A Clinical Study of the HIV Drug CPT31 in Healthy Volunteers

Study Overview
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Brief Summary
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This first-in-human study will evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of the HIV entry inhibitor CPT31 (cholesterol-PIE12-2-trimer) in healthy adults. This is a randomized, placebo-controlled, double-blind, single ascending dose study.

Detailed Description
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This is a single subcutaneous (SC) dose study. Doses will be administered in an escalating manner following satisfactory review by a Protocol Safety Review Team (PSRT) of the safety, tolerability and pharmacokinetic (PK) data through Day 6 from the lower dose levels. 32 healthy subjects will be studied in 4 groups (Groups A1 to A4). This study will comprise a placebo-controlled, double-blind, single-dose, sequential-group design in healthy subjects. Each subject will participate in 1 treatment period and reside in the Clinical Research Unit (CRU) from Day -1 through Day 6. It is planned for 6 subjects per dose level group to receive SC CPT31 and 2 subjects to receive matching placebo. Each group will be divided into 2 cohorts, with each cohort being dosed 72 hours apart. Sentinel dosing will take place in the first cohort, which will comprise 2 subjects, with 1 subject receiving CPT31 and 1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects receiving CPT31 and 1 subject receiving placebo. Blood samples for PK analysis and assessment of immunogenicity will be collected predose and up to 5 days postdose, with an additional immunogenicity sample taken at the Follow-up visit.

Official Title
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A Phase Ia Clinical Study of HIV Entry Inhibitor CPT31: Single Ascending Dose Study of Safety, Tolerability, Immunogenicity, and Pharmacokinetics in Healthy Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: CPT31
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, of any race, between 18 and 55 years of age, inclusive. Body mass index between 18.0 and 32.0 kg/m2, inclusive. In good health, determined by no clinically significant findings from medical and surgical history, physical examination, 12 lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [e.g., suspicion of Gilbert's syndrome based on total and direct bilirubin] is not acceptable) at Screening and/or Day -1 as assessed by the Investigator (or designee). Females will not be pregnant or have been within the previous 3 months, or lactating, and females of childbearing potential and males will agree to use contraception. Able to comprehend and willing to sign an Informed Consent Form (ICF) and to abide by the study restrictions. Exclusion Criteria: Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee). A ≥Grade 2 laboratory abnormality at Screening or Day -1 as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. Estimated glomerular filtration rate (eGFR per CKD-Epi equation) of <90 ml/min/1.73 m2. Known sensitivity to CPT31 or any of its components. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee). History of alcoholism or drug/chemical abuse within 2 years prior to Day -1. Alcohol consumption of > 21 units per week for males and > 14 units for females. One unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) wine. Positive urine drug screen at Screening or positive alcohol breath test result or positive urine drug screen on Day -1. Positive HIV test as documented by Combo Ag/Ab HIV 1/HIV-2 immunoassay. Positive hepatitis B surface antigen, positive hepatitis B core antibody with negative hepatitis B surface antibody test result, or positive hepatitis C antibody at Screening or within 3 months before first dose of study treatment. Participation in a clinical study involving administration of an investigational drug in the past 30 days prior to dosing. Use or intend to use any prescription or over the counter medications/products (including HIV medications being used for pre-exposure prophylaxis) other than hormone replacement therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives or acetaminophen up to 2 grams per day for no more than 3 consecutive days within 14 days prior to dosing, unless deemed acceptable by the Investigator (or designee). Use of tobacco or nicotine containing products within 3 months prior to Day -1, or positive cotinine at Screening or Day -1. Receipt of blood products within 2 months prior to Day -1. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Poor peripheral venous access. Have previously completed or withdrawn from this study or any other study investigating CPT31 and have previously received the investigational product. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study. Have any clinically significant abnormal ECG results constituting a risk while taking the investigational product, as determined by the Investigator, such as any of the following, as determined by single 12-lead ECG: QT interval corrected for heart rate using Fridericia's method (QTcF) >450 ms for males and >470 ms for females, confirmed by calculating the mean of the original value and 2 repeats; QRS duration >120 ms confirmed by calculating the mean of the original value and 2 repeats; PR interval >220 ms confirmed by calculating the mean of the original value and 2 repeats; findings which would make QTc measurements difficult or QTc data uninterpretable; history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome); risks related to bradycardia, for example, second or third degree atrioventricular block or sick sinus syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>6 subjects receiving a single subcutaneous injection of CPT31 (0.01 mg/kg) and 2 subjects receiving matching placebo SC injection | Drug: CPT31<br>* CPT31 (cholesterol-PIE12-2-trimer) is a novel D-peptide HIV entry inhibitor that binds with high affinity to a conserved hydrophobic pocket within the gp41 trimer<br>* Other names: cholesterol-PIE12-trimer;Drug: Placebo<br>* matching placebo<br>|
| Experimental: Cohort 2<br>6 subjects receiving a single subcutaneous injection of CPT31 (0.04 mg/kg) and 2 subjects receiving matching placebo SC injection | Drug: CPT31<br>* CPT31 (cholesterol-PIE12-2-trimer) is a novel D-peptide HIV entry inhibitor that binds with high affinity to a conserved hydrophobic pocket within the gp41 trimer<br>* Other names: cholesterol-PIE12-trimer;Drug: Placebo<br>* matching placebo<br>|
| Experimental: Cohort 3<br>6 subjects receiving a single subcutaneous injection of CPT31 (0.12 mg/kg) and 2 subjects receiving matching placebo SC injection | Drug: CPT31<br>* CPT31 (cholesterol-PIE12-2-trimer) is a novel D-peptide HIV entry inhibitor that binds with high affinity to a conserved hydrophobic pocket within the gp41 trimer<br>* Other names: cholesterol-PIE12-trimer;Drug: Placebo<br>* matching placebo<br>|
| Experimental: Cohort 4<br>6 subjects receiving a single subcutaneous injection of CPT31 (0.24 mg/kg) and 2 subjects receiving matching placebo SC injection | Drug: CPT31<br>* CPT31 (cholesterol-PIE12-2-trimer) is a novel D-peptide HIV entry inhibitor that binds with high affinity to a conserved hydrophobic pocket within the gp41 trimer<br>* Other names: cholesterol-PIE12-trimer;Drug: Placebo<br>* matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Number of subjects experiencing serious adverse events (SAEs) | Check-in (Day -1) through Follow-up (Day 28-30) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | maximum observed plasma concentration (ng/mL) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Tmax | time of maximum observed plasma concentration (h) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| T1/2 | apparent plasma terminal elimination half-life (h) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Area Under the Concentration Curve (AUC) 0-∞ | area under the concentration versus time curve (AUC) from time zero to infinity (h*ng/mL) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| AUC0-tlast | area under the concentration versus time curve (AUC) from time zero to time of the last quantifiable concentration (h*ng/mL) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Total Plasma Clearance (CL/F) | apparent total plasma clearance (L/h/kg) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Vz/F | apparent volume of distribution (L/kg) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Ae | amount of drug excreted in the urine (ng/mL) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Fe | percentage of dose excreted unchanged in the urine (%) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Renal Clearance (CLR) | renal clearance (L/h/kg) | Day 1 predose, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 h) | 
| Immunogenicity | Number of subjects with measurable levels of anti-CPT31 antibodies in serum | Pre-dose on Day 1 through Follow-up (Day 28-30) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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D-peptide HIV entry inhibitor