Bacteriophage Therapy in Spinal Cord Injury Patients With Bacteriuria

Official title

A Phase 1B Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Bacteriophage Therapy in Spinal Cord Injury Patients With Bacteriuria

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.

Detailed 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.

Interventions

• Drug Phage Therapy
  A 20 mL sterile solution containing one to three individual phage drug substances (TPC) with total strength (potency) 3 x 10\^8 plaque-forming units (PFU), will be administered intravesicularly twice a day (one instillation in the morning and one in the evening \[at least six hours apart\], respectively) for 7 days. The selection of individual phages to include in the TPC are personalized/customized for each participant per phage susceptibility testing to the participant's urinary E. coli (testi
• Other Placebo
  Sterile 0.9% saline solution also 20 mL, followed with a 10 mL flush of the same solution.

Primary outcome measures

• To evaluate the safety and tolerability of phage therapy in adults ≥18 years of age with spinal cord injury (SCI) and bacteriuria with Escherichia coli (E. coli) [Time frame: 2 years]

Secondary outcome measures (2)

• To evaluate the pharmacokinetics (PK) of investigational phage therapy [Time frame: 2 years]
• To evaluate of the pharmacodynamics (PD) of investigational phage therapy [Time frame: 2 years]

Eligibility criteria

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) with a diagnosis of Spinal Cord Injury/Disease (SCI/D) and neurogenic bladder. Eligible participants may include inpatients in the SCI care unit or outpatients receiving care at participating sites, regardless of the underlying cause of SCI (e.g., trauma, tumors or demyelinating).
• 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 attend clinic visits either (a) daily for the 7 days of treatment, or (b) on Day 1 and Day 7 of dosing. On Day 1, the participant will receive in-person training on instillation of 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 \[USQNB\]). 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.

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

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• Washington University in St Louis — St Louis
• Michael E. DeBakey VA Medical Center — Houston

Publications

• Terwilliger A, Clark J, Karris M, Hernandez-Santos H, Green S, Aslam S, Maresso A. Phage Therapy Related Microbial Succession Associated with Successful Clinical Outcome for a Recurrent Urinary Tract Infection. Viruses. 2021 Oct 12;13(10):2049. doi: 10.3390/v13102049. PMID 34696479
• Green SI, Kaelber JT, Ma L, Trautner BW, Ramig RF, Maresso AW. Bacteriophages from ExPEC Reservoirs Kill Pandemic Multidrug-Resistant Strains of Clonal Group ST131 in Animal Models of Bacteremia. Sci Rep. 2017 Apr 12;7:46151. doi: 10.1038/srep46151. PMID 28401893
• Salazar KC, Ma L, Green SI, Zulk JJ, Trautner BW, Ramig RF, Clark JR, Terwilliger AL, Maresso AW. Antiviral Resistance and Phage Counter Adaptation to Antibiotic-Resistant Extraintestinal Pathogenic Escherichia coli. mBio. 2021 Apr 27;12(2):e00211-21. doi: 10.1128/mBio.00211-21. PMID 33906920
• Green SI, Clark JR, Santos HH, Weesner KE, Salazar KC, Aslam S, Campbell JW, Doernberg SB, Blodget E, Morris MI, Suh GA, Obeid K, Silveira FP, Filippov AA, Whiteson KL, Trautner BW, Terwilliger AL, Maresso A. A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes. Clin Infect Dis. 2023 Oct 13;77(8):1079-1091. PMID 37279523

Identifiers

NCT: NCT06559618 · H-54876 -202512122 · 890593

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗