NCT02452047: RESTORE-IMI 1

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

Completed Phase 3 Results posted Last updated 19 October 2018

What this trial tests

Phase 3 trial testing Imipenem+Cilastatin/Relebactam in Bacterial Infections in 50 participants. Completed in 18 September 2017.

Timeline

21 August 2015

Primary endpoint
18 September 2017

18 September 2017

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	50
Start date	21 August 2015
Primary completion	18 September 2017
Estimated completion	18 September 2017

Drugs / interventions tested

• Imipenem+Cilastatin/Relebactam
• Colistimethate sodium (CMS) — full drug profile →
• Imipenem+Cilastatin
• Placebo to CMS — full drug profile →

Conditions studied

• Bacterial Infections — all drugs for Bacterial Infections →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Bacterial Infections. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Favorable Overall Response (FOR) Primary · 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 antibio

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	71.4	49.8 – 86.4
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	70.0	39.2 – 89.7

Percentage of Participants With ≥1 Adverse Events (AEs) Primary · 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.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	71.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	81.3
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	100.0

Percentage of Participants With ≥1 Serious Adverse Events (SAEs) Primary · 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.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	9.7
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	31.3
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	100.0

Percentage of Participants With ≥1 Drug-Related AEs Primary · 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.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	16.1
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	31.3
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	33.3

Percentage of Participants With ≥1 Drug-Related SAEs Primary · 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

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	0.0
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	33.3

Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs Primary · 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.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	18.8
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	33.3

Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs Primary · 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.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	12.5
Group 3: Open-Label Imipenem+Cilastatin/Relebactam	33.3

Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group Primary · 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.

Pyrexia

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	12.9
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	12.5

Blood creatinine increased

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	25.0

Percentage of Participants With ≥1 Events of Clinical Interest (ECI) Primary · 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.

Category 1 ECI

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	12.5

Category 2 ECI

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	0.0
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	12.5

Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity Secondary · Up to Day 35 (up to 14 days after completing study treatment)

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)".

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	10.3	2.8 – 27.2
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	56.3	33.2 – 76.9

Percentage of Participants With Favorable Clinical Response (FCR) at Day 28 Secondary · 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 sympto

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	71.4	49.8 – 86.4
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	40.0	16.7 – 68.8

Percentage of Participants With All-cause Mortality Up to Day 28 Secondary · Up to Day 28

The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.

Group	Value	95% CI
Group 1: Imipenem+Cilastatin/Relebactam	9.5	1.4 – 30.1
Group 2: Colistimethate Sodium + Imipenem+Cilastatin	30.0	10.3 – 60.8

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to Day 35 (up to 14 days after EOT). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Group 1: Imipenem+Cilastatin/Relebactam

Serious: 4/31 (13%)

Deaths: 2/31

Group 2: Colistimethate Sodium + Imipenem+Cilastatin

Serious: 5/16 (31%)

Deaths: 3/16

Group 3: Open-Label Imipenem+Cilastatin/Relebactam

Serious: 3/3 (100%)

Deaths: 1/3

Serious adverse events (19 terms)

Reaction	System	Group 1: Imipenem+Cilastat…	Group 2: Colistimethate So…	Group 3: Open-Label Imipen…
Pneumonia	Infections and infestations	—	—	—
Cardiac arrest	Cardiac disorders	—	—	—
Ventricular tachycardia	Cardiac disorders	—	—	—
Acute abdomen	Gastrointestinal disorders	—	—	—
Duodenal perforation	Gastrointestinal disorders	—	—	—
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—
Systemic inflammatory response syndrome	General disorders	—	—	—
Hepatic haematoma	Hepatobiliary disorders	—	—	—
Escherichia urinary tract infection	Infections and infestations	—	—	—
Lung infection	Infections and infestations	—	—	—
Septic shock	Infections and infestations	—	—	—
Abdominal wound dehiscence	Injury, poisoning and procedural complications	—	—	—
Subarachnoid haemorrhage	Injury, poisoning and procedural complications	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—
Generalised tonic-clonic seizure	Nervous system disorders	—	—	—
Mental status changes	Psychiatric disorders	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—

Other adverse events (88 terms — click to expand)

Reaction	System	Group 1: Imipenem+Cilastat…	Group 2: Colistimethate So…	Group 3: Open-Label Imipen…
Pyrexia	General disorders	—	—	—
Blood creatinine increased	Investigations	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Hypoaesthesia oral	Gastrointestinal disorders	—	—	—
Infusion site phlebitis	General disorders	—	—	—
Oedema	General disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Abdominal infection	Infections and infestations	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Blood bilirubin increased	Investigations	—	—	—
C-reactive protein increased	Investigations	—	—	—
Creatinine renal clearance decreased	Investigations	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—
Dizziness	Nervous system disorders	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—
Arteriosclerosis coronary artery	Cardiac disorders	—	—	—
Atrial flutter	Cardiac disorders	—	—	—
Tachyarrhythmia	Cardiac disorders	—	—	—
Tachycardia	Cardiac disorders	—	—	—
Hypoacusis	Ear and labyrinth disorders	—	—	—
Visual acuity reduced	Eye disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Gastritis	Gastrointestinal disorders	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—
Haematemesis	Gastrointestinal disorders	—	—	—
Ileus	Gastrointestinal disorders	—	—	—
Large intestinal haemorrhage	Gastrointestinal disorders	—	—	—
Large intestinal ulcer	Gastrointestinal disorders	—	—	—
Large intestine perforation	Gastrointestinal disorders	—	—	—
Retching	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Peripheral swelling	General disorders	—	—	—
Hepatic artery stenosis	Hepatobiliary disorders	—	—	—
Hepatic failure	Hepatobiliary disorders	—	—	—
Periportal oedema	Hepatobiliary disorders	—	—	—

Most-reported serious reactions: Pneumonia, Cardiac arrest, Ventricular tachycardia, Acute abdomen, Duodenal perforation, Upper gastrointestinal haemorrhage, Systemic inflammatory response syndrome, Hepatic haematoma.

Data from ClinicalTrials.gov NCT02452047 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae.
   van Duin D, Lok JJ, Earley M, Cober E, et al · · 2018 · cited 484× · PMID 29020404 · DOI 10.1093/cid/cix783
2. Infections Caused by Carbapenem-Resistant <i>Enterobacteriaceae</i>: An Update on Therapeutic Options.
   Sheu CC, Chang YT, Lin SY, Chen YH, et al · · 2019 · cited 334× · PMID 30761114 · DOI 10.3389/fmicb.2019.00080
3. 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.
   Motsch J, Murta de Oliveira C, Stus V, Köksal I, et al · · 2020 · cited 294× · PMID 31400759 · DOI 10.1093/cid/ciz530
4. Antibiotic resistance breakers: current approaches and future directions.
   Laws M, Shaaban A, Rahman KM. · · 2019 · cited 193× · PMID 31150547 · DOI 10.1093/femsre/fuz014
5. Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?
   Domalaon R, Idowu T, Zhanel GG, Schweizer F. · · 2018 · cited 189× · PMID 29540434 · DOI 10.1128/cmr.00077-17
6. New β-Lactamase Inhibitors in the Clinic.
   Papp-Wallace KM, Bonomo RA. · · 2016 · cited 121× · PMID 27208767 · DOI 10.1016/j.idc.2016.02.007
7. <i>In Vitro</i> Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program).
   Lob SH, Hackel MA, Kazmierczak KM, Young K, et al · · 2017 · cited 102× · PMID 28320716 · DOI 10.1128/aac.02209-16
8. Resistance to Novel β-Lactam-β-Lactamase Inhibitor Combinations: The "Price of Progress".
   Papp-Wallace KM, Mack AR, Taracila MA, Bonomo RA. · · 2020 · cited 94× · PMID 33011051 · DOI 10.1016/j.idc.2020.05.001