Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Phase I Trial to Determine the Safety and Pharmacokinetics of CRS3123 Administered Orally to Healthy Adults
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Clostridium Difficile Infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- The changes from baseline in key ECG findings
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This is a Phase I, single center, randomized, placebo-controlled, double-blind, multiple ascending dose study to evaluate the safety and tolerability of CRS3123, a methionyl-tRNA synthetase inhibitor. In this study, doses of 200, 400, and 600 mg, or 100mg are planned and will be given orally every 12 hours for 10 days. Up to 30 healthy male and female subjects 18 to 45 years, inclusive. The primary objective: of the study is to determine the safety and tolerability of escalating doses of CRS3123 following oral administration of multiple doses to healthy adults. The study duration is 46 weeks.
Detailed Description
This is a Phase I, single center, randomized, placebo-controlled, double-blind, multiple ascending dose study to evaluate the safety and tolerability of CRS3123,a fully synthetic, oral, antimicrobial that targets methionyl-tRNA synthetase of gram-positive bacteria, including Clostridium difficile. This protocol will study oral doses of 200, 400, and 600 mg, or 100mg given orally every 12 hours for 10 days. Subjects will be divided into 3 cohorts, A, B, and C. Cohorts A and C will be given 200mg and 600mg of CRS3123 or placebo.The dose for cohort B and study progression and dose escalation to Cohorts B and C will require a full (planned) SMC review of all safety data obtained through Day 18. Should safety data review of the 200 mg dose result in an unfavorable safety profile, the study design allows for reduction in dose to 100 mg to be given in Cohort B. If this is the case, there will be no Cohort C. Up to 30 healthy male and female subjects 18 to 45 years, inclusive. The primary objective: of the study is to determine the safety and tolerability of escalating doses of CRS3123 following oral administration of multiple doses to healthy adults. The secondary objective will be to determine the plasma, urine and fecal concentrations and systemic exposure of CRS3123 after multiple oral doses.The study duration is 46 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Men and women 18 to 45 years of age, inclusive
- •Ability to understand the consent process and study procedures
- •Informed consent obtained and signed
- •Subjects agree to be available for all study visits. Subjects will be asked if they have any travel plans, and whether staff could use alternate contact information that will be provided.
- •General good health, without current medical illness or clinically significant abnormal physical examination findings that classify the subject as other than healthy as determined by study investigators
- •Negative serum pregnancy test at screening on the day of admittance to the inpatient phase I unit for all female subjects
- •Negative alcohol screen per phase I unit standard procedures (Breathalyzer) and urine toxicology screen for barbiturates, benzodiazepines, THC, cocaine, opiates, methamphetamines, TCA, methadone, MDMA (ecstasy), oxycodone, and amphetamines on screening and the day of admission to the inpatient phase.
- •Agrees not to consume any alcohol 48 hours prior to admission or outpatient study visits.
- •Body mass index (BMI) of \< 35 \[weight (kg)\]/\[height (m)\^2\]
- •Agreement by subjects with reproductive potential to use an adequate method of contraception during the study and for 4 weeks after the initiation of study drug administration. Female subjects must agree to the use of TWO reliable methods of contraception starting on screening day, while receiving study drug and for 4 weeks after the initiation of study drug administration, which can include: condoms, spermicidal gel, diaphragm, hormonal or non-hormonal intrauterine device, oral contraceptive pill, and depot progesterone injections. If a male subject is sexually active, the subject and his partner will each use at least one of the listed contraceptive methods. Women who have had a surgical sterilization procedure (tubal ligation, oophorectomy, or hysterectomy) are not required to use another birth control method
Exclusion Criteria
- •Medical condition that precludes participation, including the following:
- •Hypertension with confirmed systolic blood pressure \>140 mmHg or confirmed diastolic blood pressure \>90 mmHg, measured with vital signs after 10 - 15 minutes of rest. Abnormal measures may be repeated twice more (for a total of 3 times) at 5-10 minute intervals
- •Current diagnosis of pulmonary disease
- •Current diagnosis of asthma, which has required use of asthma medications within the past year
- •History of or current diagnosis of diabetes mellitus
- •Autoimmune disorder, such as lupus, Wegener's, rheumatoid arthritis
- •History of malignancy except low-grade skin cancer, (i.e., basal cell carcinoma, which has been surgically cured)
- •Chronic renal, hepatic, or pulmonary disease or gastrointestinal tract condition that could interfere with the absorption of the study drug (e.g., surgical resection of significant proportions of the stomach or bowel, gastric bypass, gastric banding, irritable bowel syndrome, inflammatory bowel disease)
- •History of known Clostridium difficile infection
- •History of cardiac rhythm abnormality including Wolff-Parkinson-White syndrome
Arms & Interventions
Cohort A
10 subjects (8 active, 2 placebo) receive a single oral dose of 200 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: Placebo
Cohort A
10 subjects (8 active, 2 placebo) receive a single oral dose of 200 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: CRS3123
Cohort B
10 subjects (8 active, 2 placebo) receive a single oral dose of 100 or 400 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: Placebo
Cohort B
10 subjects (8 active, 2 placebo) receive a single oral dose of 100 or 400 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: CRS3123
Cohort C
10 subjects (8 active, 2 placebo) receive a single oral dose of 600 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: Placebo
Cohort C
10 subjects (8 active, 2 placebo) receive a single oral dose of 600 mg CRS3123 or placebo every 12 hours for 10 days
Intervention: CRS3123
Outcomes
Primary Outcomes
The changes from baseline in key ECG findings
Time Frame: Up to Day 29
The sequential review of reported adverse events
Time Frame: Up to Day 29
The changes from baseline in vital sign measurements
Time Frame: Up to Day 29
The changes from baseline in findings on physical examination.
Time Frame: Up to Day 29
The changes from baseline of urinalysis test
Time Frame: Up to Day 29
The changes from baseline of hematology test
Time Frame: Up to Day 29
The changes from baseline of clinical chemistry test
Time Frame: Up to Day 29
Secondary Outcomes
- Urine CRS3123 concentrations at multiple specified time points following dose administration.(Day 2, 4, 6, 8, 10-12)
- Fecal CRS3123 concentrations before oral administration of CRS3123(Day -1)
- Plasma CRS3123 concentrations at multiple specified time points following dose administration.(Day 2, 4, 6, 8, 10-12)
- Fecal CRS3123 concentrations at multiple specified time points following dose administration(Day 2, 4, 6, 8, 10-12)
- Urine CRS3123 concentrations before oral administration of CRS3123(Day -1)
- Plasma CRS3123 concentrations before oral administration of CRS3123(Day -1)