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

• ClinicalTrials.gov Identifier: NCT05453578
• Recruitment Status: Recruiting
• First Posted: July 12, 2022
• Last Update Posted: March 17, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: July 7, 2022
• First Posted Date: July 12, 2022
• Last Update Posted Date: March 17, 2023
• Actual Study Start Date: October 3, 2022
• Estimated Primary Completion Date: February 28, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 10, 2022)

• Change from baseline in log10 P. aeruginosa total colony counts in quantitative sputum cultures [ Time Frame: Day 1 through Day 30 ± 7 ]
• Desirability of Outcome Ranking (DOOR) [ Time Frame: Day 1 through Day 8 ± 1 ]
  Rank 1 (more desirable): No serious adverse events (SAE) (related to study product) and > 2 log10 reduction in P. aeruginosa colony forming units (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 (less desirable): SAE (related to study product)
• Number of grade 2 or higher treatment-emergent Adverse Events [ Time Frame: Day 1 through Day 30 ± 7 ]

Original Primary Outcome Measures (submitted: July 7, 2022)

• Change from baseline in log10 P. aeruginosa total colony counts in quantitative sputum cultures [ Time Frame: Day 1 through Day 30 ]
• Desirability of Outcome Ranking (DOOR) [ Time Frame: Day 1 through Day 8 ]
  Rank 1 (more desirable): No serious adverse events (SAE) (related to study product) and > 2 log10 reduction in P. aeruginosa colony forming units (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 (less desirable): SAE (related to study product)
• Number of grade 2 or higher treatment-emergent Adverse Events [ Time Frame: Day 1 through Day 30 ± 7 ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa
• Official Title: A Phase 1b/2, Multi-Centered, Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Microbiological Activity of a Single Dose of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa
• 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 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 ± 7 days observation period. If no 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 7 on Day 30 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 WRAIR_PAM-CF1, directed at 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 ± 7 days observation period. If no 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 7 on Day 30 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Bacterial Disease Carrier
• Cystic Fibrosis

Intervention

• Other: Placebo
  0.9 percent sodium chloride
• Biological: WRAIR_PAM-CF1
  Bacteriophage combination composed of the following four bacteriophages: WRAIR_EPa11, WRAIR_EPa39, WRAIR_EPa83 and WRAIR_EPa87

Study Arms

• Active Comparator: Stage 1/2a Arm 2
  4x10^7 plaque forming units (PFU) of WRAIR_PAM-CF1 administered intravenously with approximately 25 mL of 0.9 percent Sodium Chloride saline solution for 30 mins as a single dosage. Stage 1: N=2 (sentinel subjects); Stage 2a: N=8
  Intervention: Biological: WRAIR_PAM-CF1
• Active Comparator: Stage 1/2a Arm 3
  4x10^8 plaque forming units (PFU) of WRAIR_PAM-CF1 administered intravenously with approximately 25 mL of 0.9 percent Sodium Chloride saline solution for 30 mins as a single dosage. Stage 1: N=2 (sentinel subjects); Stage 2a: N=8
  Intervention: Biological: WRAIR_PAM-CF1
• Active Comparator: Stage 1/2a Arm 4
  4x10^9 plaque forming units (PFU) of WRAIR_PAM-CF1 administered intravenously with approximately 25 mL of 0.9 percent Sodium Chloride saline solution for 30 mins as a single dosage. Stage 1: N=2 (sentinel subjects); Stage 2a: N=8
  Intervention: Biological: WRAIR_PAM-CF1
• Placebo Comparator: Stage 2a Arm 1
  25 mL of 0.9 percent Sodium Chloride saline solution administered intravenously for 30 mins as a single dosage. N=8
  Intervention: Other: Placebo
• Placebo Comparator: Stage 2b Arm 1
  25 mL of 0.9 percent Sodium Chloride saline solution administered intravenously for 30 mins as a single dosage. N=17
  Intervention: Other: Placebo
• Active Comparator: Stage 2b Arm 2
  WRAIR_PAM-CF1 concentration determined after post stage 2a analysis, administered intravenously with 25 mL of 0.9 percent Sodium Chloride saline solution for 30 mins as a single dosage. N=17
  Intervention: Biological: WRAIR_PAM-CF1

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 7, 2022): 72
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 28, 2024
• Estimated Primary Completion Date: February 28, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 CF diagnosis based on a compatible clinical syndrome confirmed by either an abnormal sweat chloride testing or two 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 should be used for all sputum collections for a given subject.

4. P. 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 1 second < 20% of predicted value at screening, using the Hankinson equations.

3. Elevated 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Robert Turner Schooley; 18582462693; rschooley@ucsd.edu

Contact: Pranita Tamma; 4106141492; ptamma1@jhmi.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05453578
• Other Study ID Numbers: 20-0001; 5UM1AI104681-11 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: November 4, 2022