GAG-therapy Efficacy Trial Solution for Bladder pain syndrome/ Interstitial cystitis

Reimbursement of 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.

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

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.

GAG bladder instillations (hyaluronic acid + chondroitin sulfate; Ialuril) 50ml
administered with a catheter. Placebo will be artificial Tears (three options:
Hypromellose 0,3% (Artelac), Hypromellose 3mg/Dextran 70mg (Duratears) en
Povidon 20mg (Protagens), with these products an 50mL placebo instillation will
be made and administred per katheter. There are 3 periods of 6 wks with
frequency of 1 instillation/wk (ratio intervention/placebo is 2:1). 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).
If needed (e.g. vacation patient), the wash-out period can be extended and the
start of the treatment period postponed for a maximum of 5 weeks, minimal
wash-out period of 4 weeks.

During the study we found out the production of articifial tears is very
unstable and results in many delivery and storage problems. In the normal
clinic the Pharmacist changes between artificial tears to prescribe (depending
on availability). Because of this we have decided to have three placebo
options, in case of storage Artelac is the first choice, followed by Duratears
and final Protagens. In this way the study is less vunerable and continuity is
maintained. On 29th of July 2022 we had to change the placebo acutely to
another product because the production was stopped because of economical
issues.

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 artificial tears are used as moisturizing drops to treat
dry eyes. It is inert (non-irritating and hypo-allergenic). All artificial
tears have no active compound, because the production of the tears is unstable
we have included three possible options to use as placebo: In the first place:
Hypromellose 0.3%, secondly Hypromellose/dextran and lastly Povidon 20mg. Rare
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. In principle the Hypromellose 0.3% is checked for sensitivity,
hence if in storage this is the first choice of placebo. If another drop is
used as a placebo, together with the physician will be decided if that needs to
be checked for sensitivity as well.