Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 SNM referral centers in Switzerland: Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital, Zürich; Department of Urology, Cantonal Hospital St. Gallen, St. Gallen; Neuro-Urology, Swiss Paraplegic Center Nottwil, Nottwil; Department of Urology, University of Bern, Bern.

In case of successful prolonged SNM, the neuromodulator is implanted and patients are randomized using a computer program considering 3 strata according to the neuro-urological diagnosis, i.e. a) urgency frequency syndrome and/or urgency incontinence, b) chronic urinary retention, and c) combination of urgency frequency syndrome and/or urgency incontinence and chronic urinary retention. After a 2 months SNM optimization phase following neuromodulator implantation, the neuromodulator is turned ON or OFF in a 1:1 allocation by an investigator not involved in the assessment of the clinical outcome.The Figure 1 gives an overview of the procedures that the patients will undergo during the course of the study.

According to the inclusion and exclusion criteria (Table 1), we will investigate patients with refractory neurogenic LUTD. The following variables will be considered: gender, age, neurological disease, duration of neurological disease, previous treatment, bladder diary variables, urinalysis, urethro-cystoscopy, bladder washing cytology, urodynamic investigations, and questionnaires, i.e. Female Sexual Function Index (FSFI)[10]/International Index of Erectile Function (IIEF)[11] and Qualiveen[12].

We are planning a study of independent cases and controls with 1 control per case. Prior data indicate that the (spontaneous) success rate among controls is 0.15. If the true success rate for experimental subjects (SNM ON) is at least 0.5, we will need to study 27 experimental subjects (SNM ON) and 27 control subjects (SNM OFF) to be able to reject the null hypothesis that the failure rates for experimental (SNM ON) and control subjects (SNM OFF) are equal with probability (power) 0.8. The type I error probability associated with this test of this null hypothesis is 0.05. Taking into account potential drop-outs, we will include 30 patients per group.

In case the patients with refractory neurogenic LUTD fulfill the study inclusion criteria following neuro-urological evaluation (bladder diary for at least 3 days, urinalysis, urodynamic investigation, urethro-cystoscopy and bladder washing cystology, Qualiveen questionnaire[12], FSFI[10]/IIEF[11], they are included after providing written informed consent. The Figure 1 gives an overview of the procedures that the patients will undergo during the course of the study. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4 (stage one), patients undergo prolonged SNM testing for 3–6 weeks completing a bladder diary to assess the response to treatment. In accordance with the literature[5, 6], an improvement of at least 50% in the key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to the baseline values is considered a positive test and an indication for neuromodulator implantation. At the end of the test phase, the patients have a neuro-urological re-evaluation (bladder diary for at least 3 days, urinalysis, urodynamic investigation, Qualiveen questionnaire[12], FSFI[10]/IIEF[11]). In case of negative prolonged SNM testing, the tined leads are explanted. In case of successful prolonged SNM testing, the neuromodulator is generally implanted in the upper buttock (rarely in the anterior abdominal wall) (stage two). After neuromodulator implantation, each patient has a 2 months phase when the neuromodulator is turned ON using sub-sensory threshold stimulation (SNM optimization phase) to optimize the effectiveness of neuromodulation by determining the most effective stimulation parameters (choice of stimulation electrodes, intensity of stimulation) for each patient. At the end of the SNM optimization phase, patients are randomized in a double-blind parallel design to SNM ON or OFF. During an outpatient visit, neuromodulation parameters and bladder diary parameters are checked and the neuromodulator is turned ON or OFF by an investigator not involved in assessment of the clinical outcome. Considering that sub-sensory stimulation is used for SNM, the patients do not feel if the stimulation is ON or OFF. At the end of the 2 months double-blind SNM phase, the patients have a neuro-urological re-evaluation (bladder diary for at least 3 days, urinalysis, urodynamic investigation, Qualiveen questionnaire[12], FSFI[10]/IIEF[11]). During this visit, unblinding takes place and the neuromodulator is turned ON in all patients.

The investigators will inform the patients, the study monitoring board, and the ethics committee if it becomes evident that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the study monitoring board, except insofar as suspension would jeopardize the patients’ health. The investigators will take care that all patients are kept informed.

Adverse events will be assessed and categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4 in grade 1 to 5 (http://​ctep.​cancer.​gov/​protocolDevelopm​ent/​electronic_​applications/​ctc.​htm). All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow-up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.

In the case of withdrawal of consent to participate in the study, all possible efforts will be made to convince the patient to continue to have safety follow-up evaluations.

In the event one of the following situations arises among treated patients during the conduct of the study, the study will be temporarily suspended and a comprehensive safety review conducted evaluating if the study has to be terminated prematurely:

Primary: Success of SNM: Defined in accordance with the literature[5, 6] as improvement of at least 50% in the key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to the baseline values (i.e. patients with urgency frequency syndrome and/or urgency incontinence: at least 50% decrease in number of voids and/or number of leakages; patients with chronic urinary retention: at least 50% decrease in post void residual; patients with a combination of urgency frequency syndrome and/or urgency incontinence and chronic urinary retention: at least 50% decrease in number of voids and/or number of leakages, and/or at least 50% decrease in post void residual).

Secondary: A) Adverse events: Categorization according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4 in grade 1 to 5 (http://​ctep.​cancer.​gov/​protocolDevelopm​ent/​electronic_​applications/​ctc.​htm).

B) Urodynamic parameters: cystometric capacity (mL), compliance (mL/cmH₂O), detrusor overactivity (if yes: bladder volume (mL) at detrusor overactivity, maximum detrusor pressure amplitude (cmH₂O), detrusor leak point pressure (cmH₂O)), maximum detrusor pressure (cmH₂O), detrusor pressure at maximum flow rate (cmH₂O), maximum flow rate (mL/s), voided volume (mL), post void residual (mL), pelvic floor electromyographic activity (normal/detrusor sphincter dyssynergia).

C) Questionnaires, i.e. Qualiveen and FSFI/IIEF.

D) Costs of SNM.

This trial will be performed in accordance with the World Medical Association Declaration of Helsinki[13], the guidelines for Good Clinical Practice[14] and the guidelines of the Swiss Academy of Medical Sciences[15]. Handling of all personal data will strictly comply with the federal law of data protection in Switzerland[16]. The trial has been registred at clinicaltrials.gov (www.clinicaltrials.gov/ct2/show/NCT02165774).

This study has been approved by the local ethics committees (Kantonale Ethikkommission Zürich KEK-ZH-Nr. 2011–0048, St. Gallen KEK-SG-Nr. 12/069, Luzern KEK-LU-Nr. 12047, Bern KEK-BE-Nr. 094/12).