Urinary Tract Infections
Conditions
Keywords
UTI, Bacteriophage, Phage
Brief summary
Study LBx-1001 is a multi-center randomized, double-blind study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of LBP-EC01 in patients with indwelling urinary catheters, or requiring intermittent catheterization, and/or patients with asymptomatic bacteriuria caused by Escherichia coli (E. coli). This study population has been selected because LBP-EC01 is a phage cocktail where active bacterial host engagement is required to allow for amplification of the phage and evaluation of the safety and PK of the phage cocktail. Eligible patients will require confirmation of colonization with a urine sample taken within 10 days of randomization that cultures contain ≥10\^3 E. coli colony forming unit (CFU)/mL, without the patient having clinical signs or symptoms of an active urinary tract infection (UTI) requiring antibiotic treatment. Patients should have E. coli as the primary colonizing bacteria and must not have a secondary bacterial colonization at levels equal to or greater than that seen from E. coli.
Detailed description
Approximately 30 patients 18 years of age or older with a history of urinary tract infection or colonization caused by E. coli who have indwelling urinary catheters, or who require intermittent catheterization, and/or patients with asymptomatic bacteriuria caused by E. coli colonization (≥10\^3 CFU/mL) on microbiological diagnosis, without clinical signs or symptoms of infection requiring antibiotic treatment will be enrolled. Patients will be screened for presence of E. coli colonization (≥10\^3 CFU/mL) prior to randomization and evaluated for potential bacterial susceptibility to LBP-EC01. Secondary Objective: To evaluate the pharmacodynamics (PD) of LBP-EC01. Exploratory Objective: To explore the influence of LBP-EC01 on the urinary tract microbiota.
Interventions
DRUGLBP-EC01
crPhage cocktail: at approximately 1.5 x 10\^10 to 3.0 x 10\^10 PFU/vial dosed BID by intraurethral administration
DRUGPlacebo
Lactated Ringers Solution for Injection dosed BID by intraurethral administration
Sponsors
Locus Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double blind
Intervention model description
2:1 randomized, placebo controlled, blinded study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Males or females 18 years of age or older. 4. Patients with a lower urinary tract colonization caused by E. coli (≥10\^3 CFU/mL) and who meet at least one of the following criteria: * Has an indwelling urinary catheter and medical documentation of a urinary tract infection by E. coli within the past 12 months * Requires intermittent catheterization and medical documentation of a urinary tract infection by E. coli within the past 12 months * Has medical documentation of a history of asymptomatic bacteriuria (i.e., lower urinary tract colonization) with E. coli at least once in the past 12 months 5. Patients must have experience with urinary catheterization or have Medical Monitor approval if the patient does not have prior experience with catheterization. 6. In good general health as evidenced by medical history and physical examination. 7. Women of childbearing potential and men with female partners of childbearing potential must use two forms of effective contraception, at least 1 of which is a physical barrier method, during the study and which is recommended to continue for 2 weeks after completing the study.
Exclusion criteria
1. Patients with clinical signs of active UTI or other infection requiring antimicrobial treatment. These may include dysuria, urinary frequency, urinary urgency, suprapubic discomfort and flank pain in addition to non-specific symptoms of urinary leakage, change in voiding habits, worsening muscle spasm, increasing autonomic dysreflexia, sweating, malaise, and fever or hypothermia. Analgesic use is permitted. 2. Patients who have received Gram-negative bacteria antimicrobials within 14 days of randomization. Note: Patients who are currently only receiving antibiotics with only Gram-positive activity (e.g., vancomycin, daptomycin, linezolid) to treat active infections against Gram-positive non-UTIs can be included in the trial. 3. Presence of a surgically-modified bladder, except for a repaired ruptured bladder. 4. History of severe autonomic dysreflexia, which is defined as those patients who have a spinal cord injury and who have had a documented sudden increase in systolic blood pressure of greater than 40 mm Hg due to an irritation or stimulation (including bladder or bowel irritation) below the level of the spinal cord injury. Autonomic dysreflexia can include findings of hypertensive crisis or emergency, clinically significant bradycardia/tachycardia, severe headache or other severe reaction requiring an acute intervention, so consultation with the Medical Monitor should take place if a history of severe autonomic dysreflexia is suspected but not clearly identified. 5. Active severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, or neurologic disease per the investigator's discretion. 6. Any malignancies within the past 5 years (except those in remission). 7. Unless deemed acceptable by the Investigator, prescription drugs, over-the-counter (OTC) medications and supplements that acidify the urine are excluded. 8. Patients who have had allergic reactions to similar compounds, or any excipients. 9. Participation in an investigational drug or device study within 1 month (or 7 half-lives of drug, whichever is longer) prior to randomization. 10. Patients who are pregnant or expecting to conceive, are breast feeding or are planning to breast feed, within 1 month of completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of LBP-EC01: AUC | 28 days | Area under the concentration versus time curve from time 0 to the last measurable concentration |
| Number of Participants With Treatment-related Adverse Events as Assessed by DAIDS v2.1 | 35 days | Safety and tolerability of LBP-EC01: Number of participants with treatment-related adverse events as assessed by DAIDS v2.1 |
| Pharmacokinetics of LBP-EC01: Cmax | 28 days | Maximum concentration determined directly from the concentration-time profile |
| Pharmacokinetics of LBP-EC01: Tmax | 28 days | Time to maximum concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in IgE | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgE with a positive detection of \>100 IU/mL |
| Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through reduction in urinary E.coli burden as defined by at least 1 log CFU reduction from baseline. |
| Changes in IgM | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgM with a positive detection \>230 mg/dL (\>2.3 g/L) |
| Changes in IgG | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgG with a positive detection of \>1600 mg/dL (\>16.0 g/L) |
| Time to 1 Logarithmic Reduction in Urinary E.Coli Count From Baseline | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through time to 1 logarithmic reduction in urinary E.coli count from baseline |
| Recurrence of E.Coli Colonization or Incidence of Infection Based on Clinical Signs and Symptoms | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through recurrence of E.Coli colonization or incidence of infection based on clinical signs and symptoms |
| Changes in Immunoglobulin (Ig)A | 28 days | The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgA |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LBP-EC01 crPhage cocktail
LBP-EC01: crPhage cocktail | 24 |
| Placebo Lactated Ringer's solution, injection, USP
Lactated Ringers Solution for Injection: Placebo | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | LBP-EC01 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 16.36 | 70.5 years STANDARD_DEVIATION 14.37 | 67.9 years STANDARD_DEVIATION 15.64 |
| Baseline body mass index (kg/m^2) | 30.14 kilograms per meters squared STANDARD_DEVIATION 5.908 | 26.90 kilograms per meters squared STANDARD_DEVIATION 3.28 | 28.99 kilograms per meters squared STANDARD_DEVIATION 5.316 |
| Baseline height (cm) | 162.4 centimeters STANDARD_DEVIATION 8.94 | 164.9 centimeters STANDARD_DEVIATION 8.86 | 163.3 centimeters STANDARD_DEVIATION 8.86 |
| Baseline weight (kg) | 79.39 kilograms STANDARD_DEVIATION 16.555 | 73.04 kilograms STANDARD_DEVIATION 9.446 | 77.15 kilograms STANDARD_DEVIATION 14.616 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 6 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 4 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Frequency of prior UTI in last 1 month, n(%) 0 | 12 Participants | 10 Participants | 22 Participants |
| Frequency of prior UTI in last 1 month, n(%) 1 | 11 Participants | 2 Participants | 13 Participants |
| Frequency of prior UTI in last 1 month, n(%) > 1 | 1 Participants | 0 Participants | 1 Participants |
| Frequency of prior UTI in the last 12 months, n(%) 0 | 10 Participants | 8 Participants | 18 Participants |
| Frequency of prior UTI in the last 12 months, n(%) 1 | 12 Participants | 2 Participants | 14 Participants |
| Frequency of prior UTI in the last 12 months, n(%) > 1 | 2 Participants | 2 Participants | 4 Participants |
| Prior antibiotic use (within 30 days of Screening), n(%) No | 20 Participants | 12 Participants | 32 Participants |
| Prior antibiotic use (within 30 days of Screening), n(%) Yes | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 22 Participants | 11 Participants | 33 Participants |
| Sex: Female, Male Female | 21 Participants | 10 Participants | 31 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 12 |
| other Total, other adverse events | 18 / 24 | 6 / 12 |
| serious Total, serious adverse events | 1 / 24 | 1 / 12 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by DAIDS v2.1
Safety and tolerability of LBP-EC01: Number of participants with treatment-related adverse events as assessed by DAIDS v2.1
Time frame: 35 days
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LBP-EC01 | Number of Participants With Treatment-related Adverse Events as Assessed by DAIDS v2.1 | 0 Participants |
| Placebo | Number of Participants With Treatment-related Adverse Events as Assessed by DAIDS v2.1 | 0 Participants |
Primary
Pharmacokinetics of LBP-EC01: AUC
Area under the concentration versus time curve from time 0 to the last measurable concentration
Time frame: 28 days
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LBP-EC01 | Pharmacokinetics of LBP-EC01: AUC | 13000000 h*PFU/ mL | Geometric Coefficient of Variation 69000 |
Primary
Pharmacokinetics of LBP-EC01: Cmax
Maximum concentration determined directly from the concentration-time profile
Time frame: 28 days
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LBP-EC01 | Pharmacokinetics of LBP-EC01: Cmax | 4600000 PFU/mL | Geometric Coefficient of Variation 37000 |
Primary
Pharmacokinetics of LBP-EC01: Tmax
Time to maximum concentration
Time frame: 28 days
Population: PK Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LBP-EC01 | Pharmacokinetics of LBP-EC01: Tmax | 2.19 hours | Geometric Coefficient of Variation 127.32 |
Secondary
Changes in IgE
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgE with a positive detection of \>100 IU/mL
Time frame: 28 days
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBP-EC01 | Changes in IgE | Day 28/ET: Patients with positive detection (>ULN) | 8 participants |
| LBP-EC01 | Changes in IgE | Baseline: Patients with positive detection (>ULN) | 7 participants |
| Placebo | Changes in IgE | Day 28/ET: Patients with positive detection (>ULN) | 2 participants |
| Placebo | Changes in IgE | Baseline: Patients with positive detection (>ULN) | 3 participants |
Secondary
Changes in IgG
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgG with a positive detection of \>1600 mg/dL (\>16.0 g/L)
Time frame: 28 days
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBP-EC01 | Changes in IgG | Baseline: Patients with positive detection (>ULN) | 1 participants |
| LBP-EC01 | Changes in IgG | Day 28/ET: Patients with positive detection (>ULN) | 0 participants |
| Placebo | Changes in IgG | Baseline: Patients with positive detection (>ULN) | 0 participants |
| Placebo | Changes in IgG | Day 28/ET: Patients with positive detection (>ULN) | 1 participants |
Secondary
Changes in IgM
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgM with a positive detection \>230 mg/dL (\>2.3 g/L)
Time frame: 28 days
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBP-EC01 | Changes in IgM | Baseline: Patients with positive detection (>ULN) | 0 participants |
| LBP-EC01 | Changes in IgM | Day 28/ET: Patients with positive detection (>ULN) | 0 participants |
| Placebo | Changes in IgM | Baseline: Patients with positive detection (>ULN) | 1 participants |
| Placebo | Changes in IgM | Day 28/ET: Patients with positive detection (>ULN) | 0 participants |
Secondary
Changes in Immunoglobulin (Ig)A
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through changes in IgA
Time frame: 28 days
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBP-EC01 | Changes in Immunoglobulin (Ig)A | Baseline: (Patients with positive detection (>ULN)) | 2 participants |
| LBP-EC01 | Changes in Immunoglobulin (Ig)A | Day 28/ET: (Patients with positive detection (>ULN)) | 2 participants |
| Placebo | Changes in Immunoglobulin (Ig)A | Baseline: (Patients with positive detection (>ULN)) | 0 participants |
| Placebo | Changes in Immunoglobulin (Ig)A | Day 28/ET: (Patients with positive detection (>ULN)) | 2 participants |
Secondary
Recurrence of E.Coli Colonization or Incidence of Infection Based on Clinical Signs and Symptoms
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through recurrence of E.Coli colonization or incidence of infection based on clinical signs and symptoms
Time frame: 28 days
Population: PD Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LBP-EC01 | Recurrence of E.Coli Colonization or Incidence of Infection Based on Clinical Signs and Symptoms | 3 Participants |
| Placebo | Recurrence of E.Coli Colonization or Incidence of Infection Based on Clinical Signs and Symptoms | 0 Participants |
Secondary
Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through reduction in urinary E.coli burden as defined by at least 1 log CFU reduction from baseline.
Time frame: 28 days
Population: PD Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 2 | 11 Participants |
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 3 | 8 Participants |
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 5 | 10 Participants |
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 7 | 9 Participants |
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 14 | 8 Participants |
| LBP-EC01 | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 28/ET | 9 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 14 | 5 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 2 | 2 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 7 | 3 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 3 | 2 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 28/ET | 3 Participants |
| Placebo | Reduction in Urinary E.Coli Burden at Any of the Following Time Points: Day 2, Day 3, Day 5, Day 7 (EOT), Day 14 and Day 28 | Day 5 | 4 Participants |
Secondary
Time to 1 Logarithmic Reduction in Urinary E.Coli Count From Baseline
The secondary objective of this study was to evaluate the pharmacodynamics (PD) of LBP-EC01 through time to 1 logarithmic reduction in urinary E.coli count from baseline
Time frame: 28 days
Population: PD Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LBP-EC01 | Time to 1 Logarithmic Reduction in Urinary E.Coli Count From Baseline | 5.9 days | Standard Deviation 7.33 |
| Placebo | Time to 1 Logarithmic Reduction in Urinary E.Coli Count From Baseline | 8.4 days | Standard Deviation 5.41 |