A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Oral TP-271 in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- TP-271
- Conditions
- Bacterial Infections
- Sponsor
- Tetraphase Pharmaceuticals, Inc.
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- A Directed Physical Examination including chest/respiratory
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This is a phase 1, single-center, randomized, placebo-controlled, double-blind, multiple ascending-dose study to assess the safety, tolerability, and PK of oral TP-271 in healthy adult subjects. Male or female subjects aged 18 to 50 years who fulfill the inclusion/exclusion criteria will be enrolled in this study.
Detailed Description
This is a phase 1, single-center, randomized, placebo-controlled, double-blind, multiple ascending-dose study to assess the safety, tolerability, and PK of oral TP-271 in healthy adult subjects. Male or female subjects aged 18 to 50 years who fulfill the inclusion/exclusion criteria will be enrolled in this study. Up to 5 cohorts of 8 subjects each (up to a total of 40 subjects) will be enrolled. Subjects in each cohort will be randomized 6:2 to receive multiple oral doses of TP 271 or placebo. Every effort will be made to dose all subjects in a cohort on the same day. Doses of study drug will be administered orally either once daily in the morning or twice daily in the morning and evening from Days 1 to 7. In all subjects, the morning dose will be administered following an overnight fast (minimum 8 hours) of food and all beverages, except for water. For subjects in Cohorts D and E only, the evening dose will be administered following a minimum 3-hour fast of food and all beverages, except for water. Fasting in all cohorts will continue for at least 2 hours following each study drug administration. During the Screening Period (within 28 days prior to the subject receiving study drug), each subject will be assessed for eligibility. Each subject must sign and date an ICF prior to undergoing any study-related procedures.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be within the age range of 18 to 50 years, inclusive, at the time of Screening
- •Voluntarily sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved ICF to participate in the study after all relevant aspects of the study have been explained to and discussed with the subject and before undergoing any study-related procedures
- •Have a body mass index (BMI) ≥18.0 and ≤33.0 kg/m2
- •Have a negative history of and negative screening results for human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B and C
- •Have the ability to communicate with the study unit staff in a manner sufficient to carry out all protocol procedures as described
- •Female subjects must be of non-childbearing potential, either 1-year postmenopausal or surgically sterile (i.e., bilateral oophorectomy, bilateral tubal ligation, or complete hysterectomy)
- •Male subjects must be willing and able to use a barrier method of contraception or practice abstinence (including male subjects who had a vasectomy) from dosing to 90 days after final administration of the study drug
Exclusion Criteria
- •History and/or presence of any clinically significant disease or disorder, such as cardiovascular, pulmonary, renal, hepatic, neurological, gastrointestinal, endocrine, psychiatric or mental disease or disorder, or mental or legal incapacitation, which, in the opinion of the PI, may either put the subject at risk due to 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 of the eligibility range specified in Appendix D are exclusionary; for clinical laboratory values that are not included in Appendix D, values outside of the reference range are exclusionary, except for those parameters listed in Table 4).
- •Table 4 Acceptable Out-of-Range Clinical Laboratory Values
- •Low Chemistry Values:
- •Bicarbonate (a) Chloride GGT HDL cholesterol LDH LDL cholesterol Phosphorus
- •High Chemistry Values:
- •Chloride HDL cholesterol LDL cholesterol Phosphorus Triglycerides
- •Out-of-Range Urinalysis Values; High or low specific gravity Cloudy Mucus Crystals Ketones (b) Hyaline casts High or low pH Urobilinogen (c)
- •Out of Range Hematology Values; High hematocrit Basophils Monocytes MCV MCH MCHC RBC
- •a Bicarbonate \>18 mEq/L. b Acceptable only when the concurrent blood glucose is normal. c Measured when monitoring the serum bilirubin concentration. Abbreviations: GGT = gamma-glutamyltransferase; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell.
Arms & Interventions
Cohort A
50 mg TP-271 q24 (n=6), a novel, broad-spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Intervention: TP-271
Cohort B
100 mg TLP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Intervention: TP-271
Cohort C
200 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Intervention: TP-271
Cohort D
300 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Intervention: TP-271
Cohort E
400 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Intervention: TP-271
Outcomes
Primary Outcomes
A Directed Physical Examination including chest/respiratory
Time Frame: Day -1 to the End of Study visit, Day 21
changes in physical examination findings for chest/respiratory
Adverse Events
Time Frame: From the time of signing of the informed consent form throughout study completion (approximately 39 days)
Incidence, intensity, and type of adverse events.
ECG measurements including QRS interval
Time Frame: Day -1 to the end of study visit, Day 21
Changes in QRS interval\> or=10
Safety Laboratory results including coagulation
Time Frame: Day -1 to the End of study visit, Day 21
Changes in Safety Laboratory results including coagulation
A Directed Physical Examination including heart/cardiovascular
Time Frame: Day -1 to the End of study visit, Day 21
Changes in Physical Examination including heart/cardiovascular
Vital Signs including body temperature
Time Frame: Day -1 to the end of study visit, Day 21
Changes in body temperature
Safety Laboratory results including clinical chemistry
Time Frame: Day -1 to the End of study visit, Day 21
Changes in safety laboratory results including clinical chemistry
Vital Signs including respiration rate
Time Frame: Day -1 to the End of study visit, Day 21
Changes in respiration rate
Safety Laboratory results including blood glucose
Time Frame: Day -1 to the End of study visit, Day 21
Changes in Safety laboratory results including glucose
Vital Signs including Pulse Rate
Time Frame: Day -1 to the End of study visit, Day 21
Changes in Pulse Rate
Vital Signs including blood pressure
Time Frame: Day -1 to the End of study visit, Day 21
Changes in blood pressure
Safety Laboratory results including hematology
Time Frame: Day -1 to the End of study visit, Day 21
Changes in safety laboratory results including hematology
ECG measurements including PR interval
Time Frame: Day -1 to the End of study visit, Day 21
Changes in PR interval \> or=20
ECG measurements including QTcF interval
Time Frame: Day -1 to the end of study visit, Day 21
Changes in QTcF interval 30 to 60, \> or =60
Safety Laboratory results including electrolytes
Time Frame: Day -1 to the End of study visit, Day 21
Changes in safety laboratory results including electrolytes
Secondary Outcomes
- Plasma concentrations(Days 1-7)
- PK parameters - AUC (0-inf)(Days 1-7)
- PK parameters - Lambda-z(Days 1-7)
- PK parameters - Cmax(Days 1-7)
- PK parameters AUC (0-last)(Days 1-7)
- PK parameters- AUC% extrapolated(Days 1-7)
- PK parameters -T 1/2el(Days 1-7)
- Urine pharmacokinetics(Days 1-7)
- PK parameters- Tmax(Days 1-7)
- PK parameters - AUC (0-24)(Days 1-7)
- PK parameters - Vd(Days 1-7)
- PK parameters - CL(Days 1-7)