A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa

National Institute of Allergy and Infectious Diseases (NIAID)73 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 exclusion criteria will not be enrolled in the study: 1. Body weight \< 30 kg. 2. Forced Expiratory Volume in 1 second (FEV1) \< 20% of predicted value at screening, using the Hankinson equations. 3. Elevated Elevated liver function tests (LFTs) obtained at screening.\* \*a. Alanine aminotransferase (ALT) \> 5 x the upper limit of normal (ULN) or aspartate transaminase (AST) \> 5 x ULN or total bilirubin \> 3 x ULN, OR b. Total bilirubin \> 1.5 x ULN combined with either ALT \> 3 x ULN or AST \> 3 x ULN. ULN reflects local laboratory ranges. 4. Acute clinical illness requiring a new (oral, parenteral), or inhaled antibiotic(s) \</= 30 days prior to the baseline visit.\* \*Does not include chronic suppressive medications or cyclic dosing medications such as inhaled antibiotics. 5. Women who are pregnant, planning to become pregnant during the study period, or breastfeeding.\* \*Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin test during screening and agree to use an effective method of contraception for the duration of the trial.\* \*A female is considered of childbearing potential unless postmenopausal, or surgically sterilized and at least 3 months has passed since sterilization procedure. 1. Female surgical sterilization procedures include tubal ligation, bilateral salpingectomy, hysterectomy, or bilateral oophorectomy. 2. Female is considered postmenopausal if she is \>45 years old and has gone at least 12 months without a spontaneous menstrual period without other known or suspected cause. 3. Effective methods of contraception include (a) abstinence, (b) partner vasectomy, (c) intrauterine devices, (d) hormonal implants (such as Implanon), or (e) other hormonal methods (birth control pills, injections, patches, vaginal rings). 6. Active treatment of any mycobacterial or fungal organisms \</=30 days prior to baseline. Chronic treatment for suppression of fungal populations is allowable. 7. Anticipated need to change chronic antibiotic regimens during the study period.\* \*Subjects on cyclic dosing medications such as inhaled antibiotics, must be able and express willingness to keep the therapies at the time of screening constant (either remain on the therapy or not remain on the therapy) for the duration of the follow-up period (approximately 30 days). Subjects on chronic suppressive antimicrobial therapy must be able and express willingness to stay on the therapies for the duration of their follow-up period. This includes chronic azithromycin therapy. 8. Known allergy to any component of the study product. 9. Any significant finding that, in the opinion of the investigator, would make it unsafe for the subject to participate in this study. 10. Enrolled in a clinical trial within \</=30 days of the baseline/dosing visit, or participating in a clinical trial while enrolled in this clinical trial (inclusive of vaccine trials). 11. Currently or previously enrolled in this trial.

Locations (19)

The University of Arizona - Banner University Medical Center Tucson Campus - Tucson

Tucson, Arizona, United States

University of California, San Diego

La Jolla, California, United States

University of California, San Diego (UCSD) - Antiviral Research Center (AVRC)

La Jolla, California, United States

University of California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, United States

University of California Davis Health

Sacramento, California, United States

Stanford University

Stanford, California, United States

Yale North Haven Medical Center- Winchester Center for Lung Disease

North Haven, Connecticut, United States

University of South Florida/Tampa General Hospital

Tampa, Florida, United States

Emory University - Adult Cystic Fibrosis Program

Atlanta, Georgia, United States

Johns Hopkins University

Baltimore, Maryland, United States

...and 9 more locations

Outcomes

Primary Outcomes

Number of Participants That Experienced Grade 2 or Higher Treatment-emergent Adverse Events in the ITT Population

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.

Time frame: Day 1 through Day 30

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

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).

Time frame: Day 1 Post-infusion, Day 2, Day 5, Day 8, and Day 30

Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit in Stage 2a and 2b

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)

Time frame: Day 1 Post-infusion, Day 2, Day 5, and Day 8

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

Time frame: Day 1 Post-infusion, Day 2, Day 5, Day 8, and Day 30

Desirability of Outcome Ranking (DOOR) Probability Calculated Using the Greatest Reduction by Day 8 Follow-up Visit, Sensitivity Analysis for Stage 2a and 2b

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.

Time frame: Day 1 Post-infusion, Day 2, Day 5, and Day 8

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

Time frame: Baseline through Day 8

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

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).

Time frame: Baseline through Day 8

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

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).

Time frame: Baseline through Day 8

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

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).

Time frame: Baseline through Day 8

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

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.

Time frame: Baseline through Day 8

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

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.

Time frame: Baseline through Day 8

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

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.

Time frame: Baseline through Day 8

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

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.

Time frame: Baseline through Day 8

A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa

Overview

Conditions

Interventions

Eligibility

Locations (19)

Outcomes

Primary Outcomes