Overview
This is a Phase 1b study to assess the safety, tolerability, PK, and PD of investigational phage therapy (IP) in adults with SCI and bladder colonization (ASB). It is a single-center, randomized, double-blind, placebo-controlled study in adults with SCI with neurogenic bladders and bacteriuria who use indwelling catheters, or who require intermittent catheterization for bladder drainage.
Description
Approximately 30 participants will be randomized 1:1 to receive either investigational phage therapy (3 x 10^8 PFU phage(s)) or inert placebo (sterile normal saline solution) will be administered intravesicularly (instilled into the participant's bladder via catheter) twice a day (BID) for 7 days; the investigational phage therapies are personalized for each participant per phage susceptibility testing to the predominant E. coli pathogen in the participant's bladder. A mixture of up to three phages in a sterile solution will comprise the investigational phage therapy. The study duration for participants will be up to 65 days, which includes up to 30 days for screening, 7 days of IP treatment, and post-treatment assessments at Days 14, 21, 28 and 35 (7, 14, 21 and 28 days after the End of Treatment [EOT] on Day 7, respectively). Day 35 is defined as the EOS. The investigators will strive to enroll participants who are receiving inpatient care in the Spinal Cord Injury units, but enrollment of outpatients with SCI is also possible. Study enrollment will continue for up to 30 evaluable participants.
The study will consist of a Screening Period of up to 30 days. On Day -1, eligible participants will be randomized to investigational phage therapy or placebo. The Treatment Period (Days 1-7) is 7 days and participants will receive a total of 14 doses of IP. The EOT will be after IP dose 14 on Day 7. The Follow-up Period is 35 days starting the day after the EOT with study assessments on Days 14, 21, and Day 35 (EOS). Adverse event data will be collected throughout the study from Treatment Day 1 through the EOS.
Eligibility
Inclusion Criteria:
- Provision of signed and dated informed consent form.
- Stated willingness to comply with all study procedures and availability for the duration of the study.
- Adult (> age 18) inpatients in the SCI care units with neurogenic bladders or outpatients in the SCI care clinics.
- ASB with E. coli present in a quantity of ≥ 104 CFU/mL).
- Require an indwelling (transurethral or suprapubic) or intermittent catheterization for bladder drainage.
- Women of childbearing potential and men with female partners of childbearing potential must use two forms of effective contraception during the study and for two weeks afterwards.
- Participant will be hospitalized during the 7 days of treatment or will be willing to come into clinic to receive the first dose of IP and training (of participant and/or caregiver) on how to instill the IP into the bladder.
Exclusion Criteria:
- Unable to provide informed consent for themselves.
- Received a new antibiotic expected to kill the Gram-negative organisms in the urine between initial enrollment urine culture and the time of randomization.
- History of neutropenia, defined by ANC < 1000 per µL within 6 months prior to screening.
- History of organ transplantation.
- Presence of a surgically-modified bladder, except for a repaired ruptured bladder.
- HIV with a CD4 count < 200 cells per µL.
- Unstable vital signs (e.g., fever, hypotension)
- Symptoms of active urinary tract infection defined as fever, autonomic dysreflexia, generalized increase in spasticity, bladder spasms, new sweating, increase or change in lower abdominal pain, increase in burning or pain when passing urine, increase in burning or pain during catheterization, blood in the urine, or an increased sensation of urinary urgency (MedStar Health, Urinary Symptom Questionnaires for Neurogenic Bladder [USQNB]) (Section 11.2). The presence of any one of these symptoms, unless explained by a non-urinary or non-infectious condition, will be an exclusion criterion.
- Known urinary obstruction.
- Medical devices in the urinary tract (other than urinary catheters)
- Unless deemed acceptable by the sponsor-investigator, prescription drugs, OTC medications and supplements that acidify the urine are excluded.
- Stage 4 or greater chronic kidney disease
- Pregnant or breastfeeding female
- Three or more episodes of autonomic dysreflexia in prior 30 days; defined as those patients who have a SCI and who have had a documented sudden increase in systolic blood pressure of greater than 40 mmHg due to an irritation or stimulation (including bladder or bowel irritation) below the level of the SCI. Autonomic dysreflexia can include findings of hypertensive crisis or emergency, clinically significant bradycardia/tachycardia, severe headache or other severe reaction requiring an acute intervention. The sponsor-investigator will evaluate if a history of severe autonomic dysreflexia is suspected but not clearly identified.
- In the opinion of the sponsor-investigator, medical or psychiatric illness that would interfere with participation such as active, severe, progressive, or uncontrolled hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, or neurologic disease.