IV Bacteriophage Therapy for Cystic Fibrosis

Recruiting at 45 trial locations

Overseen By Pranita Tamma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Antibiotics, Antifungals

Disqualifiers: Low weight, Liver issues, Pregnancy, others

Compensation: Varies

Number of Visits: 6

Duration: 1 day

72 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications. However, you must keep your chronic antibiotic regimens constant during the study, meaning you should not change them unless necessary. If you are on chronic suppressive therapy, you must continue it throughout the trial.

What data supports the effectiveness of the treatment WRAIR-PAM-CF1 for cystic fibrosis?

Research shows that bacteriophage therapy, which is part of the WRAIR-PAM-CF1 treatment, has been successfully used to treat infections in cystic fibrosis patients, particularly those caused by drug-resistant Pseudomonas aeruginosa. Studies in animal models and some human cases suggest that phage therapy can reduce bacterial infections and inflammation, offering a promising alternative or addition to antibiotics. ^{1 2 3 4 5}

Is bacteriophage therapy safe for humans, particularly for those with cystic fibrosis?

Research suggests that bacteriophage therapy is generally safe and well-tolerated in humans, including children with cystic fibrosis, when used to treat infections like Pseudomonas aeruginosa. However, more extensive studies are needed to confirm its safety and effectiveness. ^{1 3 6 7 8}

How is the treatment WRAIR-PAM-CF1 different from other treatments for cystic fibrosis?

WRAIR-PAM-CF1 is unique because it uses bacteriophage therapy, which involves viruses that specifically target and destroy bacteria, to treat infections in cystic fibrosis patients. This approach is different from traditional antibiotics and is particularly useful against antibiotic-resistant bacteria like Pseudomonas aeruginosa. ^{1 2 3 5 9}

Eligibility Criteria

Adults over 18 with Cystic Fibrosis who have had a Pseudomonas aeruginosa infection in the last year, can produce sputum for testing, and are clinically stable. They must not be on new antibiotics or enrolled in other trials within the past month, weigh at least 30 kg, and have reasonable lung function. Pregnant or breastfeeding women and those with severe liver issues or allergies to trial components cannot participate.

Inclusion Criteria

I am 18 years old or older.

I have been diagnosed with cystic fibrosis based on symptoms and either a sweat test or genetic test.

I am willing and able to follow all study requirements.

Exclusion Criteria

I am not pregnant, planning to become pregnant, or breastfeeding, and agree to use birth control during the trial.

I haven't taken new antibiotics in the last 30 days, except for ongoing treatments.

I have not been treated for fungal or mycobacterial infections in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of intravenous bacteriophage therapy or placebo

1 day

1 visit (in-person)

Observation

Participants are observed for 30 plus or minus 7 days for safety and microbiological activity

4-5 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

5 visits (in-person)

Treatment Details

Interventions

• Placebo
• WRAIR-PAM-CF1

Trial Overview The study is examining WRAIR-PAM-CF1 bacteriophage therapy's safety and effectiveness against Pseudomonas aeruginosa in CF patients. Participants will receive one of three doses of this IV treatment or a placebo during different stages to determine the best dose based on safety and microbiological activity.

Participant Groups

Group I: Stage 2b Arm 2 Active Control 1 Intervention

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 II: Stage 1/2a Arm 3 Active Control 1 Intervention

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 III: Stage 1/2a Arm 2 Active Control 1 Intervention

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 IV: Stage 1/2a Arm 4 Active Control 1 Intervention

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 V: Stage 2a Arm 1 Placebo Group 1 Intervention

25 mL of 0.9 percent Sodium Chloride saline solution administered intravenously for 30 mins as a single dosage. N=8

Group VI: Stage 2b Arm 1 Placebo Group 1 Intervention

25 mL of 0.9 percent Sodium Chloride saline solution administered intravenously for 30 mins as a single dosage. N=17

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

A 26-year-old cystic fibrosis patient with multidrug resistant Pseudomonas aeruginosa pneumonia was successfully treated with intravenous bacteriophage therapy alongside antibiotics, leading to clinical resolution of her infection without adverse events.

Following the bacteriophage therapy, the patient did not experience a recurrence of pneumonia or cystic fibrosis exacerbation for 100 days and later underwent a successful lung transplantation, suggesting that bacteriophage therapy could be a promising option for treating resistant infections in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient. Law, N., Logan, C., Yung, G., et al.[2020]

Bacteriophage therapy shows promise as a potential treatment for multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis patients, as lytic phages can degrade biofilm matrices, but their effectiveness and safety in vivo remain uncertain.

Future clinical research should focus on well-characterized phage cocktails, potentially combined with antibiotics, and tested in both laboratory and animal models to establish reliable treatment protocols for cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges and Promises for Planning Future Clinical Research Into Bacteriophage Therapy Against Pseudomonas aeruginosa in Cystic Fibrosis. An Argumentative Review. Rossitto, M., Fiscarelli, EV., Rosati, P.[2023]

This trial aims to evaluate the safety and tolerability of bacteriophage therapy in children with cystic fibrosis (CF) who are infected with Pseudomonas aeruginosa, involving up to 10 participants over a maximum of 36 months.

Bacteriophages will be administered via endo-bronchial delivery and nebulization, alongside standard CF treatments, with safety monitored through specific criteria such as fever and spirometry changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa. Singh, J., Fitzgerald, DA., Jaffe, A., et al.[2023]

Two cystic fibrosis patients with pan-drug-resistant Pseudomonas aeruginosa were successfully treated using bacteriophages, a novel therapeutic strategy that could offer new hope for difficult-to-treat infections.

The cases emphasize the urgent need for further research and pediatric clinical trials to explore the efficacy and safety of bacteriophage therapy in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis. Hahn, A., Sami, I., Chaney, H., et al.[2023]

Phage therapy significantly reduced lethality, bacterial burden, and inflammation in a cystic fibrosis zebrafish model infected with Pseudomonas aeruginosa, marking the first successful use of this treatment in a CF animal model.

Combining phage therapy with antibiotics enhanced the treatment's effectiveness, suggesting a promising strategy to lower antibiotic doses and treatment duration for P. aeruginosa infections in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model. Cafora, M., Deflorian, G., Forti, F., et al.[2023]

Bacteriophage therapy has shown promise in reducing bacterial load in cystic fibrosis patients infected with Pseudomonas aeruginosa, with some cases reporting improvements in biofilm reduction and resistance profiles.

While complete eradication of Pseudomonas aeruginosa was rare, the treatment demonstrated potential benefits, indicating that further large-scale trials are necessary to confirm its safety and efficacy for broader use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review on the use of bacteriophage in treating Staphylococcus aureus and Pseudomonas aeruginosa infections in cystic fibrosis. Singh, J., Yeoh, E., Fitzgerald, DA., et al.[2023]

In a Phase I/II clinical trial involving 24 patients with chronic otitis caused by antibiotic-resistant Pseudomonas aeruginosa, the bacteriophage preparation Biophage-PA demonstrated significant efficacy in reducing bacterial counts and improving clinical indicators compared to a placebo.

No adverse events related to the treatment were reported, indicating that Biophage-PA is a safe option for treating chronic otitis infections resistant to conventional antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Wright, A., Hawkins, CH., Anggård, EE., et al.[2022]

In a review of adverse events (AEs) among 433 children with cystic fibrosis participating in clinical trials, a total of 8,266 AEs were reported, averaging 18.1 AEs per person per year, with respiratory AEs being the most common.

Cough was the most frequently reported respiratory AE, affecting 61% of participants, and the study found that AE rates were higher in the Spring, Fall, and Winter compared to Summer, indicating that seasonal factors may influence the frequency of AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates of adverse and serious adverse events in children with cystic fibrosis. Pittman, JE., Khan, U., Laguna, TA., et al.[2022]

Phage therapy shows promise for treating antibiotic-resistant Pseudomonas aeruginosa infections in children with cystic fibrosis, emphasizing the need for continuous treatment due to the emergence of resistant bacteria.

A modular approach using both single and mixed phage preparations can enhance the effectiveness of treatment by rapidly adapting to the lytic activity of phages, potentially overcoming challenges posed by phage-resistant bacterial strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modular Approach to Select Bacteriophages Targeting Pseudomonas aeruginosa for Their Application to Children Suffering With Cystic Fibrosis. Krylov, V., Shaburova, O., Pleteneva, E., et al.[2020]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Challenges and Promises for Planning Future Clinical Research Into Bacteriophage Therapy Against Pseudomonas aeruginosa in Cystic Fibrosis. An Argumentative Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Single-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Bacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A systematic review on the use of bacteriophage in treating Staphylococcus aureus and Pseudomonas aeruginosa infections in cystic fibrosis. [2023]

7. England pubmed.ncbi.nlm.nih.gov

A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Rates of adverse and serious adverse events in children with cystic fibrosis. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Modular Approach to Select Bacteriophages Targeting Pseudomonas aeruginosa for Their Application to Children Suffering With Cystic Fibrosis. [2020]