the reconstituted product and given as an intaperitoneal injection into mice.   2/20

[…] Clinical improvement is generally observed in t he first two weeks after the injection. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished, approximately 9 months after the first injection (mean duration of effect observed in phase III studies: 256 to 295 days with 200 ALLERGAN units of BOTOX) and complying with a minimum interval of 3 months.   Injection technique: For intramuscular injection only, depending on the indication. […] For adult patients with neurogenic detrusor overactivity, this treatment of injections into the detrusor should be included in a global multidisciplinary treatment structure, combining a urology specialist and a doctor specialising in rehabilitation medicine who has been specially trained in the use of botulinum toxin in this indication, under the supervision of an urologist. For visualisation of the bladder, the botulinum toxin is injected via a flexible or rigid cystoscope, avoiding the trigone […]”  

  1.4. Associated procedure   The administration of BOTOX comprises an intradetrusor injection using a cystoscope. The procedure allowing the administration of BOTOX has been described in the CCAM: it is “injection of botulinum toxin into the bladder muscle, via cystourethroscopy” (code JDLE900, section 8.2.3.12, version 28 of 07/07/2012). This procedure is not currently covered by National Health Insurance, however this is being investigated.    

 

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2.

SIMILAR MEDICINAL PRODUCTS

    2.1. ATC Classification (2012)   M Musculo-skeletal system M03 Muscle relaxants M03A Muscle relaxants, peripherally acting agents M03AX Other muscle relaxants, peripherally acting agents M03AX01 Botulinum toxin     2.2. Medicines in the same therapeutic category   None. It should be noted that there are other proprietary medicinal products (approved for use in hospitals) based on botulinum toxin type A (DYSPORT 300 and 500 Speywood units; XEOMIN 50 and 100 units LD50) or botulinum toxin type B (NEUROBLOC). These products are not indicated in this clinical situation.     2.3. Medicines with a similar therapeutic aim  

Medicinal products in the parasympathetic, anticholinergics catego y 3 , r 4

 Marketing Authorisation indication   f V il E m S - I c C oa A t R ed E     t 5 a   b m le g t     and 10 mg,  “Symptomatic treatment of urge incontinence  ( A I s N t N el : l   a s s o   li P fe h n ar ac m in a     s L u a c b. c   inate)  a ur n g d e /o n r c   y  in a c s r   ea m se a d y    o ur c i c n u a r r   y  in  fre p q a u ti e e n n c ts y     w a i n th d     overactive bladder syndrome.”  “Urinary incontinence, urgency and f DITROPAN 5 mg, scored  requency tablet in the unstable bladder, whether due to ( a I n N d N  i : t   s o   x g y e b n u e t r y ic ni s n   h n y e p ur e o rr g e e fl n e i x c i   a)  b i l n a   d c d o e n r d   itio d n i s s   or s d u e c r h s     as  (d m et u r lt u i s pl o e r     hydrochloride) sclerosis and spina bifida, or to idiopathic Sanofi Aventis France Lab  detrusor instability (motor urge incontinence)”. .   CERIS 20 mg, coated tablet  “Symptomatic treatment of urge incontine a nc n e d     (INN: trospium chloride)  and/or increased urinary frequency Rottapharm Lab.  u o r v g e e ra n c c t y i   ve  as  bl m a a d y d   er  occ ( u e r .   g.  in  id p i a o t p ie a n t t h s i   c  wit o h r     neurologic detrusor overactivity)”.

NR: not recorded     2.4. Other treatments   Urological surgery.

AB/IAB Treatment

Moderate IAB IV SSoc 30%; Coll.

Moderate IAB: NR SSoc 30%; Coll.

  Moderate IAB V vs. VESICARE SSoc 30%; Coll.  

                                             3 DETRUSITOL 1 mg and 2 mg, film-coated tablet (INN: tolterodine, Pfizer Lab.) is indicated in the “symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome.” This proprietary medicinal product has never been evaluated by the Transparency Committee. It has been marketed but is not reimbursable. 4 At this time, TOVIAZ has not been included for reimbursement. The Transparency Committee issued an opinion in favour of the inclusion of TOVIAZ on 15 February 2012.   4/20

3.

ANALYSIS OF AVAILABLE DATA

    The evaluation of BOTOX (botulinum toxin type A) in the treatment of neurogenic detrusor overactivity is based on: - the results from two dosage research studies (studies 511 and 518). Due to the aims of these studies, only tolerance data will be reported. - two comparative pivotal studies versus placebo with the same method (studies 515 and 516). Data from the two studies were pooled by detrusor overactivity aetiology (MS or spinal cord injury) in a post-hoc analysis.     3.1. Efficacy   Aims of studies 515 and 516 The main aim of studies 515 and 516 efficacy of two doses (200 and 300 U)was to compare the of botulinum toxin to placebo on the reduction in the number of weekly urinary incontinence episodes with botulinum toxin type A, 6 weeks after an injection into the detrusor muscle of spinal chord injury (SCI) patients or those with multiple sclerosis (MS) with a failed (due to lack of efficacy or intolerance) treatment with an anticholinergic.  

Methods These two controlled superiority studies were randomised and double-blind in three parallel groups: botulinum toxin type A (200 or 300 U) and placebo (sodium chloride solution 0.9%).   STUDY 515STUDY 516 N = 416 N = 275 (227 MS and 189 SCI) 154 MS and 121 SCI       1 st injection:   Placebo 200 U 300 U N = 241 N = 227 N = 223      

Week 12

Week 52

   

 

Week 6

Evaluation of primary endpoint

No 2 nd injection N = 182

Evaluation effect duration / safety

Week 64

   

2 nd injection: 200 U 300 U N = 199 N = 178

        Evaluation effect duration / safety

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Week > 12

2 nd injection: 200 U 300 U

STUDY 094 Efficacy and long-term safety

Randomisation was stratified by centre according to aetiology (spinal cord injury or multiple sclerosis) and the use, or not, of a concomitant anticholinergic.  

Hypotheses to calculate the number of patients required: In order to take into account people leaving the studies, 87 patients per treatment group were estimated as required for study 516 (attrition rate estimated at 10%) and 135 patients per treatment group for study 515 (attrition rate of 25%). A difference of 7.5 episodes between the BOTOX group and the placebo group in the change in weekly frequency of urinary incontinence episodes between inclusion and Week 6 was expected, given that the mean weekly frequency at inclusion was 25 episodes.   Inclusion criteria: - age≥ 18 years - weight≥ 50 kg - having at least 14 incontinence episodes per week and no more than two incontinence free days over at least 3 months. - incontinence with neurogenic detrusor overactivity, due to either traumatic spinal cord injuries, or multiple sclerosis 5   - failed treatment with one or several anticholinergic products, defined as a response judged as unsatisfactory by the investigator after at least 1 month of treatment at the optimum dose, or intolerable adverse events.  

Non-inclusion criteria:  - volume of urine per 24 hours > 3000 ml before randomisation and residual post-catheterising volume > 200 ml (for patients with spontaneous urination or mixed urination (intermittent catheterising combined with spontaneous urination). - serum creatinine of twice the normal level, - previous history of haematuria, - interstitial cystitis, - presence of bladder stones in the 6 months prior to inclusion. - previous history of bladder cancer or a suspected urinary cytological abnormality, prostate cancer. - previous history of haemophilia or other clotting factor deficiencies or disorders resulting in haemorrhagic diathesis.   Study treatments:  Botulinum toxin of 1 ml injected into 30 sites, spread across the whole detrusor muscle except for the trigone. The injections were performed with the help of a cytoscope (endoscope). Two doses were possible: 200 or 300 U. A second injection (treatment 2) of 200 or 300 U of BOTOX could be given 12 weeks after the initial dose. In this instance, a reduction of at least 30% in weekly urinary incontinence episodes compared with inclusion for patients in study 516 or at least 50% for those in study 515 were required. All patients thus received BOTOX (200 or 300 U). Patients who received BOTOX as their first treatment continued to be treated with the same dose. Those who received an injection of the placebo received either BOTOX 200 U or BOTOX 300 U depending on the pre-assigned randomisation schedule. After receiving BOTOX, patients were monitored for 52 weeks for those who had received one injection, for 64 weeks in cases of a second injection at the 12th week, which allowed safety data to be collected up to this point and the duration of the effect to be estimated. The patients who had≥after the 12th week, were not taken into 2 injections, the second being given consideration in the efficacy analysis but were included in study 094 6 investigating safety.                                              5 Patients with MS using bilateral assistance and able to walk approximately 20 meters without needing to rest (EDSS score 6.5). ≤ 6 Study 094 is evaluating the safety of BOTOX over repeated treatment cycles. This study is an open-label extension phase of studies 515 and 516, which concerned patients re-treated with BOTOX (200 U or 300 U) more than 12 weeks after the first injection. An additional follow-up period of 3 years is scheduled.   6/20

Co-treatments:  - anticholinergic agent(s): they could be continued during the study without modifying the dose. - Local anaesthetic by sedation or general anaesthetic, depending on the request of the patient. - Antibiotic therapy: in the three days prior to the first injection. In instances of a second injection and for patients with a positive urine culture, appropriate antibiotics should be administered for at least 5 days before being re-injected and continued for 3 days (or longer if necessary).   Primary efficacy endpoint: Mean reduction in the number of urinary incontinence episodes per week 7  at the 6 th  week following the 1 st  n.ioctjein    The various secondary efficacy endpoints included: - Proportion of “responder” patients at the t 6 h week; these were those who had a reduction of at least 50% in urinary incontinence episodes at the 6 th week. - Proportion of “continent” patients at the t 6 h those who had a reduction of atweek: these were least 100% in urinary incontinence at the 6 th week. - Quality of life of the patient: measured using the I-QOL scale, with the total score 8 ranging from 0 (maximum deterioration) to 100. An improvement was judged as relevant if the total score increased by at least 8 points compared with at inclusion. - Duration of effect of treatment defined as the time elapsed between the first injection and the re-qualification date for the second injection.   Urodynamic parameters measured via cystometry 9 also evaluated bladder function 6 weeks after the injection: - Maximum cystometric capacity 10  in ml). This measures the capacity of the bladder to (MCC retain urine. A significantly increased value could enable the intervals between catheterising to be indirectly estimated. - Maximum detrusor pressure 11  in cmH (Pmax 2 O). A reduction in this value, by reducing the risk of vesico-ureteric reflux, will prevent damage to the upper urinary tract. 12     Three analysis populations were defined: - The intention – to - treat (ITT) population: randomised patients. - The per protocol (PP) population: randomised patients and absence of deviation from protocol. - Safety population: randomised patients who received at least one treatment. Analysis of the primary efficacy endpoint was carried out on the ITT population, with missing data being managed using the LOCF method. 13  Only the results obtained with 200 ALLERGAN units were presented, corresponds to the dosage in the Marketing Authorisation. which Secondary analyses were carried out on the ITT and the PP populations, according to the analysis of covariance method (ANCOVA).                                               7 The number of weekly urinary incontinence episodes was recorded using a urination calendar filled in daily by the patient during a period of 7 consecutive days before each monitoring appointment. 8 Calculation of the I-QOL “Incontinence Quality of Life” score is carried out using the formula: [(Sum of items – the lowest score)/mean gross score] × 100. The evaluation was carried out during the randomisation appointment, then at appointments in weeks 6, 12, 24, and then every 6 weeks (alternating between an on-site appointment and a telephone call) up to the appointment at the end of the study on the 52nd week. 9 Cystometry comprises of recording the pressures experienced in the bladder when it is empty and when it is filling. 10 The MCC is obtained by subtracting the residual quantity of urine from the volume of water infused. It corresponds to the maximum filling volume of the bladder at which the doctor decides to stop instillation. This decision is made before pain is felt, the intradetrusor pressure is high or the filling volume is judged as being high. The normal value for a woman is around 600 ml. 11 Pmax is measured during the first uninhibited contraction of the bladder (in cm H 2 O). It is calculated by subtracting the pressure of the detrusor during the first contraction from the pressure of the detrusor at the start of the filling of the bladder. A value above 40 cm is considered being abnormally high. 12 Foley SJ, McFarlane JP, Shah PJ. Vesico-ureteric reflux in adult patients with spinal injury. Br J. Urol. 1997; 79(6): 888-891. 13 In an LOCF (Last Observation Carried Forward) analysis, the last observation for each participant is considered as the result, even if the time of the observation does not coincide with the scheduled time for the measurement.   7/20

Results   Characteristics of the population evaluated Studies 515 and 516 took place between 8 September 2006 and 4 May 2010 in 177 centres; 14 patients were included in 7 centres in France. A total of 691 patients were randomised, including 416 in study 515 (132 in the BOTOX 300 group, 135 in the BOTOX 200 group and 149 in the placebo group) and 275 in study 516 (91 in the BOTOX 300 group, 92 in the BOTOX 200 group and 92 in the placebo group). Among these patients, 559 (80.9%) received at least one injection and were monitored up to 52 weeks: 230/275 patients (83.6%) in study 516 and 329/416 patients (79.1%) in study 515. Among these 559 patients, 377 received a second BOTOX injection and 346 (91.8%) were monitored up to 64 weeks. The patient characteristics were comparable at inclusion between the two treatment groups (BOTOX 200, BOTOX 300 and placebo). 14 patients had a mean age of 45.9 yearsSpecifically, and had neurologic detrusor overactivity (NDO) for nearly 7.7 years. These patients had an average of 31.7 (± 20.67) urinary incontinence episodes per week, or an average of 4.8 (± 3.33) episodes per day (study 516) to 4.4 (± 2.71) (study 515). The cystometric capacity at inclusion was 252 ml (± 146.29) on average, and thus well below that of a healthy person (± 400 ml). Nevertheless, at inclusion, the differences between the spinal cord injury patients and those with MS were used: were younger (mean age of 41 years with more than 47% of cord injury patients  Spinal patients aged at least 40 years) than those with MS (mean age of 49.9 years with more than 71% of them aged over 40 years)  majority of spinal cord injury patients were male (69.8% in study 515 and 73.6% in study The 516) while the majority of patients with MS were female (82.8% in study 515 and 79.9% in study 516). the symptoms of MS (9.5 years versus cord damage occurred more recently than  Spinal 14 years), with the consequences of NDO being more significant for spinal injury patients: - The method of urination at the time of inclusion was catheterising for 86.2% of spinal cord injury cases, as opposed to 29.7% for patients with MS. - The maximum detrusor pressure during the first UCD at inclusion was higher for spinal cord injury patients (58.1 cmH 2 O) than those with MS (39.7 cmH 2 O). Beyond 40 cmH 2 O, there is an increased risk of vesico-ureteric reflux with the potential for kidney damage occurring over time.   Co-treatments: although patients included had been considered as having had a failed anticholinergic treatment (684/691 or 99%), nearly 50% of patients with MS continued with anticholinergic therapy. Among those with spinal cord injuries, this proportion was similar in study 515, reaching close to 72% in study 516.   Only the results from the BOTOX 200 group are reported in this opinion, which complies with the dosage validated by the Marketing Authorisation for BOTOX.                          

                                             14 By considering the pooled data of the two studies (including all aetiologies).   8/20

Results for study 515   Primary efficacy endpoint:at inclusion, the mean number of weekly urinary incontinence (UI) episodes was 32.3 (± 22.76) in the BOTOX 200 U group and 28.3 (± 15.82) in the placebo group. At the 6 th week, a significant reduction in the number of weekly UI episodes was observed in the BOTOX 200 group compared with the placebo group: - 21 (± 23.77) versus - 8.8 (± 16.18) or an adjusted difference 15 (95% CI [- 13.16; - 5.42], p < 0.001).of - 9.29 weekly UI episodes   Secondary efficacy endpoints: the results confirm those observed for the primary efficacy endpoint and are in favour of a greater efficacy for BOTOX 200 compared with the placebo: -Proportion of responder patients: at the 6 th week, there was, on average, two times more responder patients in the BOTOX 200 group (74.8%: 101/135) than in the placebo group (38.3%: 57/149), p < 0.001. -Proportion of continent patients: at the 6 th  week,there were, on average, close to four  times more continent patients in the BOTOX 200 group (36.3%: 49/135) than in the placebo group (10.1%: 15/149), p < 0,001. -Quality of life: at the 6 th higher in the BOTOX 200 groupweek, the mean I-QOL score was than in the placebo group, with an increase in mean score of + 15.75 points in favour of the BOTOX 200 group compared with the placebo group, p<0.001. -Duration of the effect of treatmentmedian duration of the effect of treatment was: the 256 days [212 days; 296 days] versus 92 days [87 days; 107 days] in the placebo group, or a duration of effect that was 2.7 times longer for BOTOX 200, p≤0.001.   Urodynamic endpoints (at Week 6): -Maximum cystometric capacity(MCC): compared with inclusion, the increase in MCC was + 151.2 ml in the BOTOX 200 group and +15.5 ml in the placebo group. An increase in the mean MCC value of 123.9 ml (95% CI [89.06; 158.73]) was therefore observed in favour of the BOTOX 200 group compared with the placebo group, p < 0.001. -Maximum detrusor pressure during the 1 st  UCD: compared with inclusion, the PdMax decreased by - 35.1 cmH 2 O in the BOTOX 200 group and by - 2.4 cmH 2 O in the placebo group. An additional decrease of - 24.44 cmH 2 O for Pdmax (95% CI [- 37.52; - 11.36]) was therefore observed in the BOTOX 200 group compared with the placebo group, p < 0.001.   The results are similar if continuation of treatment with anticholinergics or not is taken into account.   Results after a second injection of BOTOX 200 (cycle 2): A second BOTOX injection was administered to 240 patients (out of 416 patients, or 57.7%) divided according to one of the two possible treatment sequences for those who received BOTOX 200 in cycle 1 as follows: 74 patients (or 54.8% of the BOTOX 200 group) with the sequence BOTOX 200 U/ BOTOX 200 U and 51 patients with the sequence Placebo/ BOTOX 200 U. As an indication, the results are as follows:                      

                                             15 This difference is an adjusted standard deviation. An analysis of covariance was carried out with the basal value as the covariate and the randomisation stratification factors as adjustment parameters.   9/20

Table 1 – Study 515: mean number of weekly urinary incontinence episodes at Week 6 of cycle 2

Appointment

At inclusion in cycle 1

At inclusion in cycle 2

Evaluation at Week 6 of cycle 2

Statistical parameters

N Mean (SD) at inclusion in study 515 (cycle 1) *

N Me nd uscln io aD)int aS( nni  c 2 ycle of treatment**

N Mean (SD)

Mean number of weekly UI episodes at Week 6

BOTOX 200 U / BOTOX 200 U N = 74/135

N = 74 31.1 (± 17.81)

N = 74 28 (± 22.29)

N = 74 12.5 (± 24.93)

Placebo / BOTOX 200 U N = 51/149

N = 51 28.3 (± 15.82)

N = 51 32.6 (± 26.71)

N = 51   10 (± 17.35)

N N  = 74 N = 51 Week 6 of cycle  48/66 No. (%) of responder  (78.7%) 37/47 (72.7%) 2 patients    No. (%) of continent patients 26/66 (39.4%) 17/47 (36.2%) *Corresponds to cycle 1, i.e. during inclusion in the study **Corresponds to cycle 2, i.e. during a second injection with BOTOX 200 for patients in the BOTOX 200 group and to first injection with BOTOX 200 for patients initially treated with the Placebo and randomised in the Placebo/BOTOX 200 group.     Results from study 516   Primary efficacy endpoint: at inclusion, the mean number of weekly urinary incontinence (UI) episodes was 32.5 (± NC) in the BOTOX 200 U group and 36.7 (± NC) in the placebo group. At the 6 th  a reduction in the mean number of weekly UI episodes was observed in the week, BOTOX 200 group (- 21.8 ± 18.06) compared with the placebo group (- 13.2 ± 20.02), or a mean reduction in the number of weekly UI episodes in favour of the BOTOX 200 group of - 9.04 (95% CI [- 14.77; - 3.32]), p = 0.002.   Secondary efficacy endpoints: the results confirm those observed for the primary efficacy endpoint and are in favour of a greater efficacy for BOTOX 200 compared with the placebo: -Proportion of responder patients: at the 6 th  week, there were twice as many responder patients in the BOTOX 200 group (77.2%: 71/92) as in the placebo group (39.1%: 36/92), < p 0.001.  Proportion of continent patients: at the 6 th  there were five times more continent week, - patients in the BOTOX 200 group (38%: 35/92) than in the placebo group (7.6%: 7/92), p < 0,001. -Quality of life: at the 6 th the increase in mean I-QOL scoreweek, the difference observed in was + 12.32 points in favour of the BOTOX 200 group compared with the placebo group, p < 0.001. -Duration of the effect of treatment: the median duration in the effect of treatment was 295 days [211; 338] for patients in the BOTOX 200 group versus 92 days [86; 127] for those in the placebo group, or a duration in effect 3.2 times longer with BOTOX 200, p≤0.001.                

 

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Urodynamic endpoints (at Week 6): -Maximum cystometric capacity(MCC): compared with inclusion, the increase in MCC was + 157 ml in the BOTOX 200 group and + 6.5 ml in the placebo group, or an additional increase in MCC of 148.03 ml (95% CI [101.8; 194.25]) in the BOTOX 200 group compared with the placebo group, p < 0.001. -Maximum detrusor pressure during the first UCD: compared with inclusion, the PdMax decreased by - 28.5 cmH 2 the BOTOX 200 and by + 6.4 cmHO in 2 O in the placebo group, or a mean additional reduction of – 30.72 cmH 2 O (95% CI [- 45.46; - 15.97]) in the BOTOX 200 group compared with the placebo group, p < 0.001. The results are similar whether continuation of treatment with anticholinergics or not are taken into account.   Results after a second injection of BOTOX (cycle 2): A second BOTOX injection was administered to 137 patients (out of 275 patients, i.e. 49.8%), with the patients being divided as follows: 42 patients (or 45.6% in the BOTOX 200 group) with the sequence BOTOX 200 U/ BOTOX 200 U and 32 patients with the sequence Placebo/ BOTOX 200 U. As an indication, the following was observed at the 6 th week of cycle 2:   Table 2 - Study 516: mean number of weekly urinary incontinence episodes at Week 6 post-cycle 2 treatment (second   injection) Mean number of weekly UI episodes at Week 6 of cycle 2

ical Appointment  p S a t r a a ti m st eters  BOTOX 200 U / BOTOX 200 U Placebo / BOTOX 200 U  N = 42 N = 32 N At inclusion in  Mean (SD) at  N = 42 N = 32 cycle 1  inclusion in study  37.2 (± 20.03) 34.4 (± 18.49) 516 (cycle 1) * N At in c c y l c u le si   o 2  n in  in M c e lu a s n i   o ( n S  i D n )     2 a n t d 5).42   6±  (.2 (± 38.9  42 N = 0 63 = 3  )1 N    336. cycle of treatment** Evaluation at  N N = 42 N = 30 Week 6 of cycle 2  Mean (SD) 16.8 (± 29.86) 5.6 (± 9.64) N N  = 42 N = 32 Week 6 of  resp N on o. d  ( er %   ) p   a o t f i   ts  32/42 (76.2%) 26/30 (86.7%)  cycle 2  en    No. continen ( t  % p ) a   t o i f e   nts  8/42 (19%) 11/30 (36.7%)  *Corresponds to cycle 1, i.e. during inclusion in the study **Corresponds to cycle 2, i.e. during a second injection with BOTOX 200 for patients in the BOTOX 200 group and a first injection with BOTOX 200 for patients initially treated with Placebo.    

 

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