Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study

NCT03984812 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 207863
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, FTIH study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetic (PK)/pharmacodynamic (PD) attributes of GSK3732394 in healthy subjects. The data gathered in this study will further enable clinical development of GSK3732394 in HIV-infected subjects. Approximately 72 healthy subjects will be randomized in the FTIH study. Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each subject in the SAD cohort will receive a single dose of blinded GSK3732394 or blinded placebo (PBO) in 6:2 ratio. Part 1 will consist of five ascending single-dose cohorts with an additional expansion cohort included as needed. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), randomized to four weekly doses of blinded GSK3732394 or blinded PBO in 6:2 ratio to be administered on Days 1, 8, 15, and 22.

Conditions

HIV Infections

Keywords

DAIDS, FTIH, HIV-1, MAD, SAD

Outcome Measures

Primary Outcomes (18)

• Part 1: Number of Participants With Non-serious Adverse Event (SAEs) and SAEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose: results in death and is life-threatening which requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity and birth defect or congenital anomaly, or any other situation that require medical or scientific judgement. Number of participants with common more than or equal to (\>=)5 percent (%) non-serious AEs and SAEs are presented.

  Up to Day 28

• Part 2: Number of Participants With Non-SAEs and SAEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose: results in death and is life-threatening which requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity and birth defect or congenital anomaly, or any other situation that require medical or scientific judgement. All AEs were planned to be collected from the start of treatment until the follow-up visit.

  Up to Day 49

• Part 1: Number of Participants With Clinical Chemistry Parameters by Maximum Grade Increase Post-Baseline

  Blood samples were collected for the analysis of following clinical chemistry parameters: Glucose, alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), direct bilirubin, total bilirubin, calcium, creatinine, potassium, lipase and sodium. The clinical chemistry abnormalities were graded using the Division of Acquired immunodeficiency syndrome (DAIDS) criteria and grades were derived based on numeric criteria as defined in DAIDS Version 2.1 and did not take into consideration of clinical signs or symptoms. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates more severe condition. Baseline is defined as the latest pre-dose assessment. Number of participants with clinical chemistry parameters by maximum grade increase post-Baseline is presented.

  Up to Day 28

• Part 2: Number of Participants With Clinical Chemistry Parameters by Maximum Grade Increase Post-Baseline

  Blood samples were planned to be collected for the analysis of the following clinical chemistry parameters: Glucose, alkaline phosphatase, ALT, amylase, AST, direct and total bilirubin, calcium, creatinine, potassium, lipase and sodium. Baseline is defined as the latest pre-dose assessment.

  Up to Day 49

• Part 1: Number of Participants With Hematology Parameters by Maximum Grade Increase Post-Baseline

  Blood samples were collected for the analysis of following hematology parameters: Cluster of differentiation (CD) 4 cells, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. The hematology abnormalities were graded using the DAIDS criteria and grades were derived based on numeric criteria as defined in DAIDS Version 2.1 and did not take into consideration of clinical signs or symptoms. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences. Higher grade indicates more severe condition. Baseline is defined as the latest pre-dose assessment. Number of participants with hematology parameters by maximum grade increase post-Baseline is presented.

  Up to Day 28

• Part 2: Number of Participants With Hematology Parameters by Maximum Grade Increase Post-Baseline

  Blood samples were planned to be collected for the analysis of the following hematology parameters: CD4 cells, hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. Baseline is defined as the latest pre-dose assessment.

  Up to Day 49

• Part 1: Number of Participants With Urinalysis Parameters by Any Increase in Discrete or Character Values Post Baseline

  Urine samples were collected for the analysis of urine parameters including bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, protein and urobilinogen. The urinalysis abnormalities were graded using the DAIDS criteria and grades were derived based on numeric criteria as defined in DAIDS Version 2.1 and did not take into consideration of clinical signs or symptoms. Baseline is defined as the latest pre-dose assessment. Number of participants with urinalysis parameters by any increase in discrete or character values post Baseline is presented.

  Up to Day 28

• Part 2: Number of Participants With Urinalysis Parameters by Any Increase in Discrete or Character Values Post Baseline

  Urine samples were planned to be collected for the analysis of urine parameters including bilirubin, glucose, ketones, leukocyte esterase, nitrite, occult blood, protein and urobilinogen. Baseline is defined as the latest pre-dose assessment.

  Up to Day 49

• Part 1: Number of Participants With Worst Case Pulse Rate Post Baseline

  Pulse rate was measured in a semi-supine position after 5 minutes of rest. Participants are counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose value category are unchanged (e.g., High to High), or whose value became within range, are recorded in the "To within Range or No Change" category. Participants with missing Baseline value are assumed to have within range value. Participants were counted twice if the participant had both values that changed 'To Low' and 'To High'. Baseline is defined as the latest pre-dose assessment. Number of participants with pulse rate change to low or to high and no change post Baseline is presented.

  Up to Day 28

• Part 2: Number of Participants With Worst Case Pulse Rate Post Baseline

  Pulse rate was planned to be measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment.

  Up to Day 49

• Part 1: Change From Baseline in Body Temperature

  Body temperature was measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline value is defined as post-dose value minus Baseline value.

  Baseline and at Day 1 (1, 2, 4, 8, 12 hours), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28

• Part 2: Change From Baseline in Body Temperature

  Body temperature was planned to be measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.

  Baseline and Up to Day 49

• Part 1: Change From Baseline in Respiratory Rate

  Respiratory rate was measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline value is defined as post-dose value minus Baseline value.

  Baseline and at Day 1 (1, 2, 4, 8, 12 hours), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28

• Part 2: Change From Baseline in Respiratory Rate

  Respiratory rate was planned to be measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.

  Baseline and Up to Day 49

• Part 1: Number of Participants With Worst Case Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Post Baseline

  SBP and DBP was measured in a semi-supine position after 5 minutes of rest. Participants are counted in the worst case category that their value changes to low, within range or no change, or high), unless there is no change in their category. Participants whose value category are unchanged (e.g., High to High), or whose value became within range, are recorded in the "To within Range or No Change" category. Participants with missing Baseline value are assumed to have within range value. Participants were counted twice if the participant had both values that changed 'To Low' and 'To High'. Baseline is defined as the latest pre-dose assessment. Number of participants with SBP and DBP change to low and to high and no change post Baseline is presented.

  Up to Day 28

• Part 2: Number of Participants With Worst Case SBP and DBP Post Baseline

  SBP and DBP was planned to be measured in a semi-supine position after 5 minutes of rest. Baseline is defined as the latest pre-dose assessment.

  Up to Day 49

• Part 1: Number of Participants With Clinical Significant Abnormal Electrocardiogram (ECG) Findings

  A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of 5 minutes. Twelve lead ECGs were obtained by using an automated ECG machine. Number of participants with clinical significant abnormal ECG findings are presented.

  Pre-dose, 4, 12 hours on Day 1, 24 hours on Day 2, Days 8, 14, 17 and 28

• Part 2: Number of Participants With Clinical Significant Abnormal ECG Findings

  12-lead ECG recordings was planned to be measured.

  Up to Day 49

Secondary Outcomes (37)

• Part 1: Area Under the Plasma Concentration Time Curve From Zero to t (AUC[0-t]) Following Single Dose Administration of GSK3732394

  Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28

• Part 2: AUC(0-t) After Repeat Dosing of GSK3732394 in First Week

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7

• Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) Following Single Dose Administration of GSK3732394

  Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28

• Part 2: AUC(0-infinity) After Repeat Dosing of GSK3732394 in First Week

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 12 hours), Days 2, 3, 4, 5, 6 and 7

• Part 1: Maximum Observed Concentration (Cmax) Following Single Dose Administration of GSK3732394

  Day 1 (Pre-dose, 0.5, 1, 2, 4, 8, 12 hours), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 21, 24 and 28

Study Arms (9)

Part 1,Cohort 1:Subjects receiving blinded GSK3732394 10mg/PBO

EXPERIMENTAL

GSK3732394 10 milligram (mg) or PBO will be administered by subcutaneous (SC) injection to the subjects.

Drug: GSK3732394; Drug: Placebo

Part 1,Cohort 2:Subjects receiving blinded GSK3732394 40mg/PBO

EXPERIMENTAL

GSK3732394 40 mg or PBO will be administered by SC injection to the subjects. This is projected dose, dose will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part1,Cohort 3:Subjects receiving blinded GSK3732394 130mg/PBO

EXPERIMENTAL

GSK3732394 130 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 3 will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394

Part1,Cohort 4:Subjects receiving blinded GSK3732394 350mg/PBO

EXPERIMENTAL

GSK3732394 350 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 4 will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part1,Cohort5: Subjects receiving blinded GSK3732394 600mg/PBO

EXPERIMENTAL

GSK3732394 600 mg or PBO will be administered by SC injection to the subjects. This is a projected dose. The dose administered in Part 1, Cohort 5 will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part1,Cohort6: Subjects receiving blinded GSK3732394 800mg/PBO

EXPERIMENTAL

GSK3732394 800 mg or PBO will be administered by SC injection to the subjects. This is a projected dose and will be given if necessary. The dose administered in Part 1, Cohort 6 (if necessary) will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part2,Cohort1: Subjects receiving blinded GSK3732394 130mg/PBO

EXPERIMENTAL

GSK3732394 130 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The dose administered in Part 2, Cohort 1 will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part2,Cohort2: Subjects receiving blinded GSK3732394 400mg/PBO

EXPERIMENTAL

GSK3732394 400 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The administered dose in Part 2, Cohort 2 will be based on PK/PD results from preceding dosing cohorts.

Drug: GSK3732394; Drug: Placebo

Part2,Cohort3: Subjects receiving blinded GSK3732394 600mg/PBO

EXPERIMENTAL

GSK3732394 600 mg or PBO will be administered by SC injection to the subjects on Days 1, 8, 15, and 22 of the study. This is a projected dose. The administered dose in Part 2, Cohort 3 will be based on PK/PD results from preceding dosing cohorts and will not exceed the maximum exposure observed in SAD (Part 1).

Drug: GSK3732394; Drug: Placebo

Interventions

GSK3732394 DRUG

It is composed of an anti-CD4 adnectin, an anti-N17 adnectin, and a peptide inhibitor. This will be provided as a solution for injection in 1 (milliliter) mL glass vials with the unit dose strength of 100 mg/mL

Part 1,Cohort 1:Subjects receiving blinded GSK3732394 10mg/PBO; Part 1,Cohort 2:Subjects receiving blinded GSK3732394 40mg/PBO; Part1,Cohort 3:Subjects receiving blinded GSK3732394 130mg/PBO; Part1,Cohort 4:Subjects receiving blinded GSK3732394 350mg/PBO; Part1,Cohort5: Subjects receiving blinded GSK3732394 600mg/PBO; Part1,Cohort6: Subjects receiving blinded GSK3732394 800mg/PBO; Part2,Cohort1: Subjects receiving blinded GSK3732394 130mg/PBO; Part2,Cohort2: Subjects receiving blinded GSK3732394 400mg/PBO; Part2,Cohort3: Subjects receiving blinded GSK3732394 600mg/PBO

Placebo DRUG

Placebo will comprise of 0.9% weight per volume (w/v) sodium chloride.

Part 1,Cohort 1:Subjects receiving blinded GSK3732394 10mg/PBO; Part 1,Cohort 2:Subjects receiving blinded GSK3732394 40mg/PBO; Part1,Cohort 4:Subjects receiving blinded GSK3732394 350mg/PBO; Part1,Cohort5: Subjects receiving blinded GSK3732394 600mg/PBO; Part1,Cohort6: Subjects receiving blinded GSK3732394 800mg/PBO; Part2,Cohort1: Subjects receiving blinded GSK3732394 130mg/PBO; Part2,Cohort2: Subjects receiving blinded GSK3732394 400mg/PBO; Part2,Cohort3: Subjects receiving blinded GSK3732394 600mg/PBO

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
• Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Subjects who are able to understand and comply with protocol requirements and timetables, instructions, and protocol-stated restrictions
• Body mass index within the range 19 to 30 kilogram per meter square (kg/m2) inclusive, in addition to a weight range of 50kg to 100kg.
• Male and female healthy volunteers.
• All male subjects must agree to use contraception during the treatment period and for at least 100 days after the last dose of study treatment and refrain from donating sperm during this period.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies; Not a woman of childbearing potential (WOCBP), A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 28 days prior to first dose, and 40 days after, the last dose of study treatment.
• Capable of giving signed informed consent.
• A signed and dated written informed consent must be completed prior to the subject's entry into the study.

You may not qualify if:

• Subject has a history or presence of cardiovascular, dermatological, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
• Subject has abnormal blood pressure (as determined by the investigator).
• Subject had symptomatic herpes zoster within 3 months prior to screening.
• Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, TB testing that includes a positive tuberculin skin test \[TST\]; defined as a skin induration greater than 5 millimeter \[mm\] at 48 to 72 hours,and regardless of Bacillus Calmette-Guerin \[BCG\] or other vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold test.
• Subjects with lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Subjects who had breast cancer within the past 10 years.
• Subjects who had history of severe injection site reaction (i.e., required emergency care or hospitalization) following any prior injection, including reaction to vaccines.
• Subjects with history of clinically significant allergy or prior hypersensitivity including those with a documented yeast allergy.
• Subjects with history of, or current concern for, a chronic immune deficiency disorder including, but not limited to: diabetes, sickle cell anemia, and malnutrition.
• Subjects having alanine transaminase (ALT) greater than 1.1 x upper limit of normal (ULN).
• Subjects with Hemoglobin levels below the normal range.
• Subjects with Platelet count \<130,000 per cubic millimeters.
• Subjects with Creatinine clearance (CrCL) \<90 milliliters per minute.
• Subjects with bilirubin greater than 1.1xULN (isolated bilirubin greater than 1.1xULN is acceptable if bilirubin is fractionated and direct bilirubin greater than 35%).
• Subjects who has current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (1)

• Krystal M, Chabria S, Austin D, Wolstenholme A, Wensel D, Lataillade M, Abberbock J, Baker M, Ackerman P. A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection. Antivir Ther. 2022 Oct;27(5):13596535221131164. doi: 10.1177/13596535221131164.

  PMID: 36191080 DERIVED

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This is double-blind (sponsor-unblinded) study with subjects and the site staff blinded, except for an unblinded pharmacist at the site who will prepare the blinded drug product. The blind may be broken if, in the opinion of the investigator, it is in the subject's best interest for the investigator to know the study treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In Part 1 of the study each of the subjects in the SAD cohorts (SAD Cohorts 1-5; SAD Cohort 6 is a possible expansion cohort that will be added as needed) will receive a single dose of blinded GSK3732394 or blinded PBO (GSK3732394: PBO = 6:2), per their randomization assignment. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), each with 8 subjects (blinded GSK3732394: blinded PBO = 6:2) will receive four weekly doses of GSK3732394 or PBO on Days 1, 8, 15, and 22.

Study Record Dates

• First Submitted: June 10, 2019
• First Posted: June 13, 2019
• Study Start: June 17, 2019
• Primary Completion: March 23, 2020
• Study Completion: March 23, 2020
• Last Updated: October 25, 2021
• Results First Posted: April 12, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (1)