Clinical trial NCT05453578: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Bacterial Disease Carrier
Cystic Fibrosis
Keywords: Bacteriophage therapy
colonized
Cystic Fibrosis
double-blind
Microbiological Activity
placebo-controlled
Pseudomonas aeruginosa
randomized
Safety
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2022-07-12
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Change from baseline in log10 P. aeruginosa total colony counts in quantitative sputum cultures
timeFrame: Day 1 through Day 30 ± 7
measure: Desirability of Outcome Ranking (DOOR)
timeFrame: Day 1 through Day 8 + 3
measure: Number of grade 2 or higher treatment-emergent Adverse Events
timeFrame: Day 1 through Day 30 ± 7
Secondary outcomes:
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona - Banner University Medical Center Tucson Campus - Tucson
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center - Westwood Clinic
state: California
city: Sacramento
country: United States
facility: University of California Davis Health
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: North Haven
country: United States
facility: Yale North Haven Medical Center- Winchester Center for Lung Disease
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida/Tampa General Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University - Adult Cystic Fibrosis Program
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: Michigan Medicine
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: New Hyde Park
country: United States
facility: Northwell Health
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
References: