Clinical trial NCT03024034: A Phase 1 TP-271 Oral PK Single Ascending Dose Study
Official title: A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Oral TP-271 in Healthy Adult Subjects, Including 1 Cross-over Arm
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Bacterial Infections
Lead sponsor: La Jolla Pharmaceutical Company
Sponsor class: INDUSTRY
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2017-01-18
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to determine the safety and tolerability of up to 6 different single ascending oral doses of TP-271, ranging from 25 mg to 300 mg, in healthy adult male or female subjects.

Detailed description: This study is designed to assess oral TP-271, and the objectives of the study are to examine the safety, tolerability, and PK of oral TP-271 in healthy adult subjects after administration of a single dose. A single-dose, dose-escalating study design is common for early clinical studies. A cohort size of 8 subjects (6 receiving oral TP-271 and 2 receiving placebo) for the single ascending dose cohorts (Cohorts A through F) will allow sufficient data assessments of plasma and urine concentrations, plasma PK parameters, and safety without exposing large numbers of subjects to oral TP-271 in this clinical study. One additional cohort of 8 subjects will first receive treatment with TP-271 or TP-271 co-administered with ethylenediaminetetraacetic acid (EDTA) and then cross-over to treatment with the other study agent, which will allow a comparison of the bioavailability of TP-271 alone compared to TP-271 co-administered with EDTA, as well as allow additional assessment of plasma and urine concentrations, plasma PK parameters, and safety.

Eligibility criteria: 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 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 1 and 2 and hepatitis B and C antibodies
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-child bearing potential, either 1-year post menopausal or surgically sterile (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 through 90 days post-dosing 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 because of 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 the eligibility range specified in Appendix D are exclusionary; for laboratory values that are not included in Appendix D, values outside of the reference range are exclusionary with the following exceptions (Table 3):

   Table 3 Acceptable Out-of-Range Clinical Laboratory Values Low Chemistry Values High Chemistry Values Out-of-Range Urinalysis Values Out of Range Hematology Values Bicarbonate Chloride High or low specific gravity High hematocrit Chloride HDL cholesterol Cloudy Basophils GGT LDL cholesterol Mucus Monocytes HDL cholesterol Phosphorus Crystals MCV LDH Triglycerides Ketones MCHC LDL cholesterol Hyaline casts MCH Phosphorus High or low pH RBC Triglycerides Urobilinogen a Bicarbonate \>18 mEq/L. b Ketonuria is 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, EDTA, or any of the excipients in TP 271
4. Clinically significant abnormality on a 12-lead ECG including 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 Investigator to be non pathologic
5. History of seizures
6. A history within 3 years of positive result on urine screen for drugs of abuse or a positive result at Screening for any of the following drugs of abuse: tetrahydrocannabinols, cocaine, opioids, phencyclidines, amphetamine, benzodiazepine, and barbiturates
7. Use of tobacco, nicotine, or nicotine-replacement products within 3 months prior to administration of study drug through the last study 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 (12 oz) of beer, 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 dosing
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 receiving study drug on Day 1 or planned participation in another clinical study concurrent with the present trial
11. History of difficulty donating blood or poor venous access
12. Recent blood donation (1 unit or approximately 450 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 non-prescription medication, including vitamins or herbal medications, vaccination, or immunization within 7 days, or 5 half-lives (if known), whichever is longer, prior to dosing of study drug, with the following exceptions: medications used to treat an AE, and the use of acetaminophen, naproxen, and ibuprofen is permitted except for within 24 hours prior to dosing
14. Male subject donates or plans to donate sperm during the study and for at least 90 days after study drug administration.
15. Unwillingness or inability to follow the procedures outlined in the clinical study protocol

Primary outcomes:
measure: Adverse Events (AE)
timeFrame: Through study completion, approximately 39 days
measure: Physical Exams
timeFrame: Through study completion, approximately 39 days
measure: Vital Signs
timeFrame: Through study completion, approximately 39 days
measure: Safety Laboratory
timeFrame: Through study completion, approximately 39 days
measure: ECG measurements
timeFrame: Through study completion, approximately 39 days
Secondary outcomes:
measure: Plasma Pharmacokinetic (PK) Analysis
timeFrame: Days 1-5
measure: Urine Pharmacokinetic (PK) Analysis
timeFrame: Days 1-5
measure: PK parameters - Cmax
timeFrame: Days 1-5
measure: PK parameters - Tmax
timeFrame: Days 1-5
measure: PK parameters - C8
timeFrame: Days 1-5
measure: PK parameters - C12
timeFrame: Days 1-5
measure: PK parameters - C24
timeFrame: Days 1-5
measure: PK parameters - AUC(0-last)
timeFrame: Days 1-5
measure: PK parameters - AUC(0-inf)
timeFrame: Days 1-5
measure: PK parameters - AUC% extrapolated
timeFrame: Days 1-5
measure: PK parameters - Lambda-z
timeFrame: Days 1-5
measure: PK parameters - T1/2el
timeFrame: Days 1-5
measure: PK parameters - CL
timeFrame: Days 1-5
measure: PK parameters - Vd
timeFrame: Days 1-5
measure: PK parameters - epimer/parent
timeFrame: Days 1-5
Other outcomes:
Locations:
city: Austin
country: United States
facility: PPD Phase 1 Clinic
state: Texas
Study officials:
References: