A Study of Oral and Intravenous (IV) Tedizolid Phosphate in Hospitalized Participants, Ages 2 to <12 Years, With Confirmed or Suspected Bacterial Infection (MK-1986-013)

A Phase 1, Single-Administration Pharmacokinetic and Safety Study of Oral and IV Tedizolid Phosphate in Hospitalized Subjects 2 to <12 Years Old

This is a study to assess the pharmacokinetics (PK) of tedizolid phosphate and its active metabolite, tedizolid, and the safety of tedizolid phosphate following administration of a single IV (Part A) or oral suspension (Part B) administration to hospitalized participants ages 6 to <12 years (Groups 1 and 3, respectively), and 2 to <6 years (Groups 2 and 4, respectively).

Study Overview

• Status: Completed
• Conditions: Gram-Positive Bacterial Infections
• Intervention / Treatment: Drug: Tedizolid Phosphate (IV); Drug: Tedizolid Phosphate (oral suspension)

Detailed Description

Part A (IV):

• Group 1 (Cohort 1 and Cohort 2) (6 to <12 years)
• Group 2 (Cohort 1 and Cohort 2) (2 to <6 years)

Part B (Oral Suspension):

• Group 3 (6 to <12 years)
• Group 4 (2 to <6 years)

In Cohort 1 of Group 1 (IV) participants received a single administration of tedizolid phosphate at 5 mg/kg of total body weight. After all participants in Cohort 1 of Group 1 received study drug, a preliminary analysis of the safety and PK data was performed and results were used to select 4 mg/kg as the appropriate dose for Cohort 2 of Group 1 and Group 3, and to select 6 mg/kg as the starting dose for the younger participants, Cohort 1 of Group 2. After all participants in Cohort 1 of Group 2 receive study drug, another preliminary analysis of the safety and PK data will be performed and results will be used to confirm 6 mg/kg as the appropriate dose for Cohort 2 of Group 2. Similarly, the Group 4 dose will be confirmed after data review of Group 3 results.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Receiving prophylaxis for or with a confirmed or suspected infection with Gram-positive bacteria and receiving concurrent antibiotic treatment with Gram-positive antibacterial activity;
• Weight >5th percentile and <95th percentile based on age;
• Stable condition as determined from medical history, physical examination, minimally 5-lead electrocardiogram (ECG), vital signs, and clinical laboratory evaluations;
• Females must be premenarchal, abstinent, or practicing an effective method of birth control;

Exclusion Criteria:

• History of seizures, other than febrile seizures, clinically significant cardiac arrhythmia, cystic fibrosis, moderate or severe renal impairment, or any physical condition that could interfere with the study results;
• Recent (3 month) history or current infection with viral hepatitis or other significant hepatic disease;
• History of drug allergy or hypersensitivity to oxazolidinones;
• Pregnant or breast feeding;
• Significant blood loss within 60 days prior to study start;
• Any acute or chronic condition that would limit the participant's ability to complete and/or participate in this clinical study.
• Treatment with investigational medicinal product within 30 days before the infusion/dose of study drug.
• Oral administration of methotrexate, topotecan, irinotecan or rosuvastatin, during administration of oral study drug. Administration during the follow-up period is allowed, as is administration during treatment with IV study drug.
• Use of monoamine oxidase inhibitors or serotonergic agents including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin 5 hydroxytryptamine receptor agonists (triptans), meperidine, or buspirone within,14 days prior to study, or planned use while on study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 Cohort 1: Tedizolid IV 5 mg/kg (6 to <12 years); Participants 6 to <12 years of age received a single intravenous infusion of tedizolid phosphate dosed at 5 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (IV); 200 mg/vial powder for injection; Other Names: TR-701 FA; MK-1986; Sivextro
Experimental: Group 1 Cohort 2: Tedizolid IV 4 mg/kg (6 to <12 years); Participants 6 to <12 years of age received a single intravenous infusion of tedizolid phosphate dosed at 4 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (IV); 200 mg/vial powder for injection; Other Names: TR-701 FA; MK-1986; Sivextro
Experimental: Group 2 Cohort 1: Tedizolid IV 6 mg/kg (2 to <6 years); Participants 2 to <6 years of age received a single intravenous infusion of tedizolid phosphate dosed at 6 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (IV); 200 mg/vial powder for injection; Other Names: TR-701 FA; MK-1986; Sivextro
Experimental: Group 2 Cohort 2: Tedizolid IV 3 mg/kg (2 to <6 years); Participants 2 to <6 years of age received a single intravenous infusion of tedizolid phosphate dosed at 3 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (IV); 200 mg/vial powder for injection; Other Names: TR-701 FA; MK-1986; Sivextro
Experimental: Group 3: Tedizolid oral 4 mg/kg (6 to <12 years); Participants 6 to <12 years of age received a single dose of tedizolid phosphate oral suspension dosed at 4 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (oral suspension); Powder for oral suspension 20 mg/mL following reconstitution; Other Names: TR-701 FA; MK-1986; Sivextro
Experimental: Group 4: Tedizolid oral 3 mg/kg (2 to <6 years); Participants 2 to <6 years of age received a single dose of tedizolid phosphate oral suspension dosed at 3 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.	Drug: Tedizolid Phosphate (oral suspension); Powder for oral suspension 20 mg/mL following reconstitution; Other Names: TR-701 FA; MK-1986; Sivextro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Drug Concentration in Plasma (Cmax) of Tedizolid Phosphate (Prodrug)	Cmax of tedizolid phosphate in participants ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2). Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Time to Reach Peak Plasma Concentration (Tmax) of Tedizolid Phosphate (Prodrug)	Time to reach peak plasma concentration (Tmax) of tedizolid phosphate in participants ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2). Tedizolid phosphate concentrations were below the lower limit of quantification in Group 3 and Group 4. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Area Under the Plasma Concentration Time Curve (AUC) of Tedizolid Phosphate (Prodrug) From Time Zero to Last Detectable Measurement	Area under the plasma concentration time curve (AUC) of tedizolid phosphate from time zero to last detectable measurement following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Area Under the Plasma Concentration Time Curve (AUC) of Tedizolid Phosphate (Prodrug) From Time Zero to Infinity	Area under the plasma concentration time curve (AUC) of tedizolid phosphate from time zero to infinity following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Terminal Elimination Half-life (T1/2) of Tedizolid Phosphate (Prodrug)	Terminal elimination half-life (T1/2) of tedizolid phosphate following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Clearance (CL) of Tedizolid Phosphate (Prodrug) in Participants Who Received Tedizolid Phosphate Intravenously (IV)	CL of IV tedizolid phosphate in participants ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2).	Group 1 (6 to <12 years): Day 1 immediately after infusion and at 1.5, 2, 3, 4, 6, 12, and 24 hours. Group 2 (2 to <6 years): Day 1 immediately after infusion and at 3, 6, 12, 24 and 48 hours.
Clearance (CL/F) of Tedizolid Phosphate in Participants Who Received Oral Tedizolid Phosphate (Prodrug)	CL/F of oral suspension tedizolid phosphate and its active metabolite, tedizolid, in participants ages 6 to <12 years (Group 3) and 2 to <6 years (Groups 4).	Group 3 (6 to <12 years): at 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose; Group 4 (2 to <6 years): at 3, 6, 9, 12, 24 and 48 hours after the dose
Maximum Observed Drug Concentration in Plasma (Cmax) of Tedizolid (the Active Metabolite)	Maximum observed drug concentration in plasma (Cmax) of tedizolid (active metabolite) following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Time to Reach Peak Plasma Concentration (Tmax) of Tedizolid (the Active Metabolite)	Time to reach peak plasma concentration (Tmax) of tedizolid (active metabolite) following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Area Under the Plasma Concentration Time Curve (AUC) of Tedizolid (Active Metabolite) From Time Zero to Last Detectable Measurement	Area under the plasma concentration time curve (AUC) of tedizolid (active metabolite) from time zero to last detectable measurement following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Area Under the Plasma Concentration Time Curve (AUC) of Tedizolid (Active Metabolite) From Time Zero to Infinity	Area under the plasma concentration time curve (AUC) of tedizolid (active metabolite) from time zero to infinity following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Terminal Elimination Half-life (T1/2) of Tedizolid (Active Metabolite)	Terminal elimination half-life (T1/2) of tedizolid (active metabolite) following administration of IV or oral dose. Pharmacokinetic sampling occurred at the following time points: Group 1 (6 to <12 years): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (IV): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (6 to <12 years): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (2 to <6 years): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.
Clearance (CL) of Tedizolid (Active Metabolite) in Participants Who Received Tedizolid Phosphate Intravenously (IV)	CL of IV tedizolid phosphate and its active metabolite, tedizolid, in participants ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2).	Group 1 (6 to <12 years): Day 1 immediately after infusion and at 1.5, 2, 3, 4, 6, 12, and 24 hours. Group 2 (2 to <6 years): Day 1 immediately after infusion and at 3, 6, 12, 24 and 48 hours.
Clearance (CL/F) of Tedizolid (Active Metabolite) in Participants Who Received Oral Tedizolid Phosphate	CL/F of tedizolid, in participants ages 6 to <12 years (Group 3) and 2 to <6 years (Groups 4).	Group 3 (6 to <12 years): at 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose; Group 4 (2 to <6 years): at 3, 6, 9, 12, 24 and 48 hours after the dose
Dose Normalized Area Under the Plasma Concentration Time Curve (AUC) of Tedizolid (Active Metabolite) From Time Zero to Infinity	The area under the plasma concentration time curve (AUC) of tedizolid (active metabolite) from time zero to infinity following administration of IV or oral dose, normalized to dosage, was calculated. Per protocol, this outcome used pooled groups as follows: The IV Group pooled Groups 1 and 2, who received tedizolid phosphate via intravenous (IV) administration; the Oral Group pooled groups 3 and 4, who received tedizolid phosphate via oral administration. Pharmacokinetic sampling occurred at the following time points: Group 1 (part of the IV Group): Day 1 immediately after infusion and 1.5, 2, 3, 4, 6, 12, and 24 hours; Group 2 (part of the IV Group): Day 1 immediately after infusion and 3, 6, 12, 24 and 48 hours; Group 3 (part of the Oral Group): Day 1 at 1, 2, 3, 4, 6, 8, 12, and 24 hours after oral dose; Group 4 (part of the Oral Group): Day 1 at 3, 6, 9, 12, 24 and 48 hours after oral dose.	IV: immediately after the end of the infusion, and various time points up to 48 hours after the start of infusion as described above. Oral: at various time points up to 48 hours after the dose as described above.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced at Least One Adverse Event	An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.	Up to 9 days
Number of Participants Who Discontinued Study Drug Due to an Adverse Event	An adverse event is defined as any untoward medical occurrence in a person administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.	1 day
Palatability of Oral Tedizolid Phosphate Suspension in Participants Who Received Oral Tedizolid Phosphate	Palatability of oral tedizolid phosphate suspension in participants ages 6 to <12 years (Group 3) and 2 to <6 years (Group 4). Palatability was assessed using a 5-point hedonic scale and spontaneous verbal judgment. This hedonic scale consists of 5 pictures of line drawn faces corresponding to very bad, bad, neither good nor bad, good and very good. The participant was asked to mark or point to the face to show how they felt about the taste of the study drug. For preverbal children, the score was assessed by the parent/caregiver, or study staff administering or witnessing administration of the study drug.	Following single oral dose on Day 1

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Arrieta AC, Ang JY, Espinosa C, Fofanov O, Tondel C, Chou MZ, De Anda CS, Kim JY, Li D, Sabato P, Sears PS, Bradley JS. Pharmacokinetics and Safety of Single-dose Tedizolid Phosphate in Children 2 to <12 Years of Age. Pediatr Infect Dis J. 2021 Apr 1;40(4):317-323. doi: 10.1097/INF.0000000000003030.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2016
• Primary Completion (Actual): December 16, 2018
• Study Completion (Actual): December 21, 2018

Study Registration Dates

• First Submitted: April 1, 2016
• First Submitted That Met QC Criteria: April 21, 2016
• First Posted (Estimate): April 25, 2016

Study Record Updates

• Last Update Posted (Actual): December 20, 2019
• Last Update Submitted That Met QC Criteria: December 2, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bacterial Infections and Mycoses; Infections; Bacterial Infections; Gram-Positive Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Oxazolidinones; Tedizolid; Tedizolid phosphate
• Other Study ID Numbers: 1986-013; TR701-120 (Other Identifier: Cubist Protocol Number); 2015-004595-29 (EudraCT Number); MK-1986-013 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No