GAG-therapy Efficacy Trial Solution for Bladder Pain Syndrome/ Interstitial Cystitis (GETSBI Study)

Rationale:

Reimbursement in the Netherlands for GAG-therapy for bladder pain syndrome / interstitial cystitis patients with Hunner lesion subtype (BPS-IC H+) is under debate, as evidence regarding its efficacy and cost-effectiveness is lacking.

Objective:

Main objective is to determine short and long term efficacy of GAG therapy (bladder instillations) for people with BPS-IC H+ as compared to placebo treatment on dominant symptoms such as pain. Secondary objectives are to determine the 1) cost-effectiveness of GAG therapy, 2) effectiveness of GAG therapy on quality of life and bladder inflammation evaluated by urethrocystoscopy

Study design:

Multi-design study. Study is powered and set-up as double-blinded randomized intervention study and is extended with a double-blinded aggregated N-of-1 trial. As requested by the Zorginstituut Netherlands, the study will be further extended with a prospective, non-blinded intervention study to evaluate long term follow up with a low frequency therapy dose.

Study population:

People with symptomatic BPS-IC H+ (> 18 yrs old). A total of 80 patients will be included for the main study.

Intervention :

GAG bladder instillations (hyaluronic acid + chondroitin sulfate; Ialuril) 50ml administered with a catheter. Placebo will be Hypromellose 50ml administered with a catheter. Patients will receive instillations (Ialuril / placebo with ratio 2:1) in 3 periods of 6 wks with frequency of 1 instillation/wk. With wash-out periods 4 wks. After 3 periods of treatment / placebo (wk 30), blinding will cease and continue unblinded where all subjects will receive maintenance therapy Ialuril for 1x/4wk until 54 weeks (endpoint).

Main study parameters/endpoints:

Primary outcome parameter: change from baseline in maximum bladder pain (visual analogue scale (VAS) pain score (3d average and maximal pain score).

Secondary outcome parameters:

• Change from baseline in VAS score (0-10) on self-reported secondary symptoms

• Change from baseline from self-reported Global Assessment of Improvement (Likert scale)

• Change from baseline from O'Leary-Sant IC Symptom Index & Problem Index questionnaire

• Change from baseline in urethrocystoscopic evaluation of bladder mucosa (inflammation, active Hunner lesions) (clinician assessed estimated % of inflammation & degree of inflammation)

• Change from baseline in Quality of Life using ED-5D 5L questionnaire (Dutch)

• Cost effectiveness analyses using iMCQ and iPCQ questionnaires

• Changes in Patient Reported Outcome questionnaire (incl. urinary frequency)

• Adverse events using Clavien-Dindo system

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Benefits patients and group relatedness. All participants are capacitated adults and will receive a similar amount of intervention and placebo treatments. Treatment corresponds to the Dutch NVU guideline BPS. Therapy will be reimbursed for patients. During 54wks, patients will have a 6 week period where placebo is given. Due to the study design, patients can obtain a personal (individual) study efficacy result if therapy was successful in him/her.

Therapy and placebo: risks and burden This study will be submitted as low-intervention trial. GAG therapy (instillations) has been used for >25 yrs in clinical practice to treat BPS-IC. GAG-therapies are registered as medical devices. The therapy is instilled into the bladder using a catheter (by nurse / patient). Catherization has a small increased risk for developing an urine tract infection (1.9%) [Herr 2015], urethral discomfort and in rare cases urethral trauma.

The placebo compound Hypromellose 0.3% is used as moisturizing drops to treat dry eyes. It is inert (non-irritating and hypo-allergenic). Very rare (< 0.01%) side effects are reported in the Dutch 'Farmacologisch Kompas'. They report local side effects of sensitivity (burning, itch, tears e.d.). Blurry vision. and very rare systemic effects as rash, itch.Because of these reported side effects at inclusion the (over)sensitivity is checked by one drop in an eye, taking into account the possible blurry vision afterwards.