The GETSBI study investigates the efficacy of intravesical GAG therapy (IALURIL®) in Interstitial Cystitis (IC/BPS) with Hunner lesion patients with a first of its-kind dual RCT multi-crossover design. IC/BPS is a symptom-based diagnosis, based on exclusion of other identifiable diseases. It has multiple subtypes. The most severely affected subgroup has disease specific inflammatory lesions called Hunner lesions that is currently classified under ICS terminology as IC with Hunner lesions (IC HL+).[1] These lesions can be identified and regularly followed up with urethrocystoscopy according to Dutch and EAU guidelines for routine practice. This subtype accounts for approximately 10-20% of all IC/BPS patients and is therefore a rare subtype of an already rare disease. In 2015 the reimbursement for GAG therapy was cancelled in the Netherlands due to lack of evidence. The GETSBI study is a government funded trial that will deliver evidence for the decision whether GAG therapy shall be re-reimbursement within the Netherlands. Globally, randomised controlled trials (RCT) to evaluate GAG therapy have been tried, but many have failed due to a lack of IC/BPS subtyping in the inclusion criteria and failure to include sufficient patients for a powered result. [2, 3]There is not enough scientific data (no Level 1 evidence) to establish efficacy of GAG therapy in combined or separate IC/BPS subgroups. Also there has never been any cystoscopy controlled study protocol implemented for IC/BPS. Hence previous RCT’s failed, there has been a lot of debate on the proper study design to investigate the efficacy of GAG therapy in IC/BPS. The goal of this study is to investigate the efficacy of intravesical GAG therapy (IALURIL®) with a research design that is in accordance with a Level 1 evidence as defined by the Oxford CEBM evidence grading table. Our main objective was to establish a study design using a high quality methodology that can drastically reduce the number of inclusions needed for adequate power in chronic disease. This abstract elaborates on the chosen study protocol and study progress of the GETSBI study.

Study design
The study design is unique in its kind. The study protocol is primarily based on a standard RCT (randomized, placebo controlled & double blinded), but continues as an aggregated (combined) N-of-1 trial. An aggregated N-of-1 trial is an RCT within an individual patient and implements a multi-crossover design. The aggregated (or combined) N-of-1 trial combines individual N-of-1 trials to study (sub)group effects. 

Study procedures
The study will assess short-term (primary objective, 6 weeks of 1x/week intervention/placebo) and long-term efficacy (24 weeks of 1x/month IALURIL®; non-randomized/non-blinded). In the flowchart below the study procedures are displayed for the primary objective of the study. Participant are randomized into one out of three treatment arms. 

The study is performed at 9 sites during two years of recruitment. The needed inclusion is 80 participants (>80% power, 17-25% drop-out ratio) [4-6] for the classic RCT, with the back-up from the aggregated N-of-1 trial (requiring only 40 patients for similar power). 
Study population: Adults (>18 year) with symptomatic IC/BPS with established Hunner lesions objectified with urethrocystoscopy with a VAS pain score (maximum pain during the last 3 days, 0-10) of at least 4.
Study parameters: VAS pain score, 7-point Global Response Assessment (GRA) scale, VAS dominant symptom burden score (0-10), O’Leary Interstitial Cystitis Symptom and Problem index, Patient Reported Outcome Measurements, EQ-5D 5L Quality of Life questionnaire, iMCQ and iPCQ and urethrocystoscopically evaluated parameters: number of Hunner lesions, estimated % of inflammation of bladder wall, overall assessment of degree of bladder inflammation (5-point Likert scale).

Several study designs were considered to answer the study research questions. Firstly, a standard RCT. Upsides of a standard RCT are 1) the acceptance as the gold standard in clinical research and 2) the use of randomization, double blinding and placebo-groups for evaluation. It is therefore very suitable to evaluate therapy effects that apply to a group of comparable patients (between-subject comparison). Downsides are 1) the high number of patients required to achieve power, which is challenging in a rare disease such as IC/BPS HL+. 2) The lack of within-subject comparison, which can be beneficial in patients’ groups such as IC/BPS with heterogeneous symptom profiles (variety of co morbidities, subjective symptoms such as pain, urgency and dyspareunia). The aggregated N-of-1 trial is an RCT within an individual patient and implements a multi-crossover design. The benefits are: 1) randomization, double blinding and placebo evaluation as well. 2) It applies within-subject comparison principles so that both placebo and intervention are evaluated in the individual patient that has the benefit of obtaining an individual result for each participating patient. It also has the advantage that all patients receive the same amount of treatment and placebo, thereby making participation more attractive for subjects. Within-subject comparison limits confounding covariates & the multi-crossover design counterbalances the naturally occurring disease symptom variation over time. It is therefore beneficial for evaluating therapy efficacy in chronic diseases that have a heterogeneous and subjective symptom profile. 3) It requires considerably less patients for enough power compared to a RCT (in this protocol, 50%). Limitations are: 1) although recognized by Oxford CEBM as evidence level comparable to an traditional RCT, it is a less established research design, 2) study design is only applicable for studying efficacy in chronic disease and non-curing therapies, and 3) the fact that the results can be negatively impacted by potential carry-over effects (therapy effects interfere with period where placebo is assessed), so adequate wash-out periods need to be incorporated into the study protocol and therefore follow-up duration is often longer compared to a traditional RCT. 

The incorporation of the two designs, RCT and the aggregated N-of-1 trial in one protocol, in this study makes the study design unique and allows for a direct comparison between these two study designs. The outcome of the RCT design is the primary design for evaluation. Because of the lower numbers for power calculation required for the aggregated N-of-1 design, it will only replace the RCT design as primary design in case the inclusion numbers are not met for the RCT design. Although this is not the primary objective of the study, this current design will also allow us to compare the two main methods (standard RCT and aggregated N-of-1 trial) and even a single crossover RCT design, without compromising the scientific value of either of the methods to evaluate applicability for future study designs for  research in chronic urology diseases.

The use of the methodological model of aggregated N-of-1 trial has not been used in urology before. This study protocol of combining a RCT part with an aggregated N-of-1 part is a global first -of-its-kind study design that will give an insight how these two models compare to each other.

The GETSBI study is a multi-design multicentre randomized placebo-controlled study to investigate the efficacy of GAG-therapy (IALURIL®) in IC/BPS HL+. The study design is relevant  for designing more adequate study protocol that can obtain high level evidence with fewer patients. Today 10/80 patients are included and 6 months of the 2 years has passed.

van de Merwe, J.P., et al., Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol, 2008. 53(1): p. 60-7.
Nickel, J.C., et al., A multicenter, randomized, double-blind, parallel group pilot evaluation of the efficacy and safety of intravesical sodium chondroitin sulfate versus vehicle control in patients with interstitial cystitis/painful bladder syndrome. Urology, 2010. 76(4): p. 804-9.
Nickel, J.C., et al., Second multicenter, randomized, double-blind, parallel-group evaluation of effectiveness and safety of intravesical sodium chondroitin sulfate compared with inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. Urology, 2012. 79(6): p. 1220-4.