Explanation for the choice of comparators {6b}
This trial will compare the safety and microbiological activity of phages versus placebo in clinically stable CF volunteers with chronic P. aeruginosa airway colonization. Phage therapy is not currently approved as an anti-infective for use in humans by the US Food and Drug Administration (FDA). As such, most humans who have received phages as anti-infectives have received them in conjunction with, rather than in place of, antibiotic therapy [6]. This complicates the assessment of the independent role of phages on reducing bacterial colony counts in humans. Additionally, notable proportions of patients who have previously received phage therapy had comorbidities, clinical instability, and/or simultaneously received several other medications, rendering our understanding of the adverse event (AE) profile attributable to phage therapy incomplete [7]. An understanding of the independent microbiological activity and safety profile of phages is essential to furthering the science of phage therapy for human infections.
Intervention description {11a}
The product used in this study is WRAIR-PAM-CF1. WRAIR-PAM-CF1 is a cocktail of four phages in a 1:1:1:1 combination: PaWRA01Phi11, PaWRA01Phi39, PaWRA02Phi83, and PaWRA02Phi87 (formerly WRAIR_EPa11, WRAIR_EPa39, WRAIR_EPa83, WRAIR_EPa87), all of which are lytic against P. aeruginosa. These phages are naturally occurring and free of known deleterious genes, including genes essential for lysogeny (i.e., they cannot incorporate into the chromosome of the bacterial host), antibiotic resistance genes, and toxin genes. Each phage lot has been manufactured by Adaptive Phage Therapeutics (APT) in accordance with current Good Manufacturing Practices. Endotoxin levels in the phage lots are below acceptable limits set by the FDA (5 endotoxin units/kg/h). The phage mixture is administered as a total of 4 × 107 PFU, 4 × 108 PFU, or 4 × 109 PFU, depending on the target dose. The final phage combination to be administered to a trial participant is diluted to the target dose in normal saline. The minimum and maximum phage doses that are being investigated were informed by previous case reports, case series, and clinical trials, which generally used IV doses ranging from approximately 107 PFU to 1010 PFU per dose [6, 7]. All phage and placebo preparation will occur in an investigational pharmacy by an unblinded pharmacist and will be aliquoted for equal volume administrations to maintain the double-blind design.
Criteria for discontinuing or modifying allocated interventions {11b}
Volunteers may withdraw consent for study participation at any time without penalty. An investigator may also withdraw a volunteer from receiving the study product if it is determined that participation in the study is not in the best interest of the subject. Follow-up safety evaluations will be conducted, if the volunteer agrees.
If any of the following events occur, enrollment and dosing for all volunteers will be suspended until the event is assessed by the Data Safety and Monitoring Board (DSMB): (1) any volunteer develops an SAE related to the study product through the last study visit, (2) two or more volunteers in the study experience a grade 3 or higher AE that is related to study product and is of the same type through the last study visit, (3) any volunteer develops anaphylaxis within 24 h after receiving the study product, or (4) any volunteer reports two or more pulmonary exacerbations, from the time of study product administration through day 8. Moreover, an individual infusion will be stopped if a drug-related hypersensitivity reaction is suspected. Study withdrawal could also occur if the study or study site is terminated by the sponsor for any reason.
Strategies to improve adherence to interventions {11c}
Recruitment of volunteers will occur by site investigators who are clinicians who care for persons with CF. Although there are no prespecified strategies that have been developed to increase adherence, only volunteers willing and able to participate in all planned follow-up visits will be selected for trial inclusion.
Relevant concomitant care permitted or prohibited during the trial {11d}
Concomitant medications will be reviewed during each trial visit. If a volunteer is prescribed antibiotic therapy with activity against P. aeruginosa after receipt of the study product, the volunteer will continue in the trial and be included in an intent-to-treat analysis. Receipt of antibiotic therapy with activity against P. aeruginosa will be documented as a concomitant medication and the underlying condition for which the antibiotic was taken will be reported as an AE. Chronic medications, rescue medications, and over-the-counter medications are allowed.
Provisions for post-trial care {30}
All volunteers will be followed for 30 days. AEs will be assessed and followed from initial recognition of the AE through the end of the 30-day follow-up period. SAEs will be followed through resolution even if the duration of follow-up goes beyond the planned follow-up period.
Outcomes {12}
Three outcomes will be analyzed to investigate the primary objectives: (1) the number of grade 2 or higher treatment-emergent AEs through the day 30 visit, (2) change from baseline to day 30 log10 P. aeruginosa total colony counts in sputum cultures after administration of study product, and (3) desirability of outcome ranking (DOOR) using the greatest reduction by the day 8 visit. More specifically, volunteers will be placed into one of four DOOR categories (Fig. 2). The DOOR will be analyzed by estimating the probability of a randomly selected subject having a better DOOR if assigned to receive phage therapy compared to placebo.
Several exploratory endpoints will also be investigated: (1) sputum and serum pharmacokinetics of phage therapy, (2) impact on FEV1 from the administration of study product through day 30, (3) the proportion of P. aeruginosa isolates susceptible to the four individual phages and the phage mixture before and after exposure to study product, and (4) changes in QoL of participants based on responses documented in the Cystic Fibrosis Questionnaire-Revised and the Cystic Fibrosis Respiratory Symptom Diary before and after exposure to the study product.
Participant timeline {13}
The participant timeline is illustrated in Fig. 3.
Sample size {14}
The sample size was calculated to provide desired precision of the estimate of the DOOR probability in order to describe the benefit-to-risk profile of a single dose of IV phage. If the DOOR probability comparing IV phage and placebo is 70%, when the total sample size in each arm is 20 (combining volunteers from stages 2a and 2b), the two-sided normal approximate 95% confidence interval for DOOR probability is calculated at 51% and 89%, respectively, with the lower limit larger than 50%. Superiority will be considered to have been achieved if the 95% confidence interval for the probability does not cross 50%.
Based on the interim analysis after stage 2a, the planned sample size for stage 2b will be re-evaluated as to whether it provides the desired precision of estimates of the DOOR probability for a selected phage dose and placebo. The total estimated sample size for the trial is 72 participants. In the intention-to-treat population, it is estimated that there will be up to 25 volunteers in the phage arm (for the final selected dose) and 25 volunteers in the placebo arm.
Recruitment {15}
CF volunteers will be recruited from up to 20 outpatient clinics in the USA. There will be no enrollment from international sites. It is anticipated that approximately three patients will be enrolled per month. The anticipated enrollment period is from October 3, 2022, until January 31, 2024.