The Pharmacokinetics of Extended Duration High-dose Cefixime for the Decreased Susceptibility of Neisseria Gonorrhoeae: A Phase I Pilot Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01949363
First received: September 19, 2013
Last updated: August 28, 2014
Last verified: June 2014
  Purpose

This study is a Phase I, open label, non-randomized, dose-frequency escalation pharmacokinetics study among 30 healthy male and female subjects, aged 18 to 45 years to determine the pharmacokinetics and safety of high-, multi-dose cefixime for the treatment of reduced susceptibility gonorrhea. Stage 1(Cohorts A and B) will examine the pharmacokinetics of single 400mg and 800mg dose of cefixime. Stage 2(Cohorts C and D) subjects will take 800mg of cefixime every 12 hours for 2 doses. If that dosing regimen is well tolerated, the dose-frequency will escalate to 800mg every 8 hours for 3 doses, and serum levels of cefixime will be measured. Stage 3(Cohort E) will evaluate the highest tolerated dose of cefixime co-administered with a single oral dose of azithromycin 1 gram orally once in order to determine the tolerability of the regimen and whether there are significant changes in cefixime pharmacokinetics when the drugs are administered together. Study duration is approximately 49 weeks.


Condition Intervention Phase
Gonorrhoea
Drug: Azithromycin
Drug: Cefixime
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Pharmacokinetics of Extended Duration High-Dose Cefixime for the Decreased Susceptibility of Neisseria Gonorrhoeae: A Phase I Pilot Study

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Pharyngeal fluid concentrations of cefixime for Cohorts C - E: Cmax and ratio of fluid to serum concentration [ Time Frame: Day 0-1 ] [ Designated as safety issue: No ]
  • Assess subject reported adverse events, unsolicited symptoms and discomforts [ Time Frame: Up to Day 30 ] [ Designated as safety issue: Yes ]
  • Safety and tolerability assessed by laboratory monitoring, targeted clinical evaluations,: serum chemistries, liver functions tests (LFTs), hematology panel, coagulation panel, and urinalysis [ Time Frame: Screening to Day 7 ] [ Designated as safety issue: Yes ]
  • Total serum concentrations of cefixime at multiple time points for both individuals and cohorts in total [ Time Frame: Day 1, 2 and Day 7 ] [ Designated as safety issue: No ]
  • Pharmacokinetic curves of cefixime levels versus time: peak cefixime level, total area under the curve (AUC), time to peak drug level, half-life, elimination rate, total time that cefixime levels exceed 4x the MIC of 0.5 mcg/mL(serum level of 2.0 mcg/mL) [ Time Frame: Day 0-1, 2 and Day 7 ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage 2 (Cohorts C and D)
Cohort C will first be given 1200mg cefixime orally once; Cohort D will be given 800mg cefixime orally three times (every 8 hours); 6 subjects in each cohort
Drug: Cefixime
Cefixime is an FDA approved oral semi-synthetic cephalosporin antibiotic. The standard dose (400mg), high dose (800mg and 1200mg), and multiple 800mg and 1200mg doses given over a 24-hour period using a dose-frequency escalation method. Cohort A receives 400 mg orally once, Cohort B receives 800 mg orally once; Cohort C receives 1200 mg orally once; Cohort D receives 800 mg orally 3 times (every 8 hrs); Cohort E receives 1200mg orally (frequency TBD)
Experimental: Stage 1 (Cohorts A and B)
Cohort A will be given 400mg of cefixime orally once; Cohort B will be given 800mg of cefixime given orally once; 6 subjects in each cohort
Drug: Cefixime
Cefixime is an FDA approved oral semi-synthetic cephalosporin antibiotic. The standard dose (400mg), high dose (800mg and 1200mg), and multiple 800mg and 1200mg doses given over a 24-hour period using a dose-frequency escalation method. Cohort A receives 400 mg orally once, Cohort B receives 800 mg orally once; Cohort C receives 1200 mg orally once; Cohort D receives 800 mg orally 3 times (every 8 hrs); Cohort E receives 1200mg orally (frequency TBD)
Experimental: Stage 3 (Cohort E)
Cohort E will be given 1200mg cefixime orally (timing and frequency TBD) + 1 gram of Azithromycin once orally; 6 subjects
Drug: Azithromycin
Azithromycin is a macrolide antibiotic that is available in tablet or oral suspension form and is manufactured and distributed by Pfizer. Cohort E receives 1 gram orally once.
Drug: Cefixime
Cefixime is an FDA approved oral semi-synthetic cephalosporin antibiotic. The standard dose (400mg), high dose (800mg and 1200mg), and multiple 800mg and 1200mg doses given over a 24-hour period using a dose-frequency escalation method. Cohort A receives 400 mg orally once, Cohort B receives 800 mg orally once; Cohort C receives 1200 mg orally once; Cohort D receives 800 mg orally 3 times (every 8 hrs); Cohort E receives 1200mg orally (frequency TBD)

Detailed Description:

This study is a Phase I, open label, non-randomized, dose-frequency escalation pharmacokinetics study among 30 healthy male and female subjects, aged 18 to 45 years to determine the pharmacokinetics and safety of high-, multi-dose cefixime for the treatment of reduced susceptibility gonorrhea. The study will occur in three stages as described below. Stage 1: Confirm/establish the pharmacokinetics (PK) of 400mg and 800mg doses of cefixime tablet. Stage 2: Define dosing frequency necessary to achieve total serum cefixime levels that exceed 2.0 mcg/mL for over 20 hours. Stage 3: Evaluate whether co-administration of azithromycin with a high, multi-dose cefixime regimen changes the pharmacokinetics of cefixime. Stage 1 (Cohorts A and B): Six subjects will be admitted to the Johns Hopkins Bayview Clinic Trials Unit to assess each dosing regimen, for a total of 12 subjects. At time=0, subjects will undergo baseline serum cefixime levels, followed by ingestion of cefixime. Serum collections will occur at times 0, 1, 2, 4, 8, 12, 16, 20, and 24 hours. Cohort B will have the same serum collection time points as Cohort A. Cohorts A & B will be run nearly simultaneously as logistically feasible. Stage 2 (Cohorts C and D): After determining the PK parameters of single dose 800mg, the PK simulation model will be repeated, adjusting the model as needed based on findings from study Stage 1. Assuming there are no major discrepancies between Figure 2 (above) and the new PK simulations, the following regimens will be tested, beginning with Cohort C. Six subjects per dosing regimen, Cohorts C and D, will be admitted to the Johns Hopkins Bayview Medical Center, for a total of 12 subjects. The 800mg q12 hour x 2 regimen (Cohort C) will be tested first. For Cohort C, serum cefixime levels will be drawn at 12, 16, and 26 hours. If the q12 regimen is deemed safe and tolerable after review by the SMC, Cohort D will commence with the 800mg q8 hour x 3 regimen. Total serum cefixime levels will be drawn for Cohort D at 8, 16, 20 and 26 hours (see Section 7.2). Stage 3 (Cohort E): After establishing a safe, tolerable and effective treatment regimen in Stage 2, Stage 3 will determine if cefixime levels change with the addition of azithromycin. Six subjects will be admitted to the Johns Hopkins Bayview Medical Center. Cefixime serum levels will be measured following administration of a 1-gram dose of azithromycin with the chosen cefixime drug regimen established in Stage 2. Serum specimen collection times will be determined based on the dosing regimen chosen. All Stages, All Cohorts: All samples collected for PK analysis will be shipped to the University of Toledo, Dr. Jeffrey Blumer's HPLC lab for processing. Specimens will be analyzed by high performance liquid chromatography (HPLC) for total cefixime concentration levels. Targeted clinical evaluations will be used to monitor for subject reported side effects. Subjects will be asked about specific symptoms they may have experienced, including abdominal pain, nausea, vomiting, diarrhea, flatulence, headache, and rash, or any other symptoms. Additionally, subjects will be asked to maintain a Subject Diary (Appendix E) from Study Day 0 through Day 7 to record information about any symptoms experienced or medications taken. Study duration is approximately 49 weeks.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male or female subjects between 18 and 45 years, inclusive
  • Ability to understand the consent process and procedures
  • Informed consent obtained and signed
  • Body mass index (BMI) < 35 kg/m^2
  • Subjects agree to be available for all study visits
  • Negative Breathalyzer
  • Agreement by female subjects with reproductive potential to use an adequate method of contraception during the study and for 30 days after study drug administration. Female subjects must agree to the use of TWO reliable methods of contraception while receiving study drug and for 30 days after study drug administration if sexually active, which can include: condoms, spermicidal gel, diaphragm, hormonal or non-hormonal intrauterine device, surgical sterilization, oral contraceptive pill (OCP), and depot progesterone injections.

Exclusion Criteria:

  • Subjects who take any prescription medication on a regular basis (except oral contraceptives, OCPs), including but not limited to, anti-psychotics, anti-depressants, anti-epileptics, cardiac medications, anti-hypertensives etc.
  • Medical condition that precludes participation, including the following:
  • Hypertension with confirmed systolic blood pressure >140 mmHg or confirmed diastolic blood pressure >90 mmHg, measured after 10 - 15 minutes of rest
  • Morbid obesity (BMI>/=35)
  • Current diagnosis of pulmonary disease
  • History of or current diagnosis of diabetes
  • Autoimmune disorder, such as lupus, Wegener's, rheumatoid arthritis
  • History of malignancy except low-grade skin cancer, (i.e., basal cell carcinoma thought to be cured)
  • Known diagnosis of prolonged QT interval
  • History of alcohol abuse
  • History of seizure disorder
  • History of renal disease
  • Chronic renal, hepatic, or pulmonary disease or other condition that could interfere with the absorption of the study drug or predispose to adverse gastrointestinal events (e.g., surgical resection of significant proportions of the stomach or bowel, gastric bypass, gastric banding, irritable bowel syndrome, inflammatory bowel disease)
  • Positive serology results for HIV, HBsAg, or HCV antibodies
  • Subjects who have taken any prescription drugs in the previous 14 days or within 5 half-lives before dosing
  • Ingestion of over the counter medications or herbal supplements within 7 days of dosing
  • Positive urine toxicology for marijuana, cocaine, amphetamines, opiates, PCP, barbiturates or benzodiazepines
  • History of allergic reaction or intolerance to cephalosporins
  • History of allergic reaction to penicillin (all stages)
  • Subjects with an allergy to macrolides may not participate in Stage 3
  • Subjects with QTc >450ms (Fridericia's correction) on screening ECG may not participate in Stage 3.
  • Positive pregnancy test; pregnant or nursing women
  • Screening laboratory tests outside of the acceptable limits presented in Appendix C
  • Any specific condition that, in the judgment of the Investigator, precludes participation because it could affect subject safety
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01949363

Contacts
Contact: Mac Griffiss (330) 460-5030 jgriffiss@clinicalrm.com

Locations
United States, Maryland
Johns Hopkins Bayview Medical Center - Infectious Diseases Not yet recruiting
Baltimore, Maryland, United States, 21224-2735
Johns Hopkins Bayview Medical Center - Infectious Diseases Recruiting
Baltimore, Maryland, United States, 21224-2735
Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01949363     History of Changes
Other Study ID Numbers: 12-0025, HHSN272200800026C
Study First Received: September 19, 2013
Last Updated: August 28, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Gonococcal Infections, Cefixime, Neisseria gonorrhoeae, Azithromycin, antibiotic, cephalosporin

Additional relevant MeSH terms:
Gonorrhea
Disease Susceptibility
Disease Attributes
Pathologic Processes
Neisseriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Sexually Transmitted Diseases, Bacterial
Sexually Transmitted Diseases
Infection
Genital Diseases, Male
Genital Diseases, Female
Cefixime
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014