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)

Study Overview
=================
Brief Summary
-----------------
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).

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.

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

Conditions
-----------------
Gram-Positive Bacterial Infections

Intervention / Treatment
-----------------
* Drug: Tedizolid Phosphate (IV)
* Drug: Tedizolid Phosphate (oral suspension)


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 Cohort 1: Tedizolid IV 5 mg/kg (6 to <12 years)<br>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)<br>* 200 mg/vial powder for injection<br>* Other names: MK-1986;|
| Experimental: Group 1 Cohort 2: Tedizolid IV 4 mg/kg (6 to <12 years)<br>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)<br>* 200 mg/vial powder for injection<br>* Other names: MK-1986;|
| Experimental: Group 2 Cohort 1: Tedizolid IV 6 mg/kg (2 to <6 years)<br>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)<br>* 200 mg/vial powder for injection<br>* Other names: MK-1986;|
| Experimental: Group 2 Cohort 2: Tedizolid IV 3 mg/kg (2 to <6 years)<br>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)<br>* 200 mg/vial powder for injection<br>* Other names: MK-1986;|
| Experimental: Group 3: Tedizolid oral 4 mg/kg (6 to <12 years)<br>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)<br>* Powder for oral suspension 20 mg/mL following reconstitution<br>* Other names: MK-1986;|
| Experimental: Group 4: Tedizolid oral 3 mg/kg (2 to <6 years)<br>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)<br>* Powder for oral suspension 20 mg/mL following reconstitution<br>* Other names: MK-1986;|

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 |