Bacterial InfectionsPhase 3RESTORE-IMI 1NCT02452047

Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013)

A Phase 3 study testing Imipenem+Cilastatin/Relebactam, Colistimethate sodium (CMS) and Imipenem+Cilastatin in people with Bacterial Infections, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Bacterial Infections
What is being tested?: Imipenem+Cilastatin/Relebactam, Colistimethate sodium (CMS) and Imipenem+Cilastatin
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 50 participants
Where: No sites listed yet
Study dates: 21 Aug 2015to 18 Sep 2017
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Hospitalization that requires treatment with IV antibiotic therapy for a new, persistent or progressing bacterial infection involving at least 1 of 3 primary infection types (HABP, VABP, cIAI, or cUTI)
Positive culture data from the primary infection-site specimen collected within 1 week of study entry. At least one of the suspected causative pathogens from the specimen meets all of the following: 1) identified as a Gram-negative bacterium, 2) culture-confirmed imipenem resistance (and colistin resistance for Group 3 only), 3) culture-confirmed susceptibility to imipenem/relebactam and to colistin (for Groups 1 and 2 only)
Not of reproductive potential, or of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner by complying with one of the following: 1) practice abstinence, or 2) use of acceptable contraception during heterosexual activity

Who cannot join

Concurrent infection (endocarditis, osteomyelitis, meningitis, prosthetic joint infection, disseminated fungal infection, or active pulmonary tuberculosis) that would interfere with evaluation of the response to the study antibiotics
Received treatment with any form of systemic colistin for >24 hours within 72 hours before initiation of study drug (for Groups 1 and 2 only)
HABP or VABP caused by an obstructive process
cUTI which meets any of the following: 1) complete obstruction of any portion of the urinary tract, 2) known ileal loop, 3) intractable vesico-ureteral reflux, 4) presence of an indwelling urinary catheter which cannot be removed at study entry
History of serious allergy, hypersensitivity, or any serious reaction to listed antibiotics (per-protocol)
Female who is pregnant or is expecting to conceive (or a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed before completion of the study

Show all 9Show fewer

Anticipated treatment with any of the following during the study: valproic acid or divalproex sodium, or concomitant systemic (e.g. IV, oral or inhaled) antimicrobial agents with known Gram-negative bacterial coverage
Currently undergoing hemodialysis or peritoneal dialysis
Participated or anticipates participating in any other clinical study involving administration of investigational medication up to 30 days before screening or during the course of the trial

About this study

Official title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects With Imipenem-Resistant Bacterial Infection

The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (MK-7655A) versus colistimethate sodium+imipenem+cilastatin in the treatment of imipenem-resistant bacterial infections. Infections evaluated in the study will be hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), and complicated urinary tract infection (cUTI).

Conditions: Bacterial Infections
Being tested: Imipenem+Cilastatin/Relebactam, Colistimethate sodium (CMS), Imipenem+Cilastatin, Placebo to CMS
Medical subject headings: Bacterial Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Imipenem+Cilastatin/RelebactamDrug
Also called MK-7655A
Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours
Colistimethate sodium (CMS)Drug
Colistimethate base activity 300 mg (~720 mg CMS) IV infusion loading dose, followed by colistimethate base activity 75 mg to 150 mg (~180 to 360 mg CMS), depending on renal function, once every 12 hours
Imipenem+CilastatinDrug
Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours
Placebo to CMSDrug
Placebo to CMS IV infusion once every 12 hours

Study groups in NCT02452047
Study group	Role	What they receive
Group 1: Imipenem+Cilastatin/Relebactam	Experimental	Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration. Receives: Drug: Imipenem+Cilastatin/Relebactam; Drug: Placebo to CMS
Group 2: Colistimethate sodium + Imipenem+Cilastatin	Active comparator	Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration. Receives: Drug: Colistimethate sodium (CMS); Drug: Imipenem+Cilastatin
Group 3: Imipenem+Cilastatin/Relebactam	Experimental	Participants with documented imipenem-resistant and colistin-resistant bacterial infections may be eligible to receive open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration. Receives: Drug: Imipenem+Cilastatin/Relebactam

What is being measured

The primary outcome is the main question the study is designed to answer.

Percentage of Participants With Favorable Overall Response (FOR)
The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen [e.g., ≥10^5 CFU/mL at study entry is reduced to <10^4 CFU/mL]) at Early Follow-up (EFU).
Measured: Up to Day 30 (up to 9 days after completing study treatment)
Percentage of Participants With ≥1 Adverse Events (AEs)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With ≥1 Serious Adverse Events (SAEs)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With ≥1 Drug-Related AEs
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With ≥1 Drug-Related SAEs
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs
The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 21
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs
The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 21
Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group
The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had <4 participants and therefore no data are presented.
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With ≥1 Events of Clinical Interest (ECI)
The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Measured: Up to Day 35 (up to 14 days after completing study treatment)

Secondary outcomes (9)

Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity
Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (<1.2 mg/dL) was defined as "doubling of serum creatinine to >1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)".
Measured: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With Favorable Clinical Response (FCR) at Day 28
The percentage of participants with FCR at Day 28 was determined for Groups 1 and 2. FCR at Day 28 was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
Measured: Day 28
Percentage of Participants With All-cause Mortality Up to Day 28
The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.
Measured: Up to Day 28
Percentage of Participants With FCR on Therapy (OTX)
The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
Measured: OTX (Day 3)
Percentage of Participants With FCR at End of Therapy (EOT)
The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
Measured: At EOT (up to Day 21)
Percentage of Participants With FCR at EFU
The percentage of participants with FCR at EFU was determined for Groups 1 and 2. FCR at EFU was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
Measured: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX
The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10^5 colony forming units [CFU]/mL at baseline was reduced to <10^4 CFU/mL at OTX) of the uropathogen".
Measured: OTX (Day 3)
Percentage of cUTI Participants With FMR at EOT
The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10^5 CFU/mL at baseline was reduced to <10^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EOT) of the uropathogen".
Measured: At EOT (up to Day 21)
Percentage of cUTI Participants With FMR at EFU
The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EFU) of the uropathogen".
Measured: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

21 Aug 201518 Sep 2017

First posted22 May 2015 (estimated)
Study start21 Aug 2015
Primary completion18 Sep 2017
Study completion18 Sep 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Bacterial InfectionsStudies of the same condition, open and under way.
More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 50 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02452047
Sponsor's protocol ID: 7655A-013
Other IDs: 2015-000066-62, 163367, 2015
Acronym: RESTORE-IMI 1
Status last verified: Oct 2018
First submitted: 20 May 2015
Last updated: 19 Oct 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Publications

Brown ML, Motsch J, Kaye KS, File TM, Boucher HW, Vendetti N, Aggrey A, Joeng HK, Tipping RW, Du J, DePestel DD, Butterton JR, Paschke A. Evaluation of Renal Safety Between Imipenem/Relebactam and Colistin Plus Imipenem in Patients With Imipenem-Nonsusceptible Bacterial Infections in the Randomized, Phase 3 RESTORE-IMI 1 Study. Open Forum Infect Dis. 2020 Feb 19;7(3):ofaa054. doi: 10.1093/ofid/ofaa054. eCollection 2020 Mar.
PubMed 32154325
Kaye KS, Boucher HW, Brown ML, Aggrey A, Khan I, Joeng HK, Tipping RW, Du J, Young K, Butterton JR, Paschke A. Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02203-19. doi: 10.1128/AAC.02203-19. Print 2020 Apr 21.
PubMed 32094127
Motsch J, Murta de Oliveira C, Stus V, Koksal I, Lyulko O, Boucher HW, Kaye KS, File TM, Brown ML, Khan I, Du J, Joeng HK, Tipping RW, Aggrey A, Young K, Kartsonis NA, Butterton JR, Paschke A. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020 Apr 15;70(9):1799-1808. doi: 10.1093/cid/ciz530.
PubMed 31400759

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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All Bacterial Infections trials

Study at a glance

From the registry record, last updated by the sponsor on 19 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects With Imipenem-Resistant Bacterial Infection
ClinicalTrials.gov ID: NCT02452047
Acronym / sponsor ID: RESTORE-IMI 1 / 7655A-013
Conditions: Bacterial Infections
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 50 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: 21 Aug 2015 (actual)
Primary completion: 18 Sep 2017 (actual)
Study completion: 18 Sep 2017 (actual)
First posted: 22 May 2015 (estimated)
Results: Posted 19 Oct 2018

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 3

Arm	Type	Receives
Group 1: Imipenem+Cilastatin/Relebactam	Experimental	Drug: Imipenem+Cilastatin/Relebactam, Drug: Placebo to CMSParticipants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.
Group 2: Colistimethate sodium + Imipenem+Cilastatin	Active comparator	Drug: Colistimethate sodium (CMS), Drug: Imipenem+CilastatinParticipants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.
Group 3: Imipenem+Cilastatin/Relebactam	Experimental	Drug: Imipenem+Cilastatin/RelebactamParticipants with documented imipenem-resistant and colistin-resistant bacterial infections may be eligible to receive open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations >21 days may be approved by the Sponsor for participants requiring longer treatment duration.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Hospitalization that requires treatment with IV antibiotic therapy for a new, persistent or progressing bacterial infection involving at least 1 of 3 primary infection types (HABP, VABP, cIAI, or cUTI)
Positive culture data from the primary infection-site specimen collected within 1 week of study entry. At least one of the suspected causative pathogens from the specimen meets all of the following: 1) identified as a Gram-negative bacterium, 2) culture-confirmed imipenem resistance (and colistin resistance for Group 3 only), 3) culture-confirmed susceptibility to imipenem/relebactam and to colistin (for Groups 1 and 2 only)
Not of reproductive potential, or of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner by complying with one of the following: 1) practice abstinence, or 2) use of acceptable contraception during heterosexual activity

Key exclusion criteria (9 listed)

Concurrent infection (endocarditis, osteomyelitis, meningitis, prosthetic joint infection, disseminated fungal infection, or active pulmonary tuberculosis) that would interfere with evaluation of the response to the study antibiotics
Received treatment with any form of systemic colistin for >24 hours within 72 hours before initiation of study drug (for Groups 1 and 2 only)
HABP or VABP caused by an obstructive process
cUTI which meets any of the following: 1) complete obstruction of any portion of the urinary tract, 2) known ileal loop, 3) intractable vesico-ureteral reflux, 4) presence of an indwelling urinary catheter which cannot be removed at study entry
History of serious allergy, hypersensitivity, or any serious reaction to listed antibiotics (per-protocol)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Imipenem+Cilastatin/RelebactamAlso: MK-7655AImipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours	Drug	Group 1: Imipenem+Cilastatin/Relebactam, Group 3: Imipenem+Cilastatin/Relebactam
Colistimethate sodium (CMS)Colistimethate base activity 300 mg (~720 mg CMS) IV infusion loading dose, followed by colistimethate base activity 75 mg to 150 mg (~180 to 360 mg CMS), depending on renal function, once every 12 hours	Drug	Group 2: Colistimethate sodium + Imipenem+Cilastatin
Imipenem+CilastatinImipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours	Drug	Group 2: Colistimethate sodium + Imipenem+Cilastatin
Placebo to CMSPlacebo to CMS IV infusion once every 12 hours	Drug	Group 1: Imipenem+Cilastatin/Relebactam

Primary outcome

Percentage of Participants With Favorable Overall Response (FOR)
Time frame: Up to Day 30 (up to 9 days after completing study treatment)
The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen [e.g., ≥10^5 CFU/mL at study entry is reduced to <10^4 CFU/mL]) at Early Follow-up (EFU).
Percentage of Participants With ≥1 Adverse Events (AEs)
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Percentage of Participants With ≥1 Serious Adverse Events (SAEs)
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Percentage of Participants With ≥1 Drug-Related AEs
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Percentage of Participants With ≥1 Drug-Related SAEs
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs
Time frame: Up to Day 21
The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs
Time frame: Up to Day 21
The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.
Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had <4 participants and therefore no data are presented.
Percentage of Participants With ≥1 Events of Clinical Interest (ECI)
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

9 secondary outcomes

Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity
Time frame: Up to Day 35 (up to 14 days after completing study treatment)
Percentage of Participants With Favorable Clinical Response (FCR) at Day 28
Time frame: Day 28
Percentage of Participants With All-cause Mortality Up to Day 28
Time frame: Up to Day 28
Percentage of Participants With FCR on Therapy (OTX)
Time frame: OTX (Day 3)
Percentage of Participants With FCR at End of Therapy (EOT)
Time frame: At EOT (up to Day 21)
Percentage of Participants With FCR at EFU
Time frame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX
Time frame: OTX (Day 3)
Percentage of cUTI Participants With FMR at EOT
Time frame: At EOT (up to Day 21)
Percentage of cUTI Participants With FMR at EFU
Time frame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

Results and safety

Results posted to the registry on 19 Oct 2018, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Group 1: Imipenem+Cilastatin/Relebactam	31	27
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	16	11
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	3	1

Primary outcome: Percentage of Participants With Favorable Overall Response (FOR)

Time frame: Up to Day 30 (up to 9 days after completing study treatment). Number (95% Confidence Interval). Unit: Percentage of Participants

Measure	Group 1: Imipenem+Cilastatin/Relebactam n = 21	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n = 10	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n = 0
Value	71.4 (49.8 to 86.4)	70.0 (39.2 to 89.7)	–

Group 1: Imipenem+Cilastatin/Relebactam vs Group 2: Colistimethate Sodium + Imipenem+Cilastatin: Difference in FOR %: -7.3 (90% CI -27.5 to 21.4)

Population analysed: Participants in Groups 1 and 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Primary outcome: Percentage of Participants With ≥1 Adverse Events (AEs)

Time frame: Up to Day 35 (up to 14 days after completing study treatment). Number. Unit: Percentage of Participants

Measure	Group 1: Imipenem+Cilastatin/Relebactam n = 31	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n = 16	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n = 3
Value	71.0	81.3	100.0

Group 1: Imipenem+Cilastatin/Relebactam vs Group 2: Colistimethate Sodium + Imipenem+Cilastatin: Difference in AE %: -10.3 (95% CI -33.1 to 18.0)

Population analysed: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Primary outcome: Percentage of Participants With ≥1 Serious Adverse Events (SAEs)

Time frame: Up to Day 35 (up to 14 days after completing study treatment). Number. Unit: Percentage of Participants

Measure	Group 1: Imipenem+Cilastatin/Relebactam n = 31	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n = 16	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n = 3
Value	9.7	31.3	100.0

Group 1: Imipenem+Cilastatin/Relebactam vs Group 2: Colistimethate Sodium + Imipenem+Cilastatin: Difference in SAE %: -21.6 (95% CI -47.8 to 1.3)

Population analysed: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

Primary outcome: Percentage of Participants With ≥1 Drug-Related AEs

Time frame: Up to Day 35 (up to 14 days after completing study treatment). Number. Unit: Percentage of Participants

Measure	Group 1: Imipenem+Cilastatin/Relebactam n = 31	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n = 16	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n = 3
Value	16.1	31.3	33.3

Group 1: Imipenem+Cilastatin/Relebactam vs Group 2: Colistimethate Sodium + Imipenem+Cilastatin: Difference in drug-related AE %: -15.1 (95% CI -42.3 to 9.2)

Population analysed: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

9 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to Day 35 (up to 14 days after EOT). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Group 1: Imipenem+Cilastatin/Relebactam	4 of 31 (12.9%)	15 of 31 (48.4%)	2 of 31
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	5 of 16 (31.3%)	13 of 16 (81.3%)	3 of 16
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	3 of 3 (100%)	3 of 3 (100%)	1 of 3

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32154325Brown ML, Motsch J, Kaye KS, File TM, Boucher HW, Vendetti N, Aggrey A, Joeng HK, Tipping RW, Du J, DePestel DD, Butterton JR, Paschke A. Evaluation of Renal Safety Between Imipenem/Relebactam and Colistin Plus Imipenem in Patients With Imipenem-Nonsusceptible Bacterial Infections in the Randomized, Phase 3 RESTORE-IMI 1 Study. Open Forum Infect Dis. 2020 Feb 19;7(3):ofaa054. doi: 10.1093/ofid/ofaa054. eCollection 2020 Mar.
Derived from this study: PubMed 32094127Kaye KS, Boucher HW, Brown ML, Aggrey A, Khan I, Joeng HK, Tipping RW, Du J, Young K, Butterton JR, Paschke A. Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02203-19. doi: 10.1128/AAC.02203-19. Print 2020 Apr 21.
Derived from this study: PubMed 31400759Motsch J, Murta de Oliveira C, Stus V, Koksal I, Lyulko O, Boucher HW, Kaye KS, File TM, Brown ML, Khan I, Du J, Joeng HK, Tipping RW, Aggrey A, Young K, Kartsonis NA, Butterton JR, Paschke A. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020 Apr 15;70(9):1799-1808. doi: 10.1093/cid/ciz530.
Individual participant dataSharing planned: Yes. https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Imipenem+Cilastatin/Relebactam, Colistimethate sodium (CMS) and Imipenem+Cilastatin in people with Bacterial Infections, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Favorable Overall Response (FOR) (time frame: Up to Day 30 (up to 9 days after completing study treatment)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02452047, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2018.