Clinical trial NCT03910673: Intravenous Fosfomycin Pharmacokinetics Study
Official title: A Phase 1 Safety and Intrapulmonary Pharmacokinetics Study of ZTI-01 (Intravenous Fosfomycin Disodium) in Healthy Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Bacterial Infection
Multiple-drug Resistance
Pathogen Resistance
Keywords: Adults
Fosfomycin Disodium
Healthy
Intrapulmonary
Intravenous
Pharmacokinetics
Phase 1
ZTI-01
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2019-04-10
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, open-label, multiple-dose trial conducted at a single center. The treatment period will consist of three 6 g doses (18 g) of ZTI-01 as a 1-hour intravenous (IV) infusion (+10 minute window). A total of 30 enrolled subjects will be randomized to undergo a single standardized bronchoscopy with bronchoalveolar lavage (BAL) at one of five sampling times. A total of 6 subjects will be assigned to each BAL-sampling time. Up to ten additional enrolled subjects will act as alternates to obtain 30 evaluable subjects. An evaluable subject is defined as a subject who receives all doses of ZTI-01, undergoes BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and undergoes at least the one blood sampling timepoint that is concurrent with the assigned BAL sampling timepoint, with blood sampling volume that is adequate for testing. The objectives of the study are to assess safety and pharmacokinetics (PK) for a multiple dose regimen of IV-infused ZTI-01.

Detailed description: This is a Phase 1, open-label, multiple-dose trial conducted at a single center. The treatment period will consist of three 6 g doses (18 g) of ZTI-01 as a 1-hour intravenous (IV) infusion (+10 minute window). A total of 30 enrolled subjects will be randomized to undergo a single standardized bronchoscopy with bronchoalveolar lavage (BAL) at one of five sampling times. A total of 6 subjects will be assigned to each BAL-sampling time. Up to ten additional enrolled subjects will act as alternates to obtain 30 evaluable subjects. An evaluable subject is defined as a subject who receives all doses of ZTI-01, undergoes BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and undergoes at least the one blood sampling timepoint that is concurrent with the assigned BAL sampling timepoint, with blood sampling volume that is adequate for testing. The objectives of the study are to assess safety and pharmacokinetics (PK) for a multiple dose regimen of IV-infused ZTI-01.

Eligibility criteria: Inclusion Criteria:

1. Healthy\* men and women aged 18-45 years with no clinically significant findings\*\* at Screening and Baseline (Day -1 to Day 1)

   \*Healthy is defined by the absence of any medical condition described in the exclusion criteria in a subject with a normal physical exam including vital signs. If the subject has another current, ongoing medical condition, the condition cannot meet any of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is worsening in terms of clinical outcome in the last 6 months; or 3) involves need for medication.

   \*\*Including findings on medical history, physical exam, vital signs, 12-lead Electrocardiogram (ECG), or clinical laboratory tests.
2. Body Mass Index (BMI) = 18 - 30 kg / m\^2, inclusive, and body weight \> 50 kg (110 lbs).
3. Females who have been surgically sterilized via bilateral oophorectomy and/or hysterectomy at least 90 days prior to Screening are considered lacking childbearing potential and will be eligible\*.

   \*Postmenopausal females are not eligible, as the definition of menopause would require age \> 45, and all subjects in this study are age \< / = 45.
4. Females of childbearing potential must have a negative serum pregnancy test at Screening, a negative urine pregnancy test at Baseline (Day -1 to Day 1), and must use acceptable contraception\*.

   \*Acceptable contraception methods are restricted to surgical sterilization (bilateral tubal ligation) or successful Essure placement (permanent, non-surgical, non-hormonal sterilization with documented radiological confirmation at least 90 days after the procedure), use of long-acting reversible contraceptive devices (progestin-releasing subdermal implants \[Nexplanon and Implanon, Merck\], copper intrauterine devices \[Paragard, Teva\], and levonorgestrel-releasing intrauterine devices \[Mirena, Bayer; Skyla, Bayer; Liletta, Allergan/Medicines360\]), licensed hormonal products such as injectables or oral contraceptives, barrier methods such as condoms or diaphragms with spermicidal agents, and abstinence from sexual intercourse with a male partner. Subjects must have used the above-listed method for a minimum of 30 days prior to the first dose of study drug and be willing to use the method for at least 30 days after the final dose of study drug.
5. Male subjects\* whose partners are of childbearing age or pregnant must be willing to use condoms during the study and through the Day 3 follow-up call.

   \*including men who have had vasectomies
6. Able to abstain from alcoholic beverages within 48 hours before Baseline (Day -1 to Day 1) and throughout the Treatment Phase.
7. Able to abstain from caffeine use within 7 days before Baseline (Day -1 to Day 1) and throughout the inpatient period.
8. Willing to remain in Duke Early Phase Research Unit (DEPRU) during the Baseline and Treatment Phases.
9. Have a high probability for compliance and completion of the trial.
10. Sign a dated, witnessed, written Informed Consent Form (ICF).
11. Have adequate venous access for infusions and blood draws.

Exclusion Criteria:

1. Any surgical or medical condition that in the opinion of the investigator could interfere with drug absorption, distribution, metabolism, or excretion.
2. Any surgical or medical condition that in the opinion of the investigator may place the subject at increased risk while participating in the trial.
3. History or presence of cardiovascular disease including coronary artery disease and chronic hypertension (systolic pressure \> 140 mmHg or diastolic pressure \> 90 mmHg).
4. Abnormal Electrocardiogram (ECG) at screening, as determined by the investigator to be clinically significant.
5. History or presence of renal impairment or chronic renal disease.
6. History or presence of liver disease (Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or total bilirubin above the upper limit of normal).
7. History or presence of chronic pulmonary disease, including asthma, requiring use of medication in the year before screening.
8. History of intolerance or hypersensitivity to phosphonic acid derivative antibiotics or any of its constituents (i.e., oral or intravenous fosfomycin).
9. Have cancer or have a history of cancer within the past 5 years, with the exception of non-melanomatous skin cancer, treated, without evidence of recurrence.
10. Any medical condition that prevents a subject from undergoing bronchoscopy with bronchoalveolar lavage (BAL).
11. Serum creatinine above the upper limit of normal, or estimated creatinine clearance (CrCl) \< 60 mL / min as determined by Cockcroft-Gault equation\*.

    \*Cockcroft-Gault equation where age is in years, weight is in kilograms, and serum Cr is in mg/dL units: Males: CrCl (mL / min) = (140 - age) x Weight / (72 x Cr) Females: CrCl (mL / min) = \[(140 - age) x Weight / (72 x Cr)\] x 0.85
12. History of regular alcohol consumption within 6 months of Baseline (Day -1 to Day 1)\*.

    \*History of regular alcohol consumption is defined as an average weekly intake of \> 14 drinks for males or \> 7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces (45 mL) of 80 proof distilled spirits.
13. History of \> / = 10 pack-years smoking, or history of any nicotine use\* in the 6 months before Baseline (Day -1 to Day 1)\*\* or positive urinine cotinine screen at Basline (Day -1 to Day 1).

    \*Including cigarettes, pipe, cigar, chewing tobacco, nicotine patch.

    \*\*A positive urine cotinine at screening is allowed if negative at baseline.
14. History of illicit drug use within 6 months of Baseline (Day -1 to Day 1)\*.

    \*Use of cannabinoids within 1 month of Baseline (Day -1 to Day 1) is excluded, but other use of cannabinoids within 6 months is permitted.
15. Use of any prescription drugs, except acceptable contraception methods listed above, within 30 days of Baseline (Day -1 to Day 1).
16. Involvement in other investigational studies of any type (drugs, devices, procedures) within 30 days of Baseline (Day -1 to Day 1).
17. Blood or blood products donation within 30 days of Baseline (Day -1 to Day 1).
18. Planning egg or sperm donation any time before Day 3 follow-up call.
19. Use of any non-prescription medications, vitamins, consumption \> 2 times/week of products containing genuine licorice, caffeine, or dietary or herbal supplements within 7 days of Baseline (Day -1 to Day 1)\*.

    \*Excluded from this list is intermittent use of acetaminophen at doses \< / = 2 g / day. Herbal supplements must be discontinued 7 days before the initial dose of study drug on Day 1.
20. Presence of any acute illness, including febrile illness with temperature \> 37.8 degrees Celsius (\> 100.0 degrees Fahrenheit), within 7 days of Baseline (Day -1 to Day 1).
21. Currently pregnant or breastfeeding as determined by subject report.
22. Positive tests for human immunodeficiency virus (HIV) 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody.
23. Positive urine drug or positive breathalyzer test for alcohol at Screening or Baseline (Day -1 to Day 1) or positive cotinine at Baseline (Day -1 to Day 1).
24. Weight loss or gain of \> 10% within 30 days of Baseline (Day -1 to Day 1).
25. Any laboratory value at screening or enrollment that is Grade 2 or more. A laboratory value that is Grade 1 will be allowed if not considered to be clinically significant by the investigator\*.

    \*Excluded from this list of permissible Grade 1 laboratory values are (ALT), (AST), or Total bilirubin per Exclusion Criteria 6 and serum creatinine per Exclusion Criteria #11; and serum electrolytes including sodium, potassium, calcium, phosphorus and magnesium.
26. History of infection with SARS-CoV-2 (COVID-19) within 3 months of Baseline (Day -1 to Day 1) or unresolved symptoms of COVID-19.
27. Positive test for SARS-CoV-2 (COVID-19) at Screening or Baseline (Day -1 to Day 1) within 72 hours of admission

Primary outcomes:
measure: Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01
timeFrame: Day 1 to Day 2
measure: Clearance (CL) of ZTI-01
timeFrame: Day 2
measure: Intrapulmonary Pharmacokinetics of ZTI-01
timeFrame: Day 2
measure: Maximum Measured Plasma Concentration (Cmax) of ZTI-01
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Physical Examination Findings
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Abnormal Vital Sign Measurements
timeFrame: Day 1 to Day 2
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Day 1 to Day 3
measure: Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings
timeFrame: Day 1 to Day 2
measure: Terminal Elimination Half-life (t1/2) of ZTI-01
timeFrame: Day 2
measure: Terminal-phase Elimination Rate Constant (Lambdaz) of ZTI-01
timeFrame: Day 2
measure: Time to Peak Concentration (Tmax) of ZTI-01
timeFrame: Day 1 to Day 2
measure: Volume of Distribution at Steady State (Vss) of ZTI-01
timeFrame: Day 2
Secondary outcomes:
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
state: North Carolina
Study officials:
References: