A Phase 1 TP-271 Oral PK Multiple Ascending Dose Study

Phase 1

Completed

• Conditions: Bacterial Infections
• Interventions: Drug: TP-271

• Registration Number: NCT03450187
• Lead Sponsor: Tetraphase Pharmaceuticals, Inc.

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.

Study Timeline

• Study First Submitted: 2018-02-16
• Study First Submitted QC: 2018-02-22
• Study First Posted: 2018-03-01
• Study Start: 2018-03-20
• Primary Completion: 2018-12-31
• Study Completion: 2019-03-31
• Status Verified: 2021-12
• Last Update Submitted: 2021-12-16
• Last Update Posted: 2021-12-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Be within the age range of 18 to 50 years, inclusive, at the time of Screening
2. 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
3. Have a body mass index (BMI) ≥18.0 and ≤33.0 kg/m2
4. Have a negative history of and negative screening results for human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B and C
5. Have the ability to communicate with the study unit staff in a manner sufficient to carry out all protocol procedures as described
6. 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)
7. 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

1. 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

2. 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.

3. Known allergy to tetracycline antibiotics or any of the excipients in TP 271

4. Clinically significant abnormality on a 12-lead ECG, which includes the following:

   • Rhythm other than sinus
   • Corrected QT interval using Fridericia's formula (QTcF) >450 msec
   • Evidence of second- or third-degree atrioventricular (AV) block
   • Pathological Q-waves (defined as a Q-wave >40 msec or depth >0.4 to 0.5 mV)
   • Evidence of ventricular pre-excitation
   • Evidence of complete left bundle branch block (BBB), right BBB, or incomplete left BBB
   • Intraventricular conduction delay with QRS duration >120 msec
   • ST segment abnormalities, unless judged by the PI to be nonpathologic

5. History of seizures

6. History within 3 years of a positive result on a urine screen for drugs of abuse or a positive result on a urine screen at Screening for any of the following drugs of abuse: tetrahydrocannabinols, cocaine, opioids, phencyclidines, amphetamines, benzodiazepines, barbiturates, and cotinine

7. Use of tobacco, nicotine, or nicotine-replacement products within 3 months prior to initial administration of study drug to the EOS Visit

8. Typical weekly alcohol consumption of 7 or more alcoholic drinks, where 1 alcoholic drink is defined as 1 glass of beer (approximately 10 to 12 oz), 1 can of beer (12 oz), 1 glass of wine (approximately 4 to 5 oz), or distilled spirits (approximately 1 oz or 30 mL of liquor)

9. Alcohol consumption within 48 hours prior to admission

10. Participation in a clinical study within 10 half-lives of the prior study treatment or within the previous 3 months (if the half-life of investigational agent is unknown) prior to initial administration of study drug or planned participation in another clinical study concurrent with the present study

11. History of difficulty donating blood or poor venous access

12. Recent blood donation (1 unit or approximately 525 mL) within 1 month prior to receiving study drug or plans to donate prior to receiving study drug or during the clinical study

13. Use of any prescription or nonprescription medication, including vitamins or herbal medications, vaccination, or immunization within 7 days or 5 half-lives (if known), whichever is longer, prior to initial administration of study drug, with the following exceptions: medications used to treat an AE are permitted, and the use of acetaminophen, naproxen, and ibuprofen is permitted, except for within 24 hours prior to dosing

14. Male subjects who donate or plan to donate sperm during the study or within 90 days after final administration of the study drug

15. Unwillingness or inability to follow the procedures outlined in the clinical study protocol

16. Previous participation in another TP-271 study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	TP-271	50 mg TP-271 q24 (n=6), a novel, broad-spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Cohort C	TP-271	200 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Cohort B	TP-271	100 mg TLP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Cohort D	TP-271	300 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.
Cohort E	TP-271	400 mg TP-271 q24 (n=6), a novel, broad spectrum tetracycline-class antibiotic or matching placebo (n=2) once daily for 7 days.

Primary Outcome Measures

Name	Time	Method
Vital Signs including Pulse Rate	Day -1 to the End of study visit, Day 21	Changes in Pulse Rate
A Directed Physical Examination including chest/respiratory	Day -1 to the End of Study visit, Day 21	changes in physical examination findings for chest/respiratory
Adverse Events	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	Day -1 to the end of study visit, Day 21	Changes in QRS interval\> or=10
Safety Laboratory results including coagulation	Day -1 to the End of study visit, Day 21	Changes in Safety Laboratory results including coagulation
A Directed Physical Examination including heart/cardiovascular	Day -1 to the End of study visit, Day 21	Changes in Physical Examination including heart/cardiovascular
Vital Signs including body temperature	Day -1 to the end of study visit, Day 21	Changes in body temperature
Safety Laboratory results including clinical chemistry	Day -1 to the End of study visit, Day 21	Changes in safety laboratory results including clinical chemistry
Vital Signs including respiration rate	Day -1 to the End of study visit, Day 21	Changes in respiration rate
Safety Laboratory results including blood glucose	Day -1 to the End of study visit, Day 21	Changes in Safety laboratory results including glucose
Vital Signs including blood pressure	Day -1 to the End of study visit, Day 21	Changes in blood pressure
Safety Laboratory results including hematology	Day -1 to the End of study visit, Day 21	Changes in safety laboratory results including hematology
ECG measurements including PR interval	Day -1 to the End of study visit, Day 21	Changes in PR interval \> or=20
ECG measurements including QTcF interval	Day -1 to the end of study visit, Day 21	Changes in QTcF interval 30 to 60, \> or =60
Safety Laboratory results including electrolytes	Day -1 to the End of study visit, Day 21	Changes in safety laboratory results including electrolytes

Secondary Outcome Measures

Name	Time	Method
Plasma concentrations	Days 1-7	Plasma concentrations of TP-271 and its C-4 epimer TP-9555 for PK analysis
PK parameters - AUC (0-inf)	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for AUC (0-inf) (The area under the concentration vs time curve from time zero extrapolated to infinity)
PK parameters - Lambda-z	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for Lambda-z (Slope of the regression line passing through the apparent elimination phase in a concentration vs time plot)
PK parameters - Cmax	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for Cmax (the maximum observed plasma concentration)
PK parameters AUC (0-last)	Days 1-7	Area under the concentration versus time curve (AUC) from time zero to the last measured time point
PK parameters- AUC% extrapolated	Days 1-7	PL parameters will be calculated from the plasma concentration versus time data (as appropriate) for AUC% extrapolated (the percentage of AUC 90-inf) accounted for by extrapolation)
PK parameters -T 1/2el	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for T1/2el (The elimination half-life)
Urine pharmacokinetics	Days 1-7	Urine concentrations of TP-271 and it's C-4 epimer, TP-9555
PK parameters- Tmax	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for Tmax
PK parameters - AUC (0-24)	Days 1-7	AUC from time zero to 24 hours (AUC 0-24)
PK parameters - Vd	Days 1-7	PK parameters will be calculated using the apparent volume of distribution following oral dosing
PK parameters - CL	Days 1-7	PK parameters will be calculated from the plasma concentration versus time data (as appropriate) for CL (Clearance: the volume of plasma cleared per unit time)

Trial Locations

Locations (1)

PPD Phase I Clinic; 🇺🇸 Austin, Texas, United States