Phage Therapy for Recurrent UTIs in Kidney Transplant Recipients

Official title

Phase 1/ 2 Trial of Phage Therapy for Recurrent UTIs in Kidney Transplant Recipients

Overview

This proposal will take an important first step in the study of phage therapy for treatment of recurrent urinary tract infection (rUTI) in female kidney transplant recipients (KTR); a common condition that is associated with increasing multidrug resistance, sickness, loss of kidney function and death. The investigators will conduct a randomized phase I/II pilot clinical trial of targeted phage therapy versus placebo in asymptomatic female KTR with a history of rUTI due to Escherichia coli to assess safety, tolerability, and feasibility of this approach, possible efficacy, and changes in the gut and urinary microbiome during the 180 days of the study. This highly innovative and impactful proposal will provide proof of concept data and also inform the design of a subsequent larger phase III clinical trial of phage therapy for rUTI treatment in KTR and will have broad downstream effects within the fields of infectious diseases and transplantation.

Detailed description

The overarching hypothesis is that phage therapy directed against E. coli in female KTR is safe and associated with a reduction in UTI event rate via a targeted impact on the gut and urinary microbiome. This is a Phase 1/ 2 randomized, placebo-controlled clinical trial.

* A description of methods to be used to minimize bias Participants will be randomized to one of 2 arms - one active intervention phage therapy and the second is active intervention control arm (normal saline placebo). Participants will not be aware of study assignment and the medication delivered to them will look identical - clear 1mL solution in a plastic needless syringe. * The number of study groups/arms and study intervention duration:

* Investigators plan to enroll participants that fulfill eligibility criteria until they reach their goal of 16 participants in each arm (total N= 32).

This clinical trial will evaluate the effect of phage only (without concomitant antibiotics) compared to placebo for UTI prevention in asymptomatic female KTR with a history of rUTI. There are no rigorous, published trials testing this approach, nor are there new therapeutics for rUTI in KTR on-market at this time. Most IND cases or trials compare phage plus antibiotic which limits the ability to isolate the contribution from phage to treatment success. The proposed research will utilize a phase I/II pilot trial designed to assess the safety, tolerability, and feasibility of therapy, compare potential efficacy, and assess changes to microbiome profiles in the female participants who will receive either phage or placebo. As the participants will be treated when they are asymptomatic, no active control is needed and so Investigators will use normal saline placebo.

Interventions

• Drug phage therapy
  phage therapy will consist of a combination of three lytic phages that are active against the participant's E. coli isolates and will be administered intravenously twice daily for 7 days.
• Drug control
  Participants assigned to the control arm will start a 7-day course of intravenous sterile normal saline (placebo) administered twice daily.

Primary outcome measures

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Time frame: 180 days]
• Enrollment Feasibility [Time frame: 180 days]
• Proportion of participants with a phage match [Time frame: 180 days]
• Study Drug Adherence [Time frame: 180 days]

Secondary outcome measures (9)

• Treatment Efficacy [Time frame: 180 days]
• Desirability of Outcome Rankings (DOOR) Score [Time frame: 180 days]
• Proportion of Participants with UTI [Time frame: 180 days]
• Days to first symptomatic UTI from the original infecting pathogen [Time frame: 180 days]
• Microbiological Eradication of Asymptomatic Bacteriuria [Time frame: 180 days]
• Need for intravenous (IV) antibiotics [Time frame: 180 days]
• Number of days on antibiotics [Time frame: 180 days]
• Emergency room visit/ hospitalization due to UTI [Time frame: 180 days]
• Change in kidney function from baseline to end of the study period [Time frame: 180 days]

Eligibility criteria

Inclusion criteria

• Female kidney transplant recipients, aged 18 and older with a confirmed diagnosis of a history of recurring UTI with E. coli as their typical uropathogen.
• Two urine culture proven UTIs in prior 6 months or three in prior 12 months due to E coli. UTI is defined as any change in symptoms from baseline urinary comfort (dysuria, hematuria, abdominal/flank pain, increased urinary frequency) or systemic signs of infection (fever, chills, systemic inflammatory reaction syndrome etc.) associated with a positive urine culture with bacterial growth of ≥104 colony forming units/mL).
• Ability to self-administer study drug (or a family member that will do so) and willing to adhere to the phage therapy regimen.
• For participants able to become pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 6 months after the end of phage therapy administration.
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study.

Exclusion criteria

• Presents with hardware in the urinary tract (e.g. stent, percutaneous nephrostomy, chronic urinary catheter).
• Recipient of >1 kidney transplant.
• Recipient of Ileal conduit.
• Recipient of surgical neobladder.
• Diagnosed with chronic urinary retention requiring self-catheterization.
• Anatomic cause for rUTI such as ureteral stenosis.
• Within the first 3 months of kidney transplant.
• Venous access sites or in whom an existing venous access site needs to be preserved for future need (as per the participant's transplant nephrologist/ surgeon)
• Diagnosed with active cytomegalovirus or BK virus infections.
• Current pregnancy, actively trying to conceive, or lactating.
• Known allergic reactions to phage products.
• Prisoners or individuals without decisional capacity.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

United States · 1 center

• University of California, San Diego — La Jolla

Identifiers

NCT: NCT06409819 · 809673

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗