Evaluate Effects of Meropenem-Vaborbactam on QT/QTc in Healthy Volunteers

NCT03564158 | Completed Phase 1 FDA Drug

• 1 other identifier: Rempex 512
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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

Conditions

Healthy

Outcome Measures

Primary Outcomes (1)

• Placebo-corrected change-from-baseline QTcF interval (ΔΔQTcF)

  Change in placebo corrected QTcF after dosing

  24 hours after start of dosing

Secondary Outcomes (6)

• Change-from-baseline HR

  24 hours after start of dosing

• Change-from-baseline QTcF inteval

  24 hours after start of dosing

• Change-from-baseline PR interval

  24 hours after start of dosing

• Change-from-baseline QRS interval

  24 hours after start of dosing

• Change-from-baseline RR interval

  24 hours after start of dosing

Other Outcomes (2)

• Number of participants with treatment emergent adverse events as assessed by CTCAE v4.3

  7 days after treatment

• Number of participants with treatment emergent serious adverse events as assessed by CTCAE v4.3.

  7 days after treatment

Study Arms (4)

meropenem 2 g- vaborbactam 2 g

EXPERIMENTAL

Approved Dose

Drug: meropenem-vaborbactam

meropenem-vaborbactam (dose TBD)

EXPERIMENTAL

Supratherapeutic Dose

Drug: meropenem-vaborbactam

Moxifloxacin 400 mg

ACTIVE COMPARATOR

Active Control

Drug: Moxifloxacin

Normal Saline (placebo)

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

meropenem-vaborbactam DRUG

Meropenem-Vaborbactam being studied for effects on TQT

Also known as: Vabomere

meropenem 2 g- vaborbactam 2 g; meropenem-vaborbactam (dose TBD)

Placebo DRUG

Placebo

Also known as: Saline

Normal Saline (placebo)

Moxifloxacin DRUG

Active Comparator

Also known as: Moxi

Moxifloxacin 400 mg

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female subject between 18 and 55 years of age, inclusive, with a body mass index (BMI) ≥18 to ≤33 kilogram (kg)/m2.
• 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.
• 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).
• Willing to comply with all study activities and procedures and provides written informed consent prior to any study procedures

You may not qualify if:

• Known hypersensitivity to beta-lactam antibiotics (including meropenem), fluoroquinolone antibiotics (including moxifloxacin) or vaborbactam.
• 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.
• 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.
• Subject has any clinically relevant abnormalities, as determined by the Investigator, in the laboratory results at Screening or admission of each study period
• 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.
• Hemoglobin and hematocrit lower than the lower limit of normal for the reference lab at Screening.
• 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.
• History of central nervous system (CNS) disorder including convulsions.
• 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.
• Impaired renal function as evidenced by estimated glomerular filtration rate (eGFR) \<50.
• Unstable cardiovascular disease, including recent myocardial infarction or cardiac arrhythmia.
• 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.
• Positive drug, alcohol, or tobacco screen.
• Clinically-significant illness, including viral syndromes within 3 weeks of dosing.
• 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.

Sponsors & Collaborators

• Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.): lead
• Biomedical Advanced Research and Development Authority: collaborator

Study Sites (1)

Pharmaron Cpc, Inc

Baltimore, Maryland, 21201, United States

Location

MeSH Terms

Interventions

meropenem and vaborbactam; Sodium Chloride; Moxifloxacin

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Sue Cammarata

  Melinta Therapeutics, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Only Moxifloxacin will be administered open-label.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2018
• First Posted: June 20, 2018
• Study Start: May 1, 2018
• Primary Completion: November 19, 2018
• Study Completion: November 19, 2018
• Last Updated: January 10, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)