Cefiderocol Concentrations in the Lungs of Hospitalized Patients With Bacterial Pneumonia

• Sponsor: Shionogi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03862040
• Collaborator: (none)
• Enrollment: 7
• Locations: 7
• Arm: 1
• Actual Duration (Months): 7.8
• Patient Per Site: 1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary purpose of the study is to determine the degree of penetration of cefiderocol into infected lung tissue in hospitalized adults with bacterial pneumonia who are being mechanically ventilated.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Pneumonia	Drug: Cefiderocol; Drug: Standard of Care Antibiotic	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter, Single-arm, Phase 1 Study to Assess the Intrapulmonary Concentrations of Cefiderocol at Steady State in Hospitalized Subjects With Known or Suspected Bacterial Pneumonia on Treatment With Standard of Care Antibiotics and Requiring Mechanical Ventilation
• Actual Study Start Date: Feb 20, 2019
• Actual Primary Completion Date: Oct 8, 2019
• Actual Study Completion Date: Oct 15, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Cefiderocol All participants were receiving standard of care (SOC) antibiotic treatment for pneumonia. Forty hours after the start of SOC treatment, participants will be administered 2 g doses of cefiderocol (or renally adjusted doses) infused intravenously over 3 hours, every 8 hours (or every 6 hours for participants with augmented renal function), for an expected minimum of 3 doses and up to a total of 6 doses in participants with normal renal function and participants with mild or moderate renal impairment, and for an expected minimum of 6 doses and up to a total of 9 doses in participants with severe renal impairment.

Drug: Cefiderocol; Administered intravenously, at a dosage determined based on renal function.; Other Names: S-649266) ; Drug: Standard of Care Antibiotic; Standard of care antibiotic treatment for pneumonia

Outcome Measures

Primary Outcome Measures

1. Concentration of Cefiderocol in Epithelial Lining Fluid [At the third dosing (or sixth dosing for participants with severe renal impairment; 16 or 40 hours after first dose, respectively), at 3 hours after the start of the infusion or 2 hours after the end of infusion.]

   Samples for determination of cefiderocol concentrations in the epithelial lining fluid (ELF) were collected by bronchoalveolar lavage (BAL) procedure on the inflamed section of the lung (ie, a lobe where pneumonia was expected to be present based on chest radiologic imaging) after multiple doses of cefiderocol sufficient to approximate steady state concentrations in blood. The ELF sample for the determination of cefiderocol concentrations was collected at 3 hours after the start of administration of cefiderocol for the first 4 enrolled participants and at 2 hours after the end of infusion for the following 3 participants. Cefiderocol concentrations were determined using liquid chromatography/tandem mass spectrometry (LC/MS/MS), with a lower limit of quantification of cefiderocol in ELF of 0.005 μg/mL. Cefiderocol concentrations in ELF were calculated using cefiderocol concentrations in BAL, adjusted by the ratio of urea concentrations in blood and BAL.

2. Ratio of the Concentration of Cefiderocol in Epithelial Lining Fluid Relative to Plasma [At the third dosing (or sixth dosing for participants with severe renal impairment; 16 or 40 hours after start of the first dose, respectively), at 3 hours after the start of the infusion or 2 hours after the end of infusion.]

   The concentration of cefiderocol in ELF to plasma ratio (RC,E/P) represents the penetration of cefiderocol into infected lung tissue. ELF and plasma cefiderocol concentrations were determined using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The lower limit of quantification of cefiderocol in plasma and ELF was 0.1 μg/mL and 0.005 μg/mL, respectively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject is 18 years or older at the time written informed consent is obtained

2. Subject has provided written informed consent or informed consent has been provided by subject's legally authorized representative

3. Subject has a diagnosis or suspicion of bacterial pneumonia (even if later known that the subject does not have bacterial pneumonia, discontinuation of the study is not necessary)

4. Subject is hospitalized and receiving standard of care antibiotic treatment for pneumonia

5. Subject is mechanically ventilated or expected to be mechanically ventilated at least 48 hours (or 72 hours for subjects with severe renal impairment) after the first dose of cefiderocol

6. Subject has a life expectancy of at least 3 weeks from the Screening visit

7. Subject is male (no contraception required) or female and meets 1 of the following criteria:

8. Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery)

9. Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for at least 6 months and a follicle-stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months)

10. Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device (IUD), or intrauterine hormone-releasing system for the entire duration of the study

11. Of childbearing potential and practicing abstinence as a preferred and usual life style and/or agrees to continue practicing abstinence from Screening for the entire duration of the study

12. Of childbearing potential and whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Subject has a chemical pneumonia that does not require antibiotic treatment (including aspiration of gastric acid, inhalation injury). The term chemical pneumonia refers to the aspiration of substances that are toxic to the lower airways causing chemical burn and injuries in the airway.

2. Subject has a history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)

3. Subject has extensive cystic lesion(s) or severe structural abnormality (eg, cystic fibrosis, emphysema, cystic lesions of sarcoidosis or tuberculosis, postobstructive pneumonia due to lung cancer, etc) of the lung that hinders recovery of bronchoalveolar lavage fluid (BALF)

4. Subject is receiving peritoneal dialysis

5. Subject has severe renal impairment requiring hemodialysis (HD) or end-stage renal disease requiring HD

6. Subject is in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at Screening

7. Subject is a female who has a positive pregnancy test at Screening or who is lactating

8. Subject has received another investigational drug within 30 days prior to Screening

9. Subject has previously participated in this clinical study and has received at least 1 dose of cefiderocol within 7 days

10. Subject has any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of the study data

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anschutz Medical Campus	Aurora	Colorado	United States	80045
2	Hartford Hospital	Hartford	Connecticut	United States	06102
3	University of Florida	Jacksonville	Florida	United States	32209
4	U Miami Health Tower	Miami	Florida	United States	33136
5	North Western University	Chicago	Illinois	United States	60611
6	Creighton University	Omaha	Nebraska	United States	68124
7	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 19, 2018
• Study Protocol - Nov 2, 2018

More Information

Publications

None provided.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT03862040
• Other Study ID Numbers: 1713R2117
• First Posted: Mar 5, 2019
• Last Update Posted: Nov 5, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Bacterial; Anti-Bacterial Agents

Study Results

Participant Flow

Recruitment Details	This study was conducted at 3 sites in the United States. Seven adults with known or suspected bacterial pneumonia being treated with standard of care (SOC) antibiotics and requiring mechanical ventilation were enrolled.

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol (or renally adjusted doses) every 8 hours (or every 6 hours for participants with augmented renal function), administered by intravenous infusion over 3 hours for a total of 3 to 6 doses.
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol (or renally adjusted doses) every 8 hours (or every 6 hours for participants with augmented renal function), administered by intravenous infusion over 3 hours for a total of 3 to 6 doses.
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 42.9%
>=65 years	4 57.1%
Sex: Female, Male (Count of Participants)
Female	4 57.1%
Male	3 42.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%
Not Hispanic or Latino	5 71.4%
Unknown or Not Reported	1 14.3%
Race/Ethnicity, Customized (Count of Participants)
White	5 71.4%
Black or African American	1 14.3%
Other	1 14.3%

Outcome Measures

1. Primary Outcome

Title	Concentration of Cefiderocol in Epithelial Lining Fluid
Description	Samples for determination of cefiderocol concentrations in the epithelial lining fluid (ELF) were collected by bronchoalveolar lavage (BAL) procedure on the inflamed section of the lung (ie, a lobe where pneumonia was expected to be present based on chest radiologic imaging) after multiple doses of cefiderocol sufficient to approximate steady state concentrations in blood. The ELF sample for the determination of cefiderocol concentrations was collected at 3 hours after the start of administration of cefiderocol for the first 4 enrolled participants and at 2 hours after the end of infusion for the following 3 participants. Cefiderocol concentrations were determined using liquid chromatography/tandem mass spectrometry (LC/MS/MS), with a lower limit of quantification of cefiderocol in ELF of 0.005 μg/mL. Cefiderocol concentrations in ELF were calculated using cefiderocol concentrations in BAL, adjusted by the ratio of urea concentrations in blood and BAL.
Time Frame	At the third dosing (or sixth dosing for participants with severe renal impairment; 16 or 40 hours after first dose, respectively), at 3 hours after the start of the infusion or 2 hours after the end of infusion.

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of cefiderocol and who had at least 1 evaluable concentration of cefiderocol in bronchoalveolar lavage fluid.

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol (or renally adjusted doses) every 8 hours (or every 6 hours for participants with augmented renal function), administered by intravenous infusion over 3 hours for a total of 3 to 6 doses.
Measure Participants	7
3 hours after start of infusion	7.63
2 hours after end of infusion	10.4

2. Primary Outcome

Title	Ratio of the Concentration of Cefiderocol in Epithelial Lining Fluid Relative to Plasma
Description	The concentration of cefiderocol in ELF to plasma ratio (RC,E/P) represents the penetration of cefiderocol into infected lung tissue. ELF and plasma cefiderocol concentrations were determined using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The lower limit of quantification of cefiderocol in plasma and ELF was 0.1 μg/mL and 0.005 μg/mL, respectively.
Time Frame	At the third dosing (or sixth dosing for participants with severe renal impairment; 16 or 40 hours after start of the first dose, respectively), at 3 hours after the start of the infusion or 2 hours after the end of infusion.

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of cefiderocol and who had at least 1 evaluable concentration of cefiderocol in bronchoalveolar lavage fluid. Cefiderocol concentration was measured 3 hours after the start of the infusion in the first 4 enrolled participants and 2 hours after the end of infusion in the following 3 participants.

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol (or renally adjusted doses) every 8 hours (or every 6 hours for participants with augmented renal function), administered by intravenous infusion over 3 hours for a total of 3 to 6 doses.
Measure Participants	7
3 hours after start of infusion	0.0893
2 hours after end of infusion	0.231

Adverse Events

Time Frame	From the start of the first infusion of cefiderocol up to 7 days after last dose, up to 9 days.
Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol (or renally adjusted doses) every 8 hours (or every 6 hours for participants with augmented renal function), administered by intravenous infusion over 3 hours for a total of 3 to 6 doses.
All Cause Mortality
	Cefiderocol
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Cefiderocol
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Cefiderocol
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anaemia	2/7 (28.6%)
Thrombocytopenia	1/7 (14.3%)
Cardiac disorders
Atrial fibrillation	1/7 (14.3%)
Gastrointestinal disorders
Diarrhoea	1/7 (14.3%)
General disorders
Implant site dehiscence	1/7 (14.3%)
Infections and infestations
Bacteriuria	1/7 (14.3%)
Injury, poisoning and procedural complications
Contusion	1/7 (14.3%)
Tracheostomy malfunction	1/7 (14.3%)
Wound dehiscence/	1/7 (14.3%)
Investigations
Blood urea increased	1/7 (14.3%)
Metabolism and nutrition disorders
Hypokalaemia	1/7 (14.3%)
Hypernatraemia	1/7 (14.3%)
Hypophosphataemia	2/7 (28.6%)
Hyperchloraemia	1/7 (14.3%)
Renal and urinary disorders
Renal failure	1/7 (14.3%)
Acute kidney injury	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Wheezing	1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.