Bacterial Disease Carrier, Cystic Fibrosis
Conditions
Keywords
Bacteriophage therapy, colonized, Cystic Fibrosis, double-blind, Microbiological Activity, placebo-controlled, Pseudomonas aeruginosa, randomized, Safety
Brief summary
This is a phase 1b/2 study of a single dose of intravenous (IV) bacteriophage in males and non-pregnant females, at least 18 years old, diagnosed with Cystic Fibrosis (CF). This clinical trial is designed to assess the safety and microbiological activity of bacteriophage product Walter Reed Army Institute of Research- PAM-Cystic Fibrosis1 (WRAIR-PAM-CF1), directed at Pseudomonas aeruginosa in clinically stable CF individuals chronically colonized with P. aeruginosa. WRAIR-PAM-CF1 is a 4 component anti-pseudomonal bacteriophage mixture containing between 4 x 10\^7 and 4 x 10\^9 Plaque Forming Units (PFU) of bacteriophage. Enrollment will occur at up to 20 clinical sites in the United States. In stage 1, two eligible subjects will be assigned to each of the three dosing arms receiving a single dosage of the IV bacteriophage therapy (4 x 10\^7 PFU, 4 x 10\^8 PFU, and 4 x 10\^9 PFU; total of 6 sentinel subjects), followed by 30 plus or minus 7 days observation period. If no Serious Adverse Events (SAEs)(related to the study product) are identified during the 96 hours after bacteriophage administration for all Sentinel Subjects in Stage 1, the study will proceed to Stage 2. In Stage 2a, 32 subjects will be enrolled into one of 4 arms (placebo IV, 4 x 10\^7 PFU, 4 x 10\^8 PFU, and 4 x 10\^9 PFU) in a 1:1:1:1 allocation. An interim analysis will be performed after all subjects have completed follow up visit 5 on Day 8+3 to select the IV bacteriophage dose with the most favorable safety and microbiological activity profile. During Stage 2b, subjects will be randomized into the bacteriophage (dose selected based on Interim Analysis following Stage 2a) or placebo arm. The final sample size is expected to be up to 72 subjects total with up to 25 subjects in the placebo arm and up to 25 subjects in the Stage 2b bacteriophage dose.
Detailed description
This is a phase 1b/2, multicenter, randomized placebo-controlled double-blind study of a single dose of intravenous (IV) bacteriophage in males and non-pregnant females, at least 18 years old, diagnosed with Cystic Fibrosis (CF). This clinical trial is designed to assess the safety and microbiological activity of bacteriophage product Walter Reed Army Institute of Research- PAM-Cystic Fibrosis1 (WRAIR-PAM-CF1), directed at Pseudomonas aeruginosa (P. aeruginosa) in clinically stable CF individuals chronically colonized with P. aeruginosa. WRAIR-PAM-CF1 is a 4 component anti-pseudomonal bacteriophage mixture containing between 4 x 10\^7 and 4 x 10\^9 Plaque Forming Units (PFU) of bacteriophage. Enrollment will occur at up to 20 clinical sites in the United States. In stage 1, two sentinel subjects will be assigned to each of the three dosing arms receiving a single dosage of the IV bacteriophage therapy (4 x 10\^7 PFU, 4 x 10\^8 PFU, and 4 x 10\^9 PFU; total of 6 sentinel subjects), followed by 30 plus or minus 7 days observation period. If no Serious Adverse Events (SAEs) (related to the study product) are identified during the 96 hours after bacteriophage administration for all Sentinel Subjects in Stage 1, the study will proceed to Stage 2. In Stage 2a, 32 subjects will be enrolled into one of 4 arms (placebo IV, 4 x 10\^7 PFU, 4 x 10\^8 PFU, and 4 x 10\^9 PFU) in a 1:1:1:1 allocation. An interim analysis will be performed after all subjects have completed follow up visit 5 on Day 8+3 to select the IV bacteriophage dose with the most favorable safety and microbiological activity profile. During Stage 2b, subjects will be randomized into the bacteriophage (dose selected based on Interim Analysis following Stage 2a) or placebo arm. The final sample size is expected to be up to 72 subjects total with up to 25 subjects in the placebo arm and up to 25 subjects in the Stage 2b bacteriophage dose. The primary objectives of this study are to 1) describe the safety of a single dose of IV bacteriophage therapy in clinically stable CF subjects with P. aeruginosa in expectorated sputum; 2) describe the microbiological activity of a single dose of IV bacteriophage therapy in clinically stable CF subjects with P. aeruginosa in expectorated sputum; 3) describe the benefit to risk profile of a single dose of IV bacteriophage therapy in clinically stable CF subjects with P. aeruginosa in expectorated sputum.
Interventions
OTHERPlacebo
0.9 percent sodium chloride
BIOLOGICALWRAIR-PAM-CF1
Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
A double-blind/masking technique will be used in Stage 2 of the study. The three intravenous (IV) bacteriophage doses and placebo will be packaged identically for administration so that treatment blind/masking is maintained. The study investigational pharmacist will remain unblinded throughout the study and will be informed of the appropriate dose for subjects according to procedures detailed in the Manual of Procedure (MOP)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must meet all the inclusion criteria to be eligible to participate in the study: 1. Adult (\>/= 18 years) at the time of screening. 2. Confirmed Cystic Fibrosis (CF) diagnosis based on a compatible clinical syndrome confirmed by either an abnormal sweat chloride testing or CFTR gene variations.\* \*Can be obtained from documentation in medical records; actual test results not necessary. 3. Likely able to produce at least 2 mL of sputum during a 30-minute sputum collection following a hypertonic saline treatment or other approach to increase sputum production.\*\* \*\*Determined by investigator or their designee judgement. Approaches for obtaining sputum may include, but are not limited to, inhaled hypertonic saline (e.g., 3%, 7%, or 10%), inhaled hypertonic bicarbonate, inhaled mannitol, or spontaneously expectorated sputum. The same approach is recommended, whenever possible, for all sputum collections for a given subject. 4. Pseudomonas aeruginosa (regardless of Colony Forming Units (CFU)/mL) isolated from a sputum, throat culture, or other respiratory specimen in the past 12 months. 5. Confirmed P. aeruginosa isolation from a sample of expectorated sputum at the Screening Visit. 6. Capable of providing informed consent. 7. Capable and willing to complete all study visits and perform all procedures required by the protocol.
Exclusion criteria
Subjects who meet any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced Grade 2 or Higher Treatment-emergent Adverse Events in the ITT Population | Day 1 through Day 30 | An event that occurred during the treatment period was considered a treatment-emergent AE if it was not present before the first dose of investigational product or was present before the first dose of investigational product and increased in severity during the treatment period. |
| Change From Baseline to Day 30 in log10 P. Aeruginosa Total Colony Counts in Quantitative Sputum Cultures After Administration of IV Bacteriophages/Placebo in Stage 2a and 2b | Day 1 Post-infusion, Day 2, Day 5, Day 8, and Day 30 | Mean change from baseline in log10-transformed counts of P. aeruginosa colony forming units per milliliter (CFU/mL) is presented for each time point through Day 30 as well as for each participant's minimum and maximum change from baseline. Undetectable colony counts are substituted with the limit of detection (LOD) of the assay (1 x 10\^4 CFU/mL). |
| Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit in Stage 2a and 2b | Day 1 Post-infusion, Day 2, Day 5, and Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1=No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2=No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3=No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4=SAE (related to study product). The DOOR probability is estimated by: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are substituted with the LOD of the assay (1 x 10\^4 CFU/mL) |
| Change From Baseline to Day 30 in log10 P. Aeruginosa Total Colony Counts in Quantitative Sputum Cultures After Administration of IV Bacteriophages/Placebo, Sensitivity Analysis for Stage 2a and 2b | Day 1 Post-infusion, Day 2, Day 5, Day 8, and Day 30 | Mean change from baseline in log10-transformed counts of P. aeruginosa colony forming units per milliliter (CFU/mL) is presented for each time point through Day 30 as well as for each participant's minimum and maximum change from baseline. Undetectable colony counts are treated as missing. |
| Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit, Sensitivity Analysis for Stage 2a and 2b | Day 1 Post-infusion, Day 2, Day 5, and Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1 = No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2 = No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3 = No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4 = SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are treated as missing. |
| Number of Susceptible to 4-bacteriophage Cocktail Subgroup Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1=No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2=No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3=No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4=SAE (related to study product). The DOOR probability is estimated by: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are substituted with the LOD of the assay (1 x 10\^4 CFU/mL) |
| Number of Non-susceptible to 4-bacteriophage Cocktail Subgroup Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1=No SAE (related to study product) and \>2 log10 reduction in P. aeruginosa CFU/mL. Rank 2=No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3=No SAE (related to study product) and \<1 log10 reduction in P. aeruginosa CFU/mL. Rank 4=SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are substituted with the LOD of the assay (1x10\^4 CFU/mL). |
| Number of Co-colonized With Clinically Meaningful Organism Subgroup Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1=No SAE (related to study product) and \>2 log10 reduction in P. aeruginosa CFU/mL. Rank 2=No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3=No SAE (related to study product) and \<1 log10 reduction in P. aeruginosa CFU/mL. Rank 4=SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are substituted with the LOD of the assay (1x10\^4 CFU/mL). |
| Number of Not Co-colonized With Clinically Meaningful Organism Subgroup Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1=No SAE (related to study product) and \>2 log10 reduction in P. aeruginosa CFU/mL. Rank 2=No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3=No SAE (related to study product) and \<1 log10 reduction in P. aeruginosa CFU/mL. Rank 4=SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are substituted with the LOD of the assay (1x10\^4 CFU/mL). |
| Number of Susceptible to 4-bacteriophage Cocktail Subgroup, Sensitivity Analysis Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1 = No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2 = No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3 = No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4 = SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are treated as missing. |
| Number of Non-susceptible to 4-bacteriophage Cocktail Subgroup, Sensitivity Analysis Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1 = No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2 = No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3 = No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4 = SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are treated as missing. |
| Number of Co-colonized With Clinically Meaningful Organism Subgroup, Sensitivity Analysis Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1 = No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2 = No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3 = No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4 = SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are treated as missing. |
| Number of Not Co-colonized With Clinically Meaningful Organism Subgroup, Sensitivity Analysis Participants With Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit | Baseline through Day 8 | A DOOR rank is calculated for each participant based on the following ranking from most (rank 1) to least (rank 4) desirable outcome using each participant's greatest reduction from baseline in log10 P. aeruginosa CFU/mL by Day 8: Rank 1 = No SAE (related to study product) and \> 2 log10 reduction in P. aeruginosa CFU/mL. Rank 2 = No SAE (related to study product) and 1-2 log10 reduction in P. aeruginosa CFU/mL. Rank 3 = No SAE (related to study product) and \< 1 log10 reduction in P. aeruginosa CFU/mL. Rank 4 = SAE (related to study product). The DOOR probability is estimated using: Pr\[DOOR\]= Pr\[DOORIV \> DOORP\] + 1/2Pr\[DOORIV = DOORP\] where DOORIV and DOORP are the DOOR ranks for bacteriophage (phage) and placebo arms, Pr\[DOORIV \> DOORP\] is the proportion of DOOR ranks from IV phage dose exceeding DOOR ranks from placebo, and Pr\[DOORIV = DOORP\] is the proportion of phage and placebo DOOR ranks being the same. Undetectable colony counts are treated as missing. |
Countries
United States
Participant flow
Recruitment details
The study population included male and female adults, aged 18 or higher, with a confirmed cystic fibrosis diagnosis. Participants were enrolled from 03OCT2022 to 12MAR2025.
Pre-assignment details
The sentinel stage (Stage 1) was neither randomized nor blinded, and participants were assigned to each IV bacteriophage dosage. As the Stage 1 arms were assigned their dosage, rather than randomized to it, they were not included in the Intent to Treat (ITT) population nor analyses.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 64 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 8 | 0 / 26 | 0 / 8 | 0 / 24 |
| other Total, other adverse events | 1 / 2 | 2 / 2 | 2 / 2 | 3 / 8 | 4 / 26 | 3 / 8 | 9 / 24 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 8 | 0 / 26 | 1 / 8 | 0 / 24 |
Outcome results
None listed