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

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ClinicalTrials.gov Identifier: NCT05453578
Recruitment Status : Recruiting
First Posted : July 12, 2022
Last Update Posted : February 3, 2023
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE July 7, 2022
First Posted Date  ICMJE July 12, 2022
Last Update Posted Date February 3, 2023
Actual Study Start Date  ICMJE October 3, 2022
Estimated Primary Completion Date February 28, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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 ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Bacterial Disease Carrier
  • Cystic Fibrosis
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2022)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2024
Estimated Primary Completion Date February 28, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Robert Turner Schooley 18582462693 rschooley@ucsd.edu
Contact: Pranita Tamma 4106141492 ptamma1@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05453578
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Current Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date November 4, 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP