Study of the Safety and Pharmacokinetics of KSP-1007 Alone and Coadministered With Meropenem in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
This study is a first-in-human, Phase 1, randomized, double- blind, four-part, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of single (Part 1) and repeat (Part 2) escalating intravenous doses of KSP-1007. Repeated escalating doses of KSP-1007 will be co-administered with meropenem (Part 3) and single, ascending doses of KSP-1007 will be administered alone in healthy Japanese subjects (Part 4)

Detailed Description
-----------------
Carbapenem-resistant Gram-negative bacteria are responsible for serious, life-threatening infections and are regarded as an urgent threat by the Centers for Disease Control and Prevention and the World Health Organizations. One principal mechanism of carbapenem resistance is bacterial production of carbapenemases, which reduce the effectiveness of meropenem and other carbapenem class antibiotics. Sumitovant Biopharma is developing a fixed combination of meropenem and KSP-1007 for the treatment of serious bacterial infections.

Official Title
-----------------
A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Repeat Doses of KSP-1007 Alone and Coadministered With Meropenem in Healthy Subjects

Conditions
-----------------
Bacterial Infections

Intervention / Treatment
-----------------
* Drug: KSP-1007
* Other: Placebo:0.9% sodium chloride
* Drug: Meropenem


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male or female subjects 18 to 55 years of age, inclusive Females that engage in heterosexual activity must agree to use a highly selective birth control (BC) method (< 1% failure rate per year) throughout the study, or have a documented reproductive status of non-childbearing based on medical history, or is postmenopausal Males that engage in heterosexual activity that has the risk of pregnancy must agree to use effective BC and agree to not donate sperm during the study and for at least 90 days after the last dose of the study medication Body mass index (BMI) 2: 18 kg/m2 and :s 32 kg/m2 Exclusion Criteria: History of Gilbert's Syndrome History of severe allergic reactions to β-lactams or β-lactamase inhibitors or a history allergic reactions to multiple medications. Pregnant female, determined by positive serum or urine human chorionic gonadotropin pregnancy test at Screening, or prior to dosing Lactating female Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding volume drawn at Screening) of > 499 mL within 56 days prior to Day 1 Participation in a study with an investigational drug or device study with last dose of investigational drug within 30 days (90 days if the study involved a biologic, cellular, or vaccine product) or 5 half-lives, whichever is longer, before study treatment administration Subjects with abnormal hepatic and/or renal function, that could interfere with the metabolism, and/or excretion of the study treatments Abnormal blood pressure, either low (defined as < 90 mmHg systolic and/ or < 45 mmHg diastolic) or high (defined as > 140 mmHg systolic and/ or > 90 mmHg diastolic) at Screening Positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV at Screening. Subjects who test positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) also will be ineligible. Evidence of prior HBV vaccination (positive hepatitis B surface antibody [HBsAb)) is not exclusionary. Subjects unable to abstain from alcohol for 48 hours prior to admission through to completion of the Follow-up visit

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KSP-1007 single ascending dose<br>Single, ascending intravenous dose of KSP-1007 | Drug: KSP-1007<br>* Single and multiple doses, intravenous administration<br>|
| Placebo Comparator: Placebo single dose<br>Single dose of placebo (0.9% normal saline) | Other: Placebo:0.9% sodium chloride<br>* Single and multiple doses, intravenous administration<br>|
| Experimental: KSP-1007 multiple ascending dose<br>Multiple, ascending, intravenous doses of KSP-1007 | Drug: KSP-1007<br>* Single and multiple doses, intravenous administration<br>|
| Placebo Comparator: Placebo multiple dose<br>Multiple doses of placebo (0.9% saline) | Other: Placebo:0.9% sodium chloride<br>* Single and multiple doses, intravenous administration<br>|
| Experimental: KSP-1007 multiple ascending dose + Meropenem multiple dose<br>Multiple, ascending intravenous doses of KSP-1007 and multiple doses of meropenem (fixed dose) | Drug: KSP-1007<br>* Single and multiple doses, intravenous administration<br>Drug: Meropenem<br>* Multiple doses, intravenous administration<br>|
| Placebo Comparator: Placebo + Meropenem multiple dose<br>Multiple doses of placebo (0.9% normal saline) plus multiple doses of meropenem (fixed dose) | Other: Placebo:0.9% sodium chloride<br>* Single and multiple doses, intravenous administration<br>Drug: Meropenem<br>* Multiple doses, intravenous administration<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events assessed by subject . | Incidence of adverse events | up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration of KSP-1007 | The plasma concentration of KSP-1007 will be measured over time, and the peak plasma concentration, or Cmax, of KSP-1007 will be determined | Up to 5 days after dosing | 
| Plasma concentration of KSP-1007 versus time curve | The plasma concentration of KSP-1007 will be measured over time and the area under the curve, or AUC, of KSP-1007 will be determined | Up to 5 days after dosing | 
| Cumulative amount of KSP-1007 excreted in urine over time | Total amount of unchanged drug excreted in urine over a dosing interval | Up to 5 days after start of dosing | 
| Renal clearance of KSP-1007 in urine over time | Renal clearance in urine. Urine was collected up to 5 days after dosing. | Up to 5 days after start of dosing | 
| Peak plasma concentration of meropenem | The plasma concentration of meropenem will be measured over time, and the peak plasma concentration, or Cmax, of meropenem will be determined | Up to 5 days after start of dosing | 
| Plasma concentration versus time curve of meropenem | The plasma concentration of meropenem will be measured over time and the area under the curve, or AUC, of meropenem will be determined | Up to 5 days after start of dosing | 
| Cumulative amount of meropenem excreted in urine over time | Total amount of unchanged drug excreted in urine over a dosing interval. | Up to 5 days after start of dosing | 
| Renal clearance of meropenem in urine over time | Renal clearance in urine. Urine was collected up to 5 days after dosing. | Up to 5 days after start of dosing | 
| ECG QTcF interval | Change from baseline QTcF interval | 24 hours after start of dosing | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bacterial Disease, Bacterial Infection, Bacterial Infections, Bacterial, Healthy Volunteers