Study Design:
This is a single-center, placebo controlled, double blinded Phase 1b/2a study to assess
the safety, tolerability and potential efficacy of orally administered SYN-004 in adult
allo-HCT recipients. Participants will be randomized 2:1 to SYN-004 or placebo in blocks
of three, stratified in three cohorts based on study assigned antibiotic (MER,
piperacillin/tazobactam [PIP/TAZO], FEP) to be administered if the treating clinicians
determine initiation of broad-spectrum antibiotics is indicated. As such, there will be
six groups based on antibiotic cohort and randomized assignment of study drug:
Group 1: Placebo + IV MER (n=4) (MER control). Group 2: SYN-004 + IV MER (n=8) (MER
treatment). Group 3: Placebo + IV PIP/TAZO (n=4) (PIP/TAZO control). Group 4: SYN-004 +
IV PIP/TAZO (n=8) (PIP/TAZO treatment). Group 5: Placebo + IV FEP (n=4) (FEP control).
Group 6: SYN-004 + IV FEP (n=8) (FEP treatment). Study-assigned antibiotics will be dosed
as follows (adjusted for renal function as needed): MER 1 gram every 8 hours, PIP/TAZO
4.5 grams every 6 hours, FEP 1 gram every 8 hours. SYN-004 treated participants (Groups
2, 4 and 6) will be compared to control participants who receive placebo (Groups 1, 3 and
5, respectively). The study will be conducted in stages, commencing with Groups 1 and 2
who will be assigned to receive MER if antibiotics are indicated. MER is the first cohort
because anti-infective efficacy of MER is not anticipated to be affected if SYN-004 is
absorbed systemically. Accrual for Groups 3 and 4 (PIP/TAZO cohort) will begin only after
review of the data from Groups 1 and 2 by the Data and Safety Monitoring Committee (DSMC)
and agreement to proceed. PIP/TAZO is the next cohort because TAZO is a beta-lactamase
inhibitor. As such, in the unlikely event of SYN-004 systemic absorption, TAZO systemic
concentrations should be sufficient to inhibit any absorbed SYN-004. Accrual for the FEP
cohort will begin after approval by the DSMC's review of results from groups 3 and 4.
Patients planned to receive an allo-HCT will be eligible for enrollment in the study and
can be enrolled anytime from when it is known they will undergo HCT until day +1 after
HCT (day of study drug start). Written informed consent will be obtained by all patients.
To count towards the enrollment goal of 36 participants, a study participant must receive
at least 80% of scheduled study drug doses from initiation of study assigned antibiotics
through the second antibiotic pharmacokinetic assessment (7-9 days of concomitant study
drug and study assigned antibiotic). Additional participants will be enrolled to replace
participants who do not meet criteria to count towards the goal study enrollment until
the goal enrollment is achieved.
This Phase 1b/2a study will use the SYN-004 dosing regimen (150 mg, PO, q6h) used in
previous Phase 1 and Phase 2 clinical trials in healthy volunteers and patents with
LRTIs. The first dose of study drug will be administered at day +1 after HCT and will be
continued until Criteria for Discontinuation of Study Drug are met.
The study will consist of two periods: the Treatment Period and the Follow-up Period.
1. The Treatment Period will be defined as the time from first dose of study drug until
the last dose. For participants who do not meet criteria for early discontinuation,
study drug will be continued for 72 hours after last dose of MER, PIP/TAZO, or FEP.
2. The Follow-up Period begins after cessation of study drug dosing and is split into
three parts:
- Part A: up to 30 days after study drug was discontinued
- Part B: from end of Part A to day +180 after HCT
- Part C: from end of Part B to day +365 after HCT Patients enrolled in the study
will receive conditioning and HCT according to their treatment plan. Fever and
time of antibiotic start will be defined per local standard of care of
patients. Cessation of antibiotic therapy and/or changes to antibiotic therapy
will be at the discretion of the treating physician.
All participants will be evaluated as outlined in the Schedule of Assessments. At
predetermined points during the study as outlined in the SOA, blood samples, urine
samples, fecal swabs, and fecal samples will be collected for the indicated analyses.
