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TerminatedNCT00589693Updated Dec 28, 2012Results posted

To Compare Safety and Efficacy of Doripenem Versus Imipenem-Cilastatin in Patients With Ventilator-Associated Pneumonia

A Phase 3 interventional study of Doripenem and Imipenem-Cilastatin in Ventilator-Associated Pneumonia, sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.. Terminated at 102 sites in 21 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2012-12-28.

Sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. · Phase 3, Interventional, and Treatment

Why this study was terminated
Observed lower cure rates and higher mortality rates in one of the treatment groups.
Phase
Phase 3
Study type
Interventional
Enrollment
274
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of this study is to show that doripenem is as effective as imipenem-cilastatin in the treatment of patients with ventilator-associated pneumonia.

Read the detailed description

This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), active-controlled (agent that is compared with a study medication to test whether the study medication has a real effect in a clinical study), double-dummy (placebo [inactive substance that is compared with a medication to test whether the medication has a real effect in a clinical study] is administered to maintain the blind when the comparator medication cannot be made identical to the study medication), parallel-group (each group of patients will be treated at the same time), multicenter study to assess the effectiveness and safety of 7 day course of doripenem, compared with 10 day course of imipenem-cilastatin in patients with ventilator-associated pneumonia. This study will consists of 3 phases: (1) a pretreatment phase with a maximum of 24 hours for the screening/baseline visit, (2) a double blind, double dummy, treatment phase of 10 days (Day 1 to Day 10) and an end-of-treatment (EOT) assessment within 24 hours after the last dose of study medication therapy administered on Day 10 or at the time of early withdrawal from study medication, and (3) a post treatment (follow-up) phase consisting of an early follow-up (EFU) visit within 7 to 14 days after the last dose of study medication, and last follow-up (LFU) visit within 28 to 35 days after the last dose of study medication for all patients including those who discontinued study medication early. Two hundred and seventy four patients will be randomly assigned to receive either doripenem or imipenem with placebo of the other medication given simultaneously to maintain the blind (eg, 1 group will receive blinded doripenem from Days 1 to 7 and imipenem placebo Days 1 to 10, other group will receive blinded imipenem Days 1 to 10 and doripenem placebo Days 1 to 7). A sample of secretions from the lower respiratory tract will be obtained by bronchoalveolar lavage (BAL) or mini-BAL within 36 hours prior to administration of study medication from the enrolled patients and sent for culture. Patients, whose baseline BAL or mini-BAL culture results will yield at least 1 qualifying pneumonia pathogen will continue to receive study medication therapy and patients, whose baseline BAL or mini-BAL culture results did not yield at least 1 qualifying pneumonia pathogen will be discontinued from study medication therapy but will remain enroll in the study and will be followed for safety. Safety evaluations including adverse events, clinical laboratory evaluations, vital signs and physical examinations will be monitored throughout the study period. The total duration of an individual patient's participation in the study will be approximately 5 to 6 weeks.

02

Conditions studied

  • Ventilator-Associated Pneumonia

Keywords

  • Ventilator-Associated Pneumonia
  • Pneumonia, hospital-acquired
  • Doripenem
  • Imipenem-cilastatin
03

In context

Pneumonia

2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.

This study's enrollment of 274 is above the median of 106 across 1,247 interventional studies indexed under Pneumonia.

Browse Pneumonia studies →

Lead sponsor

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. is the lead sponsor of 458 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Patients must have new or worsening radiographic infiltrates consistent with ventilator-associated pneumonia that was not related to cardiac or other disease processes
  • Have at least 1 of the following: fever (core body temperature greater than 39.0°C); hypothermia (core body temperature of less than 35.0°C); leukocytosis (increased WBC count); and leukopenia (decreased WBC count)
  • Have developed ventilator-associated pneumonia and have been on mechanical ventilation for more than or equal to 48 hours and on mechanical ventilation at the time that study medication is assigned
  • Have been hospitalized or been in a chronic care facility for consecutive 5 days or more within the last 90 days
  • Have a baseline Clinical Pulmonary Infection Score (CPIS) more than or equal to 6 and an Acute Physiology and Chronic Health Evaluation (APACHE) II score more than 8 and less than 35

Exclusion criteria

Exclusion Criteria:

  • Have received antibiotics for this episode of ventilator-associated pneumonia for more than 24 hours before study medication administration
  • Known presence at baseline of only methicillin-resistant Staphylococcus aureus or Stenotrophomonas infection
  • Acute respiratory distress syndrome
  • Has any of the following conditions: chest trauma with severe lung bruising or loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both, increased amounts of fluid in the lung cavities requiring drainage or pus in the cavity
  • Has active seizure disorder within the last 2 years or brain injury such that imipenem cilastatin would not be administered to the patient in usual practice
  • Has lung cancer within the last 2 years, chronic bronchitis with an increase in severity within the last 30 days, chronic enlargement of the bronchi or bronchioles related to inflammatory disease or obstruction, lung abscess(s), anatomical bronchial obstruction, respiratory tuberculosis on treatment, suspected atypical pneumonia, chemical pneumonitis, cystic fibrosis, congestive heart failure, severe burns to greater than 15% of the body, evidence of severe and chronic liver disease
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
274 participants (actual)

Study arms

  • Experimental
    Doripenem

    Doripenem from Days 1 to 7 and imipenem-cilastatin placebo from Days 1 to 10

    Drug: Doripenem · Drug: Placebo

  • Active comparator
    Imipenem-Cilastatin

    Imipenem-Cilastatin Days 1 to 10 and doripenem placebo from Days 1 to 7

    Drug: Imipenem-Cilastatin · Drug: Placebo

Interventions

  • DrugDoripenem

    Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 4-hour infusion of doripenem will be administered every 8 hours for 7 days.

  • DrugImipenem-Cilastatin

    Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 1-hour infusion of imipenem-cilastatin will be administered every 8 hours for 10 days.

  • DrugPlacebo

    Form=solution, route=intravenous. Doripenem pacebo will be administered from Days 1 to 7 in imipenem-cilastatin arm and imipenem-cilastatin placebo will be administered in doripenem arm.

06

What researchers measure

Primary outcomes

  1. Clinical Cure Rate at the End-of-treatment (EOT) Visit

    The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary.

    Time frame: End-of-treatment (Day 10 or Day 11)

Secondary outcomes

  1. Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline

    The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline.

    Time frame: End-of-treatment (Day 10 or Day 11)

  2. Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline

    The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp.

    Time frame: End-of-treatment (Day 10 or Day 11)

  3. Number of Patients Who Had Emergence of P. Aeruginosa Resistance

    Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline

    Time frame: Up to 6 weeks

  4. 28-day All-cause Mortality Rate

    Number of deaths which occured up to 28 days of the study period due to all causes

    Time frame: Up to 28 days

07

Results

Posted Jul 18, 2012
Limitations and caveats
41 patients (21 doripenem, 20 imipenem-cilastatin) were enrolled at 5 sites that were found to be Good Clinical Practice non-compliant and were excluded from the primary efficacy and safety analyses.

Participant flow

274 enrolled patients were randomnly assigned to the 127 study centers. 524 patients were to be enrolled, however as the study was terminated early only 274 patients were actually enrolled.

Participant flow — Overall Study
MilestoneDoripenemImipenem-cilastatin
Started115112
Completed7183
Not completed4429
Withdrew: Randomized in error126
Withdrew: Adverse event44
Withdrew: Death2616
Withdrew: Lack of efficacy01
Withdrew: Lost to follow-up10
Withdrew: Physician decision01
Withdrew: Protocol violation11

Outcome measures

PrimaryClinical Cure Rate at the End-of-treatment (EOT) Visit

The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary.

Time frame:
End-of-treatment (Day 10 or Day 11)
Reported as:
Number · Participants
Clinical Cure Rate at the End-of-treatment (EOT) Visit
ParticipantsDoripenemImipenem-cilastatin
Clinical Cure Rate at the End-of-treatment (EOT) Visit3650
Statistical analysis
  • Doripenem vs Imipenem-cilastatin · Normal approximation of 2 proportions · Difference of 2 binomial proportions: -11.2 · 95% CI -26.3 to 3.8
SecondaryClinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline

The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline.

Time frame:
End-of-treatment (Day 10 or Day 11)
Reported as:
Number · Participants
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline
ParticipantsDoripenemImipenem-cilastatin
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline76
Statistical analysis
  • Doripenem vs Imipenem-cilastatin · Normal approximation of 2 proportions · Difference of 2 binomial proportions: -18.8 · 95% CI -57.2 to 19.5
SecondaryClinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline

The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp.

Time frame:
End-of-treatment (Day 10 or Day 11)
Reported as:
Number · Participants
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline
ParticipantsDoripenemImipenem-cilastatin
Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline3234
Statistical analysis
  • Doripenem vs Imipenem-cilastatin · Normal approximation of 2 proportions · Difference of 2 binomial proportions: -5.6 · 95% CI -23.0 to 11.7
SecondaryNumber of Patients Who Had Emergence of P. Aeruginosa Resistance

Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline

Time frame:
Up to 6 weeks
Reported as:
Number · Participants
Number of Patients Who Had Emergence of P. Aeruginosa Resistance
ParticipantsDoripenemImipenem-cilastatin
Number of Patients Who Had Emergence of P. Aeruginosa Resistance36
Statistical analysis
  • Doripenem vs Imipenem-cilastatin · Fisher Exact · p = 0.14
Secondary28-day All-cause Mortality Rate

Number of deaths which occured up to 28 days of the study period due to all causes

Time frame:
Up to 28 days
Reported as:
Number · Participants
28-day All-cause Mortality Rate
ParticipantsDoripenemImipenem-cilastatin
28-day All-cause Mortality Rate1713
Statistical analysis
  • Doripenem vs Imipenem-cilastatin · Normal approximation of 2 proportions · Difference of 2 binomial proportions: 6.7 · 95% CI -5.0 to 18.5

Adverse events

Collected over 6 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Doripenem—55/115 (47.8%)82/115 (71.3%)
Imipenem-cilastatin—45/112 (40.2%)80/112 (71.4%)
Most frequent serious events
Showing 10 of 101
Most frequent serious events
EventDoripenemImipenem-cilastatin
SepsisInfections and infestations8/1153/112
Septic shockInfections and infestations6/1156/112
Cardiac arrestCardiac disorders3/1156/112
PneumoniaInfections and infestations5/1153/112
Renal failureRenal and urinary disorders5/1151/112
HypoxiaRespiratory, thoracic and mediastinal disorders0/1154/112
Brain oedemaNervous system disorders3/1154/112
Pulmonary embolismRespiratory, thoracic and mediastinal disorders1/1153/112
Cardiac failureCardiac disorders2/1153/112
Multi-organ failureGeneral disorders2/1153/112
Most frequent other events
Showing 10 of 24
Most frequent other events
EventDoripenemImipenem-cilastatin
AnaemiaBlood and lymphatic system disorders26/11525/112
Urinary tract infectionInfections and infestations13/11516/112
DepressionPsychiatric disorders14/1158/112
Decubitus ulcerSkin and subcutaneous tissue disorders14/11511/112
DiarrhoeaGastrointestinal disorders11/11512/112
HypokalaemiaMetabolism and nutrition disorders12/11512/112
ConstipationGastrointestinal disorders9/11511/112
AgitationPsychiatric disorders11/1157/112
HypotensionVascular disorders11/1158/112
PyrexiaGeneral disorders11/11510/112

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)DoripenemImipenem-cilastatinTotal
<=18 years011
Between 18 and 65 years7272144
>=65 years433982
Age Continuous
Age Continuous(years)DoripenemImipenem-cilastatinTotal
Mean57.5 ± 16.5354.6 ± 18.4656.1 ± 17.53
Sex: Female, Male
Sex: Female, Male(Participants)DoripenemImipenem-cilastatinTotal
Female433780
Male7275147
Region Enroll
Region Enroll(participants)DoripenemImipenem-cilastatinTotal
EUROPE6971140
NORTH AMERICA161228
REST OF WORLD9615
SOUTH AMERICA212344
08

Study locations

102 sites
  • Jonesboro, Arkansas, United States
  • Newark, Delaware, United States
  • Washington, District of Columbia, United States
  • Jacksonville, Florida, United States
  • Moline, Illinois, United States
  • Hazard, Kentucky, United States
  • Biddeford, Maine, United States
  • Baltimore, Maryland, United States
  • Detroit, Michigan, United States
  • Butte, Montana, United States
  • Buffalo, New York, United States
  • Winston Salem, North Carolina, United States
  • Cincinnati, Ohio, United States
  • Oklahoma City, Oklahoma, United States
  • Nashville, Tennessee, United States
  • Houston, Texas, United States
  • Milwaukee, Wisconsin, United States
  • Buenos Aires, Argentina
  • Cordoba, Argentina
  • Entre Rios, Argentina
  • Monte Grande, Argentina
  • Rio Negro, Argentina
  • Rosario, Argentina
  • Adelaide, Australia
  • Box Hill, Australia
  • Clayton, Australia
  • Melbourne, Australia
  • Parkville N/A, Australia
  • Brussel, Belgium
  • Gent, Belgium
  • Belo Horizonte, Brazil
  • Curitiba, Brazil
  • Fortaleza, Brazil
  • Porto Alegre, Brazil
  • Rio De Janeiro, Brazil
  • Santo Andre, Brazil
  • Sao Jose Do Rio Preto, Brazil
  • Sao Paulo, Brazil
  • Halifax, Nova Scotia, Canada
  • Ottawa, Ontario, Canada
  • Greenfield Park N/A, Quebec, Canada
  • Argenteuil, France
  • Limoges Cedex 1, France
  • Paris Cedex 15, France
  • Pierre - Benite Cedex, France
  • Tours, France
  • Dresden, Germany
  • Halle/Saale, Germany
  • Homburg/Saar, Germany
  • Lübeck, Germany
  • Mannheim, Germany
  • Ulm, Germany
  • Cuilapa, Guatemala
  • Escuintla Escuintla, Guatemala
  • Guatemala, Guatemala
  • Budapest N/A, Hungary
  • Budapest Na, Hungary
  • Budapest, Hungary
  • Székesfehérvár, Hungary
  • Bangalore, India
  • Coimbatore, India
  • Ludhiana, India
  • New Delhi, India
  • Pune, India
  • Afula, Israel
  • Petah Tikva, Israel
  • Ramat-Gan, Israel
  • Chihuahua, Mexico
  • Guadalajara, Mexico
  • Monterrey, Mexico
  • San Luis Potosi, Mexico
  • Zapopan, Mexico
  • Manila, Philippines
  • Quezon City, Philippines
  • Lisboa, Portugal
  • Porto, Portugal
  • Brasov, Romania
  • Targu Mures, Romania
  • Timisoara, Romania
  • Moscow, Russian Federation
  • Saratov, Russian Federation
  • Smolensk, Russian Federation
  • St Petersburg, Russian Federation
  • Yaroslavl, Russian Federation
  • Barcelona, Spain
  • L'Hospitalet De Llobregat, Spain
  • Las Palmas De Gran Canaria, Spain
  • Madrid N/A, Spain
  • Madrid, Spain
  • Tarragona, Spain
  • Chiang Mai, Thailand
  • Khon Kaen, Thailand
  • Nakhonratchasima, Thailand
  • Adana, Turkey
  • Ankara, Turkey
  • Istanbul, Turkey
  • Kayseri, Turkey
  • Samsun, Turkey
  • Trabzon, Turkey
  • Kharkov, Ukraine

Showing the first 100 of 102 sites across 21 countries.

09

References and documents

Publications

  • Kollef MH, Chastre J, Clavel M, Restrepo MI, Michiels B, Kaniga K, Cirillo I, Kimko H, Redman R. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Crit Care. 2012 Nov 13;16(6):R218. doi: 10.1186/cc11862. PubMed 23148736 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Dec 28, 2012, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00589693
Lead sponsor
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Responsible party
Sponsor
First posted
Jan 10, 2008
Start date
Apr 2008
Primary completion
Jun 2011
Completion
Jun 2011
Results posted
Jul 18, 2012
Last update
Dec 28, 2012

Study contacts

Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial
study director · Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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