| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Urinary incontinence caused by neurogenic detrusor overactivity due to either spinal cord injury or multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Loss of bladder control and involuntary urination due to either spinal cord injury or multiple sclerosis |
|
| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046543 |
| E.1.2 | Term | Urinary incontinence |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To assess the efficacy of two Dysport® doses (600 units (U) and 800 U), compared to placebo in reducing UI from Baseline to Week 6 following the first investigational medicinal product (IMP) administration. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of two Dysport® doses (600 U and 800 U), compared to placebo in improving bladder diary measures, urodynamic and patient-reported efficacy endpoints following the first IMP administration, including assessing duration of effect.
• To assess the efficacy of two Dysport® doses (600 U and 800 U) in improving bladder diary measures, urodynamic and patient-reported efficacy endpoints following retreatment IMP administrations, including assessing duration of effect.
• To assess the safety of two Dysport® doses (600 U and 800 U) for the treatment of UI due to NDO. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The following inclusion criteria will be assessed at the beginning of the Screening process:
1) Written informed consent prior to any study-related procedure.
2) Male or female, aged 18 to 80 years inclusive.
3) UI for at least 3 months prior to Screening as a result of NDO due to SCI or MS.
4) Subjects with SCI must have a stable neurological injury at T1 level or below which occurred at least 6 months prior to Screening.
OR
Subjects with MS must be clinically stable in the investigator’s opinion, with no exacerbation (relapse) of MS for at least 3 months prior to Screening.
5) Subjects in the non-urodynamic subset only, must have NDO (defined as the presence of involuntary detrusor contractions during the storage phase of urodynamic filling cystometry) on a historic urodynamic assessment performed in the 12 months prior to Screening
• If urodynamics are not performed in the 12 months prior to Screening or if results are not available, then a urodynamic filling cystometry assessment must be performed during Screening, per local practice (see inclusion criterion # 16).
6) Subjects must have had an inadequate response after at least 4 weeks of oral medications used in the treatment of NDO (e.g. anticholinergics, beta-3 agonists)and/or have intolerable side-effects.
7) Subjects who are to continue on concomitant oral medications for NDO during the study must be on a stable dose for at least 4 weeks prior to Screening.
8) Subjects who are to continue on concomitant oral medications for NDO during the study must be willing to continue on the same medications and doses during Screening and for at least 12 weeks following the first IMP administration.
9) Routinely performing CIC to ensure adequate bladder emptying (regularly performing CIC at a regimen of every 4–6 hours during waking hours, or more frequently). CIC regimen must be stable for at least 4 weeks prior to Screening (CIC may be performed by the subject or caregiver).
10) Subjects must be willing to continue on the same CIC regimen during Screening and for at least 12 weeks following the first IMP administration.
11) Female subjects of childbearing potential must have a negative pregnancy test result and be willing to use reliable contraceptive measures throughout study participation. Reliable forms of contraception include but are not limited to:
• hormonal contraceptives (e.g. oral, patch, injection)
• double barrier (e.g. male condom plus spermicide, or female diaphragm plus
spermicide)
• intrauterine device
• male partner has had a vasectomy
• total abstinence from intercourse with male partners (periodic abstinence is not
acceptable).
Female subjects meeting any of the following criteria are not considered to be of
childbearing potential:
• postmenopausal (≥47 years of age and amenorrhoeic for at least 12 consecutive months)
• have been sterilised surgically (e.g. bilateral tubal ligation)
• have had a hysterectomy
• have had a bilateral oophorectomy.
12) Documented urinary tract ultrasound is available in the 6 months prior to Screening, confirming that no medical issues exist that would preclude entry to the study (e.g. bladder stones or unexplained renal mass).
• If not performed in the 6 months prior to Screening or results are not available, then a urinary tract ultrasound must be conducted during Screening.
13) Ability to complete all study requirements in the opinion of the investigator, including regularly completing the 7-day bladder diary and attending all scheduled study visits. The caregiver may assist with the completion of study documentation and procedures (including the bladder diary and questionnaires), if required.
The following inclusion criteria will be assessed following completion of screening bladder diary:
14) An average of at least two episodes per day of UI recorded on the screening bladder diary.
15) No more than two incontinent-free days documented on the screening bladder diary.
The following inclusion criterion will be assessed following completion of screening
urodynamic assessment (if required):
16) NDO (defined as the presence of involuntary detrusor contractions (IDCs) during the storage phase of urodynamic filling cystometry) on:
• standardised study specific urodynamics (all subjects in urodynamic subset)
• local site practice urodynamics (subjects in the non-urodynamic subset without a documented urodynamic assessment in the 12 months prior to Screening) |
|
| E.4 | Principal exclusion criteria |
The following exclusion criteria will be assessed throughout the Screening process:
1) Any current condition (other than NDO) that may impact on bladder function, including but not limited to:
• predominant stress UI (rather than NDO-related incontinence)
• bladder stones
• current symptomatic urinary tract infection
• current active genitourinary infection, e.g. genital warts
• uterine prolapse
• cystocele
• rectocele.
Mild uterine prolapse, cystocele or rectocele that does not impact on bladder function
is not exclusionary.
2) Previous or current, tumour or malignancy affecting the spinal column or spinal cord, or any other nonstable cause of SCI.
3) Surgery less than 6 months prior to Screening for bladder stones.
4) Surgery less than 6 months prior to Screening for uterine prolapse, cystocele or rectocele.
5) Previous open surgery for NDO, e.g. augmentation cystoplasty.
6) Previous urethral stent placement or sphincterotomy.
7) Previous or current diagnosis of, or symptoms/signs/investigations suggestive of, significant urological or pelvic disease, including but not limited to:
• urinary tract malignancy (e.g. bladder, prostate, urethral or kidney cancer)
• hydronephrosis
• interstitial cystitis/bladder pain syndrome
• müllerian duct cysts
• radiation cystitis
• genitourinary tuberculosis.
8) Previous or current uninvestigated haematuria. Subjects with investigated haematuria may enter the study if significant urological/renal pathology has been ruled out to the satisfaction of the investigator.
9) Any condition that will prevent cystoscopic treatment administration or CIC usage e.g. urethral strictures.
10) Current indwelling bladder catheter, or removal of indwelling bladder catheter less than 4 weeks prior to Screening.
11) BTX-A treatment within 9 months prior to Screening for any urological condition
(e.g. detrusor or urethral sphincter treatments).
12) BTX-A treatment within 3 months prior to Screening for any non-urological condition.
13) Bladder instillation with any pharmacologic agent less than 3 months prior to
Screening.
14) Use of capsaicin or resiniferatoxin less than 6 months prior to Screening.
15) Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence
within 4 weeks prior to Screening. Any implanted neuromodulation device must be switched off at least 4 weeks prior to Screening and must remain off throughout study participation.
16) Any concomitant therapy usage that, in the investigator’s opinion, would interfere with the evaluation of safety or efficacy of the IMP, and/or confound the study results.
17) History of chronic drug or alcohol abuse.
18) Female subject who is pregnant or planning to become pregnant during the study, or is currently lactating (breastfeeding).
19) Any medical condition or disease that might interfere with neuromuscular function, e.g. diagnosed myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral
sclerosis.
20) Use of medications that affect neuromuscular transmission, such as curare-like depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics.
21) Previous primary or secondary non response to any botulinum toxins for the targeted condition.
22) Known hypersensitivity to BTX-A or to any components in the IMP formulation (including cow’s milk protein).
23) History of allergy to, or intolerance to, the anaesthetic or antibiotic agents that the investigator intends to use during the study.
24) Unable to stop medications with anticoagulant/antiplatelet effects for at least 3 days prior to each IMP administration and to recommence the day following each IMP administration (low molecular weight heparins may be used within 3 days of IMP administration).
25) Any condition that may cause excessive bleeding (e.g. haemophilia or clotting factor
deficiencies).
26) Any condition or situation which, in the investigator’s opinion, puts the subject at significant risk, may confound the study results, or may interfere with the subject’s participation in the study.
27) Treatment with any new investigational drug or device in the 4 weeks prior to Screening or scheduled to be used during the study period. In addition, at least 5
elimination half-lives must have occurred since discontinuing any new
investigational drug prior to Screening.
The following exclusion criteria will be assessed following completion of screening bladder diary and when screening laboratory blood results become available:
28) Voided urine volume ≥3 L during a single 24-hour period on the screening bladder diary.
29) Serum creatinine ≥2 times the upper limit of normal on screening serum chemistry testing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Mean change from study Baseline (assessed at Screening) to Week 6 after the first IMP administration in the weekly number of UI episodes:
• measured on a 7-day bladder diary. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Bladder diary measures:
• weekly number of UI episodes
• daily urinary frequency (total, spontaneous void only, CIC only)
• 24-hour voided volume (total, spontaneous void only, CIC only)
• volume per void (total, spontaneous void only, CIC only).
Urodynamic measures (urodynamic subset only):
• maximum cystometric capacity (MCC)
• maximum detrusor pressure (MDP) during storage
• volume at first involuntary detrusor contraction (Vol@1stIDC)
• maximum detrusor pressure at first involuntary detrusor contraction (PdetMax@1stIDC)
• end fill pressure (EFP)
• detrusor compliance (DC).
Patient-reported outcome questionnaires:
• incontinence quality of life (I-QoL) total summary score
• EuroQol 5-dimension 5-level (EQ-5D-5L)
• modified patient global impression - improvement (mPGI-I) score.
Proportion of subjects at post-treatment timepoints following the first and subsequent
treatments with:
• no episodes of UI (i.e. continence is achieved)
• UI response at several levels (i.e. ≥30% improvement, ≥50% improvement,
≥75% improvement, etc.)
• no IDCs on urodynamic assessment (i.e. urodynamic cure is achieved)
(urodynamic subset only).
Duration of effect following the first and subsequent treatments measured by:
• time to request retreatment
• time to eligibility for retreatment
• time between treatments. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Refer to schedule of events in protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belgium |
| Brazil |
| Chile |
| Colombia |
| France |
| Germany |
| Israel |
| Mexico |
| New Zealand |
| Peru |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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