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

NCT ID: NCT05453578

Last Updated: 2025-12-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 72 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-03
• Study Completion Date: 2025-04-10

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.

Conditions

Bacterial Disease Carrier; Cystic Fibrosis

Keywords

Bacteriophage therapy; colonized; Cystic Fibrosis; double-blind; Microbiological Activity; placebo-controlled; Pseudomonas aeruginosa; randomized; Safety

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

WRAIR-PAM-CF1

Intervention Type: BIOLOGICAL

Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.

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

Group Type: ACTIVE_COMPARATOR

WRAIR-PAM-CF1

Intervention Type: BIOLOGICAL

Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.

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

Group Type: ACTIVE_COMPARATOR

WRAIR-PAM-CF1

Intervention Type: BIOLOGICAL

Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

0.9 percent sodium chloride

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

0.9 percent sodium chloride

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

Group Type: ACTIVE_COMPARATOR

WRAIR-PAM-CF1

Intervention Type: BIOLOGICAL

Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.

Interventions

Placebo

0.9 percent sodium chloride

Intervention Type: OTHER

WRAIR-PAM-CF1

Bacteriophage combination composed of the following phages: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

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

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

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

Michigan Medicine

Ann Arbor, Michigan, United States

University of Minnesota Medical Center

Minneapolis, Minnesota, United States

Northwell Health

New Hyde Park, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Case Western Reserve University

Cleveland, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Countries

United States

References

Tamma PD, Souli M, Billard M, Campbell J, Conrad D, Ellison DW, Evans B, Evans SR, Greenwood-Quaintance KE, Filippov AA, Geres HS, Hamasaki T, Komarow L, Nikolich MP, Lodise TP, Nayak SU, Norice-Tra C, Patel R, Pride D, Russell J, Van Tyne D, Chambers HF, FowlerJr VG, Schooley RT; Antibacterial Resistance Leadership Group. Safety and microbiological activity of phage therapy in persons with cystic fibrosis colonized with Pseudomonas aeruginosa: study protocol for a phase 1b/2, multicenter, randomized, double-blind, placebo-controlled trial. Trials. 2022 Dec 28;23(1):1057. doi: 10.1186/s13063-022-07047-5.

Reference Type: DERIVED

PMID: 36578069 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

20-0001

Identifier Type: -

Identifier Source: org_study_id

2UM1AI104681-08

Identifier Type: NIH

Identifier Source: secondary_id

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