Gag Therapy for Recurrent urine tract infection Assessing Comparability to International Nitrofurantoin Gold standard study.

Antibiotic (AB) prophylaxis is the most common applied therapy for recurrent
urinary tract infection (rUTI) in the Netherlands. However it contributes to
antibiotic resistance, which is an increasing problem in healthcare. There is
thus a large societal incentive to decrease AB use and apply alternative
therapies. Previous studies (Damiano et al 2011, Goddard et al 2018) have shown
that GAG therapy (bladder instillations with GAG molecules) is valuable in the
treatment of rUTI. However there is insufficient evidence comparing the
effectiveness of GAG therapy with the effectiveness of antibiotic prophylaxis
in the prevention of rUTI.

We hypothesize that GAG therapy is an effective alternative for antibiotic
prophylaxis in the prevention of recurrent urinary tract infections.
Furthermore we hypothesize that GAG therapy will lead to less antibiotic
resistance than antibiotic prophylaxis.

The main objective of the study is to compare efficacy between GAG therapy and
gold standard treatment (AB prophylaxis) in the prevention of rUTI.

Primary question
Is GAG therapy as efficacy as antibiotic prophylaxis in the prevention of rUTI?

Secondairy questions
- Is there a difference in time to first recurrence of UTI between both
treatments?
- Does GAG therapy lead to less antibiotic resistance than antibiotic
prophylaxis?
- How do patients preceive their symptoms during both therapies?
- Is there a difference in cost-effectiveness between both therapies?
- Is there a difference in therapy specific patient reported outcomes between
both treatments?
- Is there a difference in quality of life during both treatments?

Cross-over randomized controlled trial. Study is set-up as non-inferiority,
parallel group trial, with a 1:1 randomization.

Intervention:
Bladder instillations with 50ml of sterile Ialuril weekly for 6 weeks, followed
by monthly maintenance therapy for 6 months. Every bladder instillation will
take around 30 minutes. The bladder instillations can be inserted by a nurse in
the hospital, at the general practitioners office or by the patient them self.

Control:
Antibiotic prophylaxis with oral nitrofurantoin 100mg daily (1dd100mg or
2dd50mg) for 6 months. In case of resistance/intolerance/allergy for
nitrofurantoin alternatively trimethoprim 100mg daily will be given for 6
months.

There is a four week wash-out period between treatments. The order of the
treatments is determined through randomisation

The burden
Intervention (GAG therapy): Weekly bladder instillations for 6 weeks,
thereafter instillations will be given monthly for the total duration of 6
months.
Control group: 1 tablet of antibiotic profylaxis every day for the duration of
6 months
Both groups:
Appointments: 3 site visits and 5 telephonic visits. Questionnaires: prior to a
(telephonic) visit 3-5 questionairs must be filled out (depending on the
visit). A study diary needs to be filled out to report weekly protocol
adherence. Urine samples are taken at site visits.

The risk
The intervention: bladder instillations with GAG therapy are inserted with a
catheter. Risk: UTI, discomfort during catheterization.
The controle: antibiotic prophylaxis (nitrofurantoin or trimethoprim). Risk:
side effects or allergic reaction (nausea, vomiting, itching, fungal infection)
Risks are negligible in both groups.