1. Trial Synopsis

of 4 Research Proposal

1. Trial Synopsis

Simon Hein, M.D.

Department of Urology, University Medical Centre Freiburg Coordinating Hugstetter Str. 55, D-79106 Freiburg, Germany investigator Tel.: +49/761/270-28910 Fax: +49/761/270-28780 Email: [email protected]

Clinical Significance of Residual Fragments in 2015: Impact, Detection and How Title of trial to Avoid Them

Review of the literature concerning outcome parameters relevant to patients with Objective persisting residual fragments after active stone treatment and techniques to detect and avoid them

Inclusion criteria:

Clinical studies, including systematic reviews (SR), RCTs, cohort studies, case-control studies, case series, EAU and AUA guidelines on urolithiasis Inclusion and exclusion criteria Exclusion criteria:

Case reports, epidemiological studies, cross-sectional studies, cadaveric studies, animal studies

Primary endpoint:

Stone-related clinical events (medical treatment, retreatment)

Secondary endpoint(s): Outcome(s) Sensitivity and specificity of different imaging modes Radiation exposure of imaging modes Stone free rate of SWL and endourology (URS/ PNL) Complications of SWL and endourology Frequency of ancillary procedures in SWL and endourology Current and future techniques to avoid residual fragments

Trial type Cross-sectional, comprehensive review (non-systematic)

Statistical analysis Descriptive analyses of primary and secondary endpoints.

Sample size Max. 60 references to be included

Time for preparation of the trial (months): 3 Data acquisition (months): 3 Trial duration Statistical analysis (months): 0 Manuscript drafting (months): 3

2. The Medical Problem page 2 of 4

The treatment of urolithiasis has changed dramatically with minimally invasive techniques gradually replacing open surgery since the beginning of the 1970s. In the era of open surgery, complete stone clearance defined a successful treatment [1]. With the introduction of extracorporeal shock wave lithotripsy (SWL), fragments of targeted stones and subsequent expulsion came into focus [2]. ‘Clinically insignificant residual fragments’ (CIRF) were defined as asymptomatic residual fragments of 4 mm or less after SWL [3]. Indeed, occurrence of residual fragments (RF) is not restricted to SWL of renal stones. RF may as well remain after percutaneous nephrolithotomy (PNL) and (flexible) ureteroscopy (fURS) of the kidney and ureter [1, 4]. However, the impact of residual fragments on subsequent stone associated incidents, reoccurrence and growth, remains a subject of discussion [5]. In this review we address various issues concerning the fate of residual fragments (and the patients carrying them), their detection and current and future techniques to avoid them.

3. Justification of Design Aspects

3.1 Inclusion and exclusion criteria

Inclusion criteria:

Clinical studies including systematic reviews (SR), RCTs, cohort studies, case-control studies, case series, non-systematic reviews and EAU and AUA guidelines on urolithiasis

Exclusion criteria:

Case reports, epidemiological studies, cross-sectional studies, cadaveric studies, animal studies

Assessment of clinical outcome parameters of clinical trials (best available evidence) to answer identified problems relevant to the patient.

3.2 Search Method

Databases:

PubMed®, MEDLINE®, Embase™, Ovid®, Google Scholar™, and the Cochrane Library.

Search term:

Boolean searching will be performed using following terms:

“ shock wave lithotripsy”, “ureteroscopy”, “percutaneous nephrolithotomy”, “imaging”, “computed tomography”, “clinically insignificant residual fragments”, “CIRF”, and “residual fragments”.

Terms will be linked by Boolean operators AND and OR.

EAU/AUA guidelines will be assessed concerning recommendations and cited references.

3.3 Outcome measures

Results will be evaluated concerning primary and secondary endpoints.

Primary endpoint:

Stone-related clinical events (medical treatment, retreatment)

Secondary endpoint(s):

Sensitivity and specificity of different imaging modes Radiation exposure of imaging modes Stone free rate of SWL and endourology (URS/ PNL) Complications of SWL and endourology page 3 of 4

Frequency of ancillary procedures in SWL and endourology Current and future techniques to avoid residual fragments

3.4 Methods against bias

Evaluation and rating of extracted article by 2 independent reviewers (S.H. and M.S.). In cases of divergent ratings, results will be verified by a third independent reviewer (A.M.).

4. Statistical Analysis

Results will be described using descriptive statistics. No further statistical analysis will be performed.

5. Trial Management

5.1 Key participants

# Name Affiliation Responsibility/Role Dept. of Urology, University 1 Simon Hein, M.D. Principal investigator Medical Centre Freiburg Dept. of Urology, University 2 Arkadisz Miernik, M.D., Ph.D. Co-Investigator Medical Centre Freiburg

Dept. of Urology, University 3 Konrad Wilhelm, M.D Medical Centre Freiburg Co-Investigator

Dept. of Urology, University Fabian Adams, M.D. Medical Centre Freiburg Co-Investigator 4 Dept. of Urology, University Daniel Schlager, M.D. Medical Centre Freiburg Co-Investigator 5 Department of Urology and 6 Thomas Herrmann, M.D., Ph.D. Urooncology, Hanover Medical Co-Investigator School (MHH) SLK Kliniken Heilbronn Jens Rassweiler, M.D., Ph.D., Dr. 7 Department of Urology and Co-Investigator h.c., Prof. Pediatric Urology Dept. of Urology, University 8 Martin Schoenthaler, M.D., Ph.D. Medical Centre Freiburg Co-Investigator

5.2 Supporting facilities

6. Financing

Institutional funding (Department of Urology, University Medical Centre Freiburg)

6.1 Co-financing of the trial by a company: None

7. References page 4 of 4

1. Altunrende, F., et al., Clinically insignificant residual fragments after percutaneous nephrolithotomy: medium-term follow-up. J Endourol, 2011. 25(6): p. 941-5. 2. Osman, M.M., et al., 5-year-follow-up of patients with clinically insignificant residual fragments after extracorporeal shockwave lithotripsy. Eur Urol, 2005. 47(6): p. 860-4. 3. Rassweiler, J.J., et al., Treatment of renal stones by extracorporeal shockwave lithotripsy: an update. Eur Urol, 2001. 39(2): p. 187-99. 4. Ozgor, F., et al., Clinically insignificant residual fragments after flexible ureterorenoscopy: medium-term follow-up results. Urolithiasis, 2014. 42(6): p. 533-8. 5. Tan, Y.H. and M. Wong, How significant are clinically insignificant residual fragments following lithotripsy? Curr Opin Urol, 2005. 15(2): p. 127-31.