RESTORE-IMI 1 Trial Compares IMI/REL and IMI+CST in Patients with Bacterial Infections

Keith Kaye, MD, presented the analysis of the RESTORE-IMI 1 phase 3 trial which evaluated imipenem/cilastatin/relebactam versus imipenem/cilastatin plus colistin.

Carbapenem-resistant Enterobacteriaceae (CRE) infections are most commonly found in health care settings among patients who are receiving treatment for other conditions. As CRE infections continue to become resistant to antibiotics, new data is needed to find options to treat affected patients.

In a Poster Abstract Session at ID Week 2018 in San Francisco, California, Keith Kaye, MD, professor of medicine at the University of Michigan Medical School, presented data on the RESTORE-IMI study which evaluated relebactam, a beta-lactamase inhibitor, which is a potential treatment option for treating carbapenem-resistant infections when used in combination with imipenem/cilastatin.

Conducting clinical trials to explore new agents for carbapenem-resistant infections are a critical avenue of research but are often challenging to conduct due to the difficulty in meeting requirements of finding study sites that have patients with resistant pathogens and the research capabilities to conduct such studies.

In an exclusive interview with Contagion®, Dr. Kaye discussed the challenges of conducting studies in patients with resistant pathogens (see video).

“The types of patients who develop infections with carbapenem-resistant organisms tend to be much sicker with a greater, both acute and chronic severity of illness and can be more complicated to enroll in clinical trials,” Dr. Kaye, a Contagion® Editorial Advisory member, stressed.

RESTORE-IMI 1 was a phase 3, randomized, active-comparator, controlled, double-blind study in which investigators set out to evaluate the efficacy and safety of imipenem/cilastatin/relebactam (IMI/REL) compared with imipenem/cilastatin plus colistin (IMI+CST) in patients enrolled at multiple sites.

Participants included were adults 18 and older with hospital-acquired bacterial pneumonia (HABP) ventilator associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI).

Dr. Kaye and him team compared a “supplemental analysis population based on local microbiology data (SmMITT eligibility) with the primary analysis population (mMITT) from the RESTORE-IMI 1 trial (of IMI/REL vs IMI+CST.”

Patients were eligible for inclusion in the microbiologically modified intent-to-treat (mMITT) group if pathogens were imipenem-nonsusceptible, but CST- and IMI/REL-susceptible, based on central lab minimum inhibitory concentration (MIC).

The supplemental microbiologically modified intent-to-treat (SmMITT) group was comprised of patients in the mMITT plus all patients who met inclusion criteria only based on local lab MIC.

In the study, the participants were randomized 2:1 to receive either IMI/REL (500 mg/250 mg) every 6 hours or CST loading dose of 300 mg colistin base activity, followed 12 hours later by a CST maintenance dose (150 mg) every 12 hours plus IMI (500 mg) every 6 hours. The minimum duration of IV study therapy was 5 days (cIAI, cUTI) or 7 days (HABP/VABP) with a maximum duration of 21 days.

In the SmMITT population, 41 participants were included, 28 received IMI/REL and 13 received IMI+ CST. The group was comprised of 31 patients from the mMITT group plus 10 participants included based on local MIC. Twelve of the participants had HABP/VABP, 8 had cIAI, and 21 had cUTI.

Dr. Kaye spoke with Contagion® and described important aspects of the study that the investigators analyzed as well as the clinical implications (see video).

Primary outcomes of the trial were mortality, overall clinical cure, or improvement and safety outcomes, including incidence of acute kidney injury and allergic and adverse reactions.

Overall response in the mMITT was 71.4% in the IMI/REL group compared with 90.0% in the CST+IMI group. In the SmMITT group, overall response was 75.0% in the IMI/REL group compared with 76.9% in the CST+IMI group.

At day 28, clinical response in the mMITT group was 71.4% in the IMI/REL group vs 40% in the CST+ IMI group. In the SmMITT group, clinical response at day 28 was 75% in the IMI/REL group vs 53% in the CST+ IMI group.

All-cause mortality at day 28 in the mMITT group consisted of 9.5% in the IMI/REL group compared to 30.0% in the CST+IMI group. In the SmMITT group, all-cause mortality was reported as 10.7% in the IMI/REL group compared to 23.1% in the CST+IMI group.

“For overall outcomes for the various types of infections, it was noninferior compared to IMI+ CST, but overall in terms of the clinical and timely improvement, in terms of signs and symptoms of infection, results really favored IMI/REL,” Dr. Kaye explained.

In the abstract, the authors write “baseline characteristics, including infecting pathogens, were comparable in SmMITT and mMITT (SmMITT: 68% male; 46% ≥65 y; 24% APACHE II score >15; 22% creatinine clearance <60 mL/min).”

The investigators determined that rate of efficacy outcomes was comparable between the SmMITT and mMITT populations with the exception of cIAI in the SmMITT population which had higher response rates.

“One of the major findings, as well, is IMI/REL had a significant advantage over (IMI+CST) in regard to toxicity, particularly acute kidney injury,” Dr. Kaye explained, “Colistin is notorious for its nephrotoxic effects and IMI/REL performed much better than IMI+CST in regards to nephrotoxicity.”

The authors conclude that the results were consistent across the 2 analysis populations. Furthermore, in the abstract, they write that the analysis provides results supportive of the expected use of IMI/REL in the future based on local lab result influenced treatment decisions.