Evaluate the Efficacy and Safety of U101 Oral Capsules in the Prevention of Uncomplicated rUTIs in Women

This is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the efficacy and safety of U101 versus placebo in women with recurrent urinary tract infections (UTIs).

The study will be conducted primarily on an outpatient basis and consist of (1) a Screening Period, (2) a Main Study (24 weeks), and (3) an optional Open-Label Extension (OLE) program/Follow-Up Period (total 24 weeks). The study plans to enroll a total of 348 participants.

Female participants (≥ 20 and < 76 years old) who have experienced rUTIs (defined as ≥ 2 UTI events in a 6-month period or ≥ 3 UTI events in a 12-month period) but confirmed resolved infection before randomization will be the potential candidates to enroll in this study.

During the screening period, patients with a history of rUTIs who present at the study sites will be identified. The potential participants will proceed with other study-specific activities to confirm their eligibility. Once confirmed, participants will be stratified based on their menopausal status (Yes/No) and study site then randomized into the main study in a 1:1 ratio to receive U101 or matching placebo.

During the main study, one capsule (100 mg) of U101 or matching placebo will be administered orally three times per day (TID) for 8 weeks followed by one capsule of U101 or matching placebo twice per day (BID) for 16 weeks. The total study duration will be 24 weeks and participants will be required to attend site visits every 4 weeks (routine visits).

If participants develop symptoms or have a positive urinalysis result suggestive of a UTI at any time after receiving the first dose of study medication during the main study and the OLE/Follow-up period, they are instructed to contact the study staff to arrange for a special visit for examination (suspected UTI visit). If the investigator suspects a UTI recurrence and prescribes systematic antibiotics as a result, the study medication will be interrupted. After the resolution of the infection, the study medication will be reintroduced again on a TID dosing schedule.

Participants will be offered to enroll in the open-label extension (OLE) program or enter the Follow-Up Visits after they complete the 24-week main study.

The purpose of the OLE is to collect additional safety and efficacy data. Eligible participants and the investigators will decide whether the participants should receive U101 treatment (TID for 8 weeks followed by BID for 16 weeks) or enter the long-term follow-up period without any treatment. To receive U101 treatment during the OLE, participants must experience at least 1 UTI episode during the 24-week main study. The OLE will last for 24 weeks and all participants will be scheduled for two visits at Week 8 and Week 24. The OLE may be terminated contingent on the primary analysis results of the main study.

Participants who are not eligible for or who choose not to receive U101 will enter the long-term safety follow-up. This Follow-up period has the same visit schedules (at Week 8 and Week 24) as the OLE; however, no treatment will be administered.

The primary analysis will be conducted at the end of the 24-week main study.

Inclusion criteria

• Provide a signed informed consent form.
• Non-pregnant, non-nursing females ≥ 20 and < 76 years old.
• Having a history of ≥ 2 UTI events during the preceding 6 months or ≥ 3 UTI events during the preceding 12 months (including any UTI event that occurs on the date of ICF signing). At least one of the previous UTI events must have microbiologic evidence (e.g., per the investigator's judgment based on urine culture results).
• The last urine culture (including those conducted for suspected UTI event or retest) before the randomization has to be negative.
• Having a negative urinalysis result and no symptoms suggestive of a UTI on the day of randomization.

Exclusion criteria

• Females who are pregnant, nursing, have a desire for pregnancy or have a positive pregnancy test at screening.
• Women of childbearing potential who are unwilling or unable to use an acceptable contraceptive method to avoid pregnancy for the entire study period (use of spermicide is prohibited). Women of childbearing potential are defined as premenopausal females capable of becoming pregnant.
• Serum aspartate transaminase (AST), serum alanine transaminase (ALT) and serum total bilirubin > 1.5 x upper limit of normal (ULN).
• Serum creatinine > 1.5 x ULN.
• Prothrombin time (PT) or INR > 1.2 x ULN.
• Platelet counts < 100,000/μL.
• Serum vitamin D level < 11 ng/mL.
• HbA1c > 8.0%.
• Positive test for hepatitis B (both HBsAg and HBeAg), hepatitis C (anti-HCV antibody) or HIV (anti-HIV antibody).
• Symptoms suggestive of a systemic inflammatory response (fever > 38℃ or WBC count > 12,000) at the screening.
• A major functional or anatomical abnormality of the urogenital tract (e.g., renal cell carcinoma, outlet obstruction, etc.).
• Diagnosis of pelvic organ prolapse ≥ grade 2 (according to pelvic organ prolapse quantification POP-Q classification) without any treatment within 6 months of the screening visit.
• Diagnosis of complicated UTIs within 6 months of the screening visit.
• Residual urine volume > 100 mL within a month of the screening visit.
• History of interstitial cystitis, pelvic inflammatory disease, or chronic pelvic pain syndrome.
• Having any of the following procedures within a week of the screening: urinary catheterization (e.g., Foley catheter), ureteral stent, percutaneous nephrostomy, or cystostomy.
• Intravesical instillation of hyaluronic acid within 6 months of the screening visit.
• Treatment with pentosan polysulfate sodium (PPS) within 6 months of the screening visit.
• Use of antibiotic prophylaxis for rUTI within a month of the screening visit.
• Use of local hormone therapy (cream, gel, insert, ring, or tablets) in urogenital areas within a month of the screening.
• Any history of thrombocytopenia, hemophilia, or bladder cancer; history of endoscopy-confirmed gastrointestinal ulcers within 3 years prior to randomization.
• Active malignancy (under intensive cancer treatment or considered in progression) or a history of any malignancy involving the pelvic cavity within 5 years prior to randomization, with the exception of adequately treated basal cell carcinoma and cervical cancer in-situ. Subjects in stable condition will be evaluated and discussed individually with the investigator.
• Immunocompromised or history of organ transplant.
• History of allergies to pentosan polysulfate sodium.
• Having planned major surgery within 24 weeks after the study.
• Participation in any interventional clinical trial within 30 days of the screening visit.
• Other significant medical problem(s) or intercurrent acute illness(es) that in the opinion of the Investigators, would make participation in the study unsafe, complicate the interpretation of study outcome data, or otherwise interfere with achieving the study objective.
• Subjects who are illiterate.
• Subjects having a family history of macular degeneration or having been diagnosed with macular degeneration (except for those with asymptomatic age-related macular degeneration) .