A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Single-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Intravenous TP-271 in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- TP-271
- Conditions
- Pneumonia
- Sponsor
- Tetraphase Pharmaceuticals, Inc.
- Enrollment
- 57
- Locations
- 1
- Primary Endpoint
- Adverse Events (AE)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This is a single-center, randomized, placebo-controlled, double-blind, single-ascending-dose, inpatient study to assess the safety, tolerability, and pharmacokinetics of TP-271 in healthy subjects. Subjects aged 18 to 50 years who fulfill the inclusion/exclusion criteria will be enrolled in this study.
Detailed Description
Up to seven cohorts of eight subjects each (up to a total of 56 subjects) will be enrolled. The eight subjects within each cohort will be randomized 6:2 to receive a single intravenous dose of TP-271 or placebo. The planned doses are: Cohort A: 0.15 mg/kg Cohort B: 0.45 mg/kg Cohort C: 1.0 mg/kg Cohort D: 2.0 mg/kg Cohort E: 3.0 mg/kg Cohort F: 4.0 mg/kg Cohort G: 5.0 mg/kg Doses of IMP will be administered intravenously on the morning of Day 1 following an overnight fast (minimum 8 hours). During the Screening Period (within the 28 days prior to the subject receiving TP-271 or placebo) each subject will be assessed for eligibility. Each subject must sign and date an ICF prior to undergoing any study-related procedures. All cohorts will follow the same study design (Figure 1). On Day -1, subjects will be admitted to the study unit so their eligibility can be confirmed. Subjects will be required to stay overnight at the study unit on Day -1. On Day 1, eligible subjects will be enrolled and randomized to receive either TP-271 or placebo. Subjects will be required to stay at the study unit from Day 1 through Day 5 to assess safety and obtain required PK samples. On Day 5, subjects will be discharged from the study unit. A final safety assessment will be performed once between Day 7 and Day 10 following the subject's dose of IMP.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be within the age range of 18 to 50 years, inclusive, at the time of Screening.
- •Voluntarily sign an IRB/Research Ethics Committee (IRB/REC)-approved ICF to participate in the study after all relevant aspects of the study have been explained and discussed with the subject and before undergoing any study related procedures.
- •Have a body mass index (BMI) ≥18.0 and ≤33.0 kg/m
- •Be clear of any history of, and have negative screen for, HIV 1 and 2 and hepatitis B and C.
- •Have the ability to communicate with the investigative site staff in a manner sufficient to carry out all protocol procedures as described.
- •Females must be of non-child bearing potential, either 1-year post-menopausal or surgically sterile (bilateral oophorectomy, bilateral tubal ligation, or complete hysterectomy).
- •Male subjects must be willing and able to use a barrier method of birth control or practice abstinence (even if they have had a vasectomy) from dosing through 90 days after the dose of IMP.
Exclusion Criteria
- •History and/or presence of any clinically significant disease or disorder such as cardiovascular, pulmonary, renal, hepatic, neurological, gastrointestinal, and psychiatric/mental disease/disorders, which, in the opinion of the PI, may either put the subject at risk because of participation in the study, influence the results of the study, or influence the subject's ability to participate in the study.
- •Clinical laboratory values that fall outside the eligibility range specified in the table in Appendix C are exclusionary. For the laboratory values that are not included in Appendix C, values outside of the reference range are exclusionary with the following exceptions:
- •Low Chemistry Values High Chemistry Values Out of Range UA Out of Range Hematology Bicarbonate (\> 18 mEq/L Chloride GGT HDL Cholesterol LDH LDL Cholesterol Phosphorus Triglycerides Chloride HDL Cholesterol LDL Cholesterol Phosphorus Triglycerides High or low specific gravity Cloudy Mucus Crystals Ketones (when blood glucose is normal) Hyaline casts High or low pH
- •High hematocrit Basophils Monocytes MCV MCHC MCH RBC
- •Blood pressure and pulse outside of the following ranges are exclusionary:
- •Systolic blood pressure 85 - 145 mm Hg
- •Diastolic blood pressure 50 - 95 mm Hg
- •Pulse rate 45 - 95 beats per minute (bpm)
- •Known allergy to tetracycline antibiotics or to any of the excipients in TP-
- •Clinically significant abnormal 12-lead ECG, including the following:
Arms & Interventions
Cohort A
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 0.15 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort B
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 0.45 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort C
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 1.0 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort D
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 2.0 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort E
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 3.0 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort F
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 4.0 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Cohort G
IV dose of TP-271, a novel, broad-spectrum tetracycline-class antibiotic, 5.0 mg/kg single dose, 60 minute infusion or Placebo - sterile 0.45% saline for 60 minute IV infusion
Intervention: TP-271
Outcomes
Primary Outcomes
Adverse Events (AE)
Time Frame: Through study completion, appromiximately 39 days
The incidence, intensity, and type of adverse events (AE) Outcome measures to be collected in support of the primary objective (safety and tolerability) include: * The incidence, intensity, and type of AEs (from time of signing of informed consent form \[ICF\] through EOS); * Changes in physical examination findings (Day -1 and EOS); * Changes in vital signs (Day -1 through EOS); * Changes in safety laboratory (chemistry, hematology, coagulation, urinalysis) results (Days -1 through EOS); and * Changes in ECG measurements (Days -1 through EOS).
Physical Exams
Time Frame: Through study completion, appromiximately 39 days
Changes in physical examination findings
Vital Signs
Time Frame: Through study completion, appromiximately 39 days
Changes in vital signs
Safety Laboratory
Time Frame: Through study completion, appromiximately 39 days
Changes in safety laboratory (chemistry, hematology, coagulation, urinalysis) results
ECG measurements
Time Frame: Through study completion, appromiximately 39 days
Changes in ECG measurements
Secondary Outcomes
- PK parameters - epimer/parent(Days 1-5)
- Urine Pharmacokinetic (PK) Analysis(Days 1-5)
- PK parameters - Tmax(Days 1-5)
- PK parameters - C8(Days 1-5)
- PK parameters - AUC(0-last)(Days 1-5)
- PK parameters - AUC(0-inf)(Days 1-5)
- PK parameters - CL(Days 1-5)
- Plasma Pharmacokinetic (PK) Analysis(Days 1-5)
- PK parameters - Cmax(Days 1-5)
- PK parameters - C24(Days 1-5)
- PK parameters - AUC%extrap(Days 1-5)
- PK parameters - Vd(Days 1-5)
- PK parameters - C12(Days 1-5)
- PK parameters - Lambda-z(Days 1-5)
- PK parameters - T1/2el(Days 1-5)