Clinical trial NCT03564158: Evaluate Effects of Meropenem-Vaborbactam on QT/QTc in Healthy Volunteers
Official title: A Randomized, Placebo- and Positive-Controlled, Crossover Study to Evaluate the Effect of Meropenem-Vaborbactam on the QT/QTc Interval in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Melinta Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2018-06-20
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: This Thorough-QT (TQT) study in healthy volunteers will be conducted in two phases. Phase One will be used to identify a safe supratherapeutic dose to be used in the TQT study (Phase Two). Phase Two will be a 4-way crossover TQT study. Thirty-two subjects will receive all 4 of the following treatments in randomized sequence.

1. meropenem-vaborbactam 4 g (meropenem 2 g- vaborbactam 2 g) therapeutic dose infused intravenously over 3 hours
2. meropenem-vaborbactam supratherapeutic dose to be determined infused intravenously over 3 hours.
3. Placebo (normal saline) to match meropenem-vaborbactam volume infusion over 3 hours
4. Moxifloxacin 400 mg positive control (oral; open-label)

Detailed description: This Thorough-QT (TQT) study in healthy volunteers will be conducted in two phases. Phase One (n=15) will be used to identify a safe supratherapeutic dose to be used in the TQT study (Phase Two). Phase Two will be a randomized, placebo and positive-controlled, 4-way crossover TQT study. Thirty-two subjects will receive all 4 of the following treatments in randomized sequence.

1. meropenem-vaborbactam 4 g (meropenem 2 g- vaborbactam 2 g) therapeutic dose infused intravenously over 3 hours
2. meropenem-vaborbactam supratherapeutic dose to be determined infused intravenously over 3 hours.
3. Placebo (normal saline) to match meropenem-vaborbactam volume infusion over 3 hours
4. Moxifloxacin 400 mg positive control (oral; open-label)

Eligibility criteria: Inclusion Criteria:

1. Male or female subject between 18 and 55 years of age, inclusive, with a body mass index (BMI) ≥18 to ≤33 kilogram (kg)/m2.
2. All women of child-bearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose. Accepted methods of contraception include: mechanical products (e.g., intrauterine device) or double-barrier methods (e.g., diaphragm, condoms, cervical cap) with spermicide or hormonal contraceptives (i.e., oral, implanted or injectable contraceptive hormones) or abstinence. Oral contraceptives must be used together with a second method of birth control. If the female subject has a male partner who has had a vasectomy, one additional form of medically acceptable contraception (condom or spermicide) must also be used. The subject's understanding of this requirement must be documented by the Investigator.

   Males with female partners of childbearing potential must agree to use a highly effective, medically acceptable form of contraception from the Screening period through 30 days after the last dose. Males with female partners of childbearing potential who themselves are surgically sterile (status post vasectomy) must agree to use condoms with spermicide over the same period of time. Male subjects must agree to practice the above birth control methods for 30 days after the final dose. Males must agree to not donate sperm through 30 days after the final dose.
3. Stable health based on no clinically-significant findings on the medical history, physical examination, or clinical laboratory test results at screening and prior to study drug administration (as determined and documented by the Investigator).
4. Willing to comply with all study activities and procedures and provides written informed consent prior to any study procedures

Exclusion Criteria:

1. Known hypersensitivity to beta-lactam antibiotics (including meropenem), fluoroquinolone antibiotics (including moxifloxacin) or vaborbactam.
2. An uninterpretable or abnormal screening electrocardiogram (ECG) indicating a second or third degree atrioventricular block, or any rhythm other than sinus rhythm that is interpreted by the investigator to be clinically significant or one or more of the following: QRS interval \>110 milliseconds (ms); QTcF \>430 ms (males) and \>450 ms (females); PR interval \>200 ms; heart rate (HR) \<50 beats per minutes (bpm); or \>90 bpm.
3. History of risk factors for torsades de pointes, including unexplained syncope, known long QT syndrome, heart failure, myocardial infarction, angina. Subjects will also be excluded if there is a family history of long QT syndrome or Brugada syndrome or unexplained sudden death.
4. Subject has any clinically relevant abnormalities, as determined by the Investigator, in the laboratory results at Screening or admission of each study period
5. Serum potassium, serum magnesium, or albumin-corrected calcium lower than the lower limit of normal for the reference lab at Screening or admission of each study period. Calcium will be corrected for albumin using the formula: Corrected Calcium = (0.8 \* (Normal Albumin - Pt's Albumin)) + Serum Ca where Normal Albumin is 4.0 g/dL.
6. Hemoglobin and hematocrit lower than the lower limit of normal for the reference lab at Screening.
7. Subject has an abnormal liver function tests: alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or bilirubin greater than 1.2X the upper limits of normal at Screening.
8. History of central nervous system (CNS) disorder including convulsions.
9. A sustained supine systolic blood pressure \>140 mmHg or \<90 mmHg or a supine diastolic blood pressure \>90 mmHg or \<50 mmHg at Screening or Check in (Day -1). Blood pressure may be retested once in the supine position. The blood pressure abnormality is considered sustained if either the systolic or the diastolic pressure values are outside the stated limits after 2 assessments, in which case the subject should not be randomized.
10. Impaired renal function as evidenced by estimated glomerular filtration rate (eGFR) \<50.
11. Unstable cardiovascular disease, including recent myocardial infarction or cardiac arrhythmia.
12. History of acquired immunodeficiency syndrome or history of a positive test result for human immunodeficiency virus (HIV), hepatitis C virus (HCV) antibody, or hepatitis B surface antigen (HBsAg) at Screening.
13. Positive drug, alcohol, or tobacco screen.
14. Clinically-significant illness, including viral syndromes within 3 weeks of dosing.
15. Women who are pregnant (or planning to become pregnant within the next 6 months) or currently breastfeeding. A negative serum pregnancy test is required before enrolling in the study.
16. Participation in another investigational drug or device study or treated with an investigational drug within 30 days or 5 half lives, whichever is longer, before dosing. Any subject who participated in Phase One of this trial is not eligible to participate in Phase Two.
17. Consumed more than 28 units of ethanol per week at any time in the 6 months before dosing (1 unit of ethanol is equivalent to 8 ounces of beer, 4 ounces of wine, or 1 ounce of spirits) or history of alcoholism and/or drug/chemical abuse.
18. Use of prescription medications (with the exception of oral contraceptives and hormone replacement therapy), including nonsteroidal anti-inflammatory drugs or sucralfate and medications known to prolong the QT/QTc interval or natural health products/herbal preparations within 14 days or 5 half lives (whichever is longer) before study drug dosing, or use of an over-the-counter (OTC) medication (excluding acetaminophen), vitamins, or supplements (including omega-3 fish oils) within 7 days before study drug dosing.
19. Use of alcohol , caffeine , or xanthine containing products, Seville oranges (sour), grapefruit, or grapefruit juice, within 72 hours before study drug dosing.
20. Current use or has used tobacco- or nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, etc.) 30 days before study drug dosing.
21. Strenuous activity (e.g., sports) from 96 hours (4 days) prior to entry into the clinical research unit and throughout the study (until the final follow-up call is conducted).
22. Donated more than 500 milliliter (mL) of blood or significant blood loss within 60 days prior to signing the informed consent form.
23. Any other medical, psychological, or social condition that, in the opinion of the principal investigator or the medical monitor, would prevent the subject from fully participating in the study, would represent a concern for study compliance, or would constitute a safety concern to the subject.
24. An employee of the investigator or study center with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as a family member of the employee or investigator.

Primary outcomes:
measure: Placebo-corrected change-from-baseline QTcF interval (ΔΔQTcF)
timeFrame: 24 hours after start of dosing
Secondary outcomes:
measure: Change-from-baseline HR
timeFrame: 24 hours after start of dosing
measure: Change-from-baseline QTcF inteval
timeFrame: 24 hours after start of dosing
measure: Change-from-baseline PR interval
timeFrame: 24 hours after start of dosing
measure: Change-from-baseline QRS interval
timeFrame: 24 hours after start of dosing
measure: Change-from-baseline RR interval
timeFrame: 24 hours after start of dosing
measure: Change-from-baseline QT interval
timeFrame: 24 hours after start of dosing
Other outcomes:
measure: Number of participants with treatment emergent adverse events as assessed by CTCAE v4.3
timeFrame: 7 days after treatment
measure: Number of participants with treatment emergent serious adverse events as assessed by CTCAE v4.3.
timeFrame: 7 days after treatment
Locations:
city: Baltimore
country: United States
facility: Pharmaron Cpc, Inc
state: Maryland
Study officials:
affiliation: Melinta Therapeutics, Inc.
name: Sue Cammarata
role: STUDY_DIRECTOR
References: