Study to Evaluate Safety and Activity of TRL345 in Healthy Volunteers

Study Overview
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Brief Summary
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This study in healthy volunteers will provide a basis for evaluation of TRL345 as a first in human study, specifically, important safety, tolerability, and pharmacokinetic data, and provide serum samples for ex vivo studies of concentration-dependent antiviral activity to support the dose selection for as well as design and conduct of a clinical study in transplant patients.

Detailed Description
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Human cytomegalovirus (HCMV) is the most common medically significant infection in transplant patients. HCMV is usually a serious and even fatal infection in newborn SCID infants requiring hematopoietic stem cell transplant. HCMV is also the leading cause of congenital viral infection, with an incidence in the United States of 1-3% of live births. Primary HCMV infection during early pregnancy poses a 30-40% risk of intrauterine transmission. Approximately 10-15% of congenitally infected infants are symptomatic, presenting with intrauterine growth restriction and permanent birth defects, including neurological deficiencies, retinopathy, and sensori-neuronal deafness; of the infected but asymptomatic infants, 15-20% will later develop permanent sequelae. Trellis Bioscience is developing TRL345, a fully human monoclonal antibody that has specificity to the AD-2 site I in gB of HCMV, both for transplant patients and for the prevention of maternal HCMV infection during pregnancy. Antibody therapy provides an alternative to antiviral drugs with an expectation of qualitatively lower toxicity. The leading small molecule antiviral effective against HCMV, ganciclovir (and its oral prodrug formulation valganciclovir), has side effects (including neutropenia, nephrotoxicity, and potential mutagenicity) that make its use problematic for major indications, including congenital transmission or the early post-transplant period for HCT. Although the recently approved small molecule antiviral letermovir has reduced neutropenic activity and is therefore useful in hematopoietic cell transplantation (HCT), it has not eliminated CMV reactivation in adult HCT patients.

Official Title
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A Phase 1, Double-Blind, Single Ascending Dose Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of TRL345 in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: TRL345, a human monoclonal antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and non-pregnant, non-breast-feeding female subjects at between 18 and 65 years of age, inclusive, and representative of the general population Willing and able to provide written informed consent. Availability for the entire duration of the study, and willingness to adhere to protocol requirements In good health, as determined by lack of clinically significant abnormalities in health assessments performed at the Screening Visit, as judged by the Principal Investigator (PI) or as delegated by the PI to a physician or nurse practitioner as sub-investigator. Men and women of childbearing potential (WOCBP) must be willing to practice a highly effective method of contraception that may include, but is not limited to, abstinence, sex only with persons of the same sex, monogamous relationship with vasectomized partner, vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods, or intrauterine device (IUD) for 28 days before Screening and through Day 76. Men must also refrain from donating sperm from Day 1 through Day 76. Exclusion Criteria: Inability to tolerate blood draws or has poor venous access Body mass index (BMI) <18.5 or ≥35 kg/m2 Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 160 mmHg; diastolic blood pressure lower than 50 or over 100 mmHg; or, heart rate less than 45 or over 100 bpm) at the Screening Visit ECG with clinically significant findings, including: Conduction disturbance (complete left or complete right bundle branch block or nonspecific intraventricular conduction disturbance with QRS ≥120 msec, PR interval ≥220 msec, any second- or third-degree atrioventricular block, or prolongation of the QT interval corrected according to Fridericia's correction [>450 msec male and >460 msec female]) Significant repolarization (ST-segment or T-wave) abnormality; or Significant atrial or ventricular arrhythmia; or Frequent atrial or ventricular ectopy (e.g., frequent premature atrial contractions, 2 premature ventricular contractions in a row); or ST-elevation consistent with ischemia or evidence of past or evolving myocardial infarction. Presence of any gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g., diarrhea, vomiting),or progressive liver or kidney disease Diagnosis of diabetes mellitus History of acute or chronic pancreatitis or upper right quadrant postprandial discomfort or pain within the last 2 years Clinically relevant medical conditions that, in the opinion of the PI, may interfere with the evaluation of the trial drug, e.g., progressive cardiovascular disease Concurrent acute or chronic infections (e.g., viral infections, except chronic recurrent herpes simplex infections) Significant abnormal safety labs, defined as: Greater than 30% outside of the normal range for any of the following: hemoglobin, white blood cell (WBC) count, platelet count, neutrophil count and blood urea nitrogen Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin or indirect bilirubin >2 × the upper limit of normal Activated partial thromboplastin time (aPTT) prolongation >1.5 x ULN Hemoglobin A1C (HbA1C) >5.6% Fasting glucose level of ≥100 mg/dl (5.6 mmol/L) Renal function based on the, i.e., estimated creatinine clearance < 70 mL/min (Cockcroft-Gault formula using ideal body weight) Hemoglobin ≤ 128 g/L (males) and ≤ 115 g/L (females), and hematocrit ≤ 37% (males) and ≤ 32.0% for females Positive test results for HIV, Hepatitis B (HBsAg), or Hepatitis C (HCV) at the Screening Visit History of significant drug abuse within one year prior to the Screening Visit and/or ongoing History of significant alcohol abuse within one year prior to the Screening Visit defined as more than fourteen units of alcohol per week [one unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) Positive test for drugs of abuse, ETOH and nicotine (cotinine) at the Screening Visit Positive serum beta-human chorionic gonadotropin test for pregnancy, pregnant, or nursing women Unwilling to refrain from donating blood or plasma during the study. Use of any new prescription medication or over-the-counter (OTC) product (including natural food supplements, vitamins, herbs) within 14 days prior to dosing Receipt of any vaccine or booster within 14 days prior to Day 1 or planned vaccination or booster within 4 weeks after IP administration Any planned medical intervention or personal event that might interfere with the ability to comply with the study requirements Is current study site staff paid entirely or partially by the contract for this trial, or staff who are supervised by the PI or sub-PI Receipt of an investigational product, or participation in another trial involving a marketed or investigational drug within 30 days of Day 1, or 5 half-lives of the investigational drug, whichever is longer Any other comorbidity or condition that, in the opinion of the Investigator would make the subject unsuitable for the study or unable to comply with the study requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 - 1 mg/kg<br>Randomized 6:2 (TRL345:placebo) via IV infusion | Drug: TRL345, a human monoclonal antibody<br>* Anti-Human Cytomegalovirus (HCMV) IgG1κ Human Monoclonal Antibody<br>|
| Experimental: Dose Level 2 - 10 mg/kg<br>Randomized 6:2 (TRL345:placebo) via IV infusion | Drug: TRL345, a human monoclonal antibody<br>* Anti-Human Cytomegalovirus (HCMV) IgG1κ Human Monoclonal Antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of abnormal physical exam findings | Clinically-significant abnormal physical exam findings will be reviewed | 11 weeks | 
| Severity of abnormal physical exam findings | Clinically-significant abnormal physical exam findings will be reviewed. Severity scale used in this trial is Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (https://www.fda.gov/media/73679/download). | 11 weeks | 
| Incidence of abnormal serum chemistries and hematology | Clinically-significant abnormal laboratory results findings will be reviewed | 11 weeks | 
| Severity of abnormal serum chemistries and hematology | Clinically-significant abnormal laboratory results findings will be reviewed. Severity scale used in this trial is Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (https://www.fda.gov/media/73679/download). | 11 weeks | 
| Incidence of abnormal vital signs (temperature) | Clinically-significant abnormal temperatures will be reviewed | 11 weeks | 
| Severity of abnormal vital signs (temperature) | Clinically-significant abnormal temperatures will be reviewed | 11 weeks | 
| Incidence of abnormal vital signs (blood pressure) | Clinically-significant abnormal blood pressures will be reviewed | 11 weeks | 
| Severity of abnormal vital signs (blood pressure) | Clinically-significant abnormal blood pressures will be reviewed | 11 weeks | 
| Incidence of abnormal vital signs (heart rate) | Clinically-significant abnormal heart rates will be reviewed | 11 weeks | 
| Severity of abnormal vital signs (heart rate) | Clinically-significant abnormal heart rates will be reviewed | 11 weeks | 
| Incidence and Severity of Adverse Events | reported AEs will be reviewed | 11 weeks | 
| Incidence of Serious Adverse Events | reported SAEs will be reviewed | 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL345 overall and by DG (Cmax) | determined by ELISA | 11 weeks | 
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL345 overall and by DG (Cmin) | determined by ELISA | 11 weeks | 
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL345 overall and by DG (CL) | determined by ELISA | 11 weeks | 
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL345 overall and by DG (Vss) | determined by ELISA | 11 weeks | 
| Characterize the pharmacokinetics (PK) of a single IV infusion of TRL345 overall and by DG (T1/2) | determined by ELISA | 11 weeks | 
| Assess the immunogenicity of TRL345 as measured by anti-drug antibodies (ADAs) | Incidence of baseline and IP-emergent ADA (i.e., anti-TRL345 antibodies) in serum will determined by electrochemiluminescence assay | 11 weeks |