The Safety, Tolerability and Efficacy of LP-10 in Subjects With Refractory Moderate to Severe Hemorrhagic Cystitis

This is a multi-center, dose-ranging study including male and female subjects with refractory moderate to severe hemorrhagic cystitis as determined by a physician. A total of up to 12 subjects are anticipated and will be enrolled in study sites in the United States. Enrollment is expected to be completed within one year of initiating the study. The proposed trial will recruit 12 subjects in a dose-escalation trial where 4 subjects will be allocated into each one of three groups.

• LP-10 (Drug): Intravesical tacrolimus

Primary outcomes

• Patient Reported Mean episodes of visible blood [At every patient visit, up to 2 weeks following initial treatment]: Pre-post changes in mean episodes of visible blood in urine (or blood clots) on 3-day bladder diaries at baseline and primary endpoint

Secondary outcomes

• Urine Dipstick Mean episodes of Visible Blood [At every patient visit, up to 2 weeks following initial treatment]: Mean episodes of visible blood in urine (or blood clots) and urine dipstick for quantitative grading of microscopic hematuria on bladder diaries
• Mean urine hemoglobin concentration [At every patient visit, up to 2 weeks following initial treatment]: Mean urine hemoglobin concentration
• Urine analysis with microscopy [At every patient visit, up to 2 weeks following initial treatment]: Urine analysis with microscopy including red blood cells per high power field test
• Whole blood Add to dictionary levels [At every patient visit, up to 2 weeks following initial treatment]: Whole blood tacrolimus levels
• Blood chemistry and liver function test [At every patient visit, up to 2 weeks following initial treatment]: Blood chemistry and liver function test
• Patient Reported Global Response Assessment Survey Score [At every patient visit, up to 2 weeks following initial treatment]: Changes in Global Response Assessment (GRA)
• Patient Reported Urinary frequency [At every patient visit, up to 2 weeks following initial treatment]: Changes in urinary frequency and incontinence measured on diaries
• Bladder Cystoscopy [At initial treatment and on final patient visit, up to 2 weeks following initial treatment]: Cystoscopic changes in bladder
• Patient Reported Health Related Quality of Life Survey Score [At every patient visit, up to 2 weeks following initial treatment]: Changes in Health Related Quality of Life (HRQOL) scores
• Post void residual urine volume [At every patient visit, up to 2 weeks following initial treatment]: Post void residual urine volume
• Patient Reported Pain and Urgency [At every patient visit, up to 2 weeks following initial treatment]: Change in pain and urgency 10 cm visual analog scales (VAS)
• Incidence of Treatment-Emergent Adverse Events [At every patient visit, up to 2 weeks following initial treatment]: Safety data will be collected by ongoing monitoring of adverse events, during the entire duration of the study, including need for blood transfusion, bladder irrigation, emergency room visit, hospitalization, urinary catheterization, and/or surgery in addition to patient reporting of changes in urinary frequency, hematuria/ clots, incontinence, spasm or discomfort.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Males and females, at least 18 years

* History of sterile moderate to severe HC (Grade 2-4) for at least 3 months documented in the medical record with at least 1 episode of macroscopic hematuria with or without clot
* Previous use of medications and/or treatment(s) for HC without success
* Patients of child-bearing capability agree to use a reliable form of birth control (condoms and/or oral contraceptives) during the course of instillation therapy and for 1 week thereafter
* Willing and capable of understanding and complying with all requirements of the protocol, including proper completion of the 3 day Hemorrhagic Cystitis Diary (HC Diary) and self-administered questionnaires

Exclusion Criteria:

* History of interstitial cystitis/painful bladder syndrome
* HC due to infection (bacterial, viral or fungal)
* Vesicoureteral reflux disease based on cystogram within past 12 months
* Subject is currently or has previously participated in another therapeutic or device study within 3 months of screening and has not returned to baseline
* Pregnant or lactating
* History of bleeding diathesis or active bleeding peptic ulcer disease
* Life expectancy less than 12 months
* PSA > 10.0 ng/dl (measured within the last 3 months)
* Known allergy to liposomes and/or egg yolk and/or tacrolimus
* Urinary retention requiring daily catheterization
* Previous augmentation cystoplasty
* Subjects currently taking prescribed treatment for HC will be able to continue the treatment throughout the course of the study. If the patient cannot be maintained on a stable dose of the medication(s) throughout the treatment and follow-up period they will be excluded
* Subject with history of intravesical treatment(s) within 1 week prior to Study Visit 1
* Sacral and/or pudendal nerve neuromodulation device (Interstim) within the last 6 months. Subjects would not be excluded if they had Interstim greater than 6 months ago and is on a stable setting.
* Evidence of renal impairment (creatinine > two times the upper limit of normal at Visit 1), hepatic impairment (AST or ALT > three times the upper limit of normal at Visit 1), clinically significant cardiovascular, respiratory, or psychiatric diseases per investigator's judgment
* Post-void residual (PVR) urine volume of > 150 mL at screening
* The presence of any clinically significant systemic disease or condition that in the opinion of the investigator would make the patient unsuitable for the study