Study of the Safety of Trogarzo™ Administered as an Undiluted IV Push or an Intramuscular Injection

Study Overview
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Brief Summary
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This study is designed to assess the safety and pharmacokinetic profile of 800 mg Trogarzo once every two weeks administered via IV Push or intramuscular injection. An initial Sentinel Group of 5 participants will begin receiving 800mg Trogarzo on a gradual schedule of increasing concentration and decreasing administration time until undiluted IV Push over 30 seconds is achieved, while safety and pharmacokinetics are evaluated. If no safety signals are seen, the Core Group of 15 participants will be enrolled. The Core Group will receive 800mg Trogarzo via undiluted IV Push over 30 seconds while safety and pharmacokinetics are monitored. After completion of the IV Push portion of the study, a second group of 20 participants will be enrolled to evaluate the safety and pharmacokinetics of administration of 800mg via intramuscular injection.

Detailed Description
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This goal of this Phase 3 is to evaluate the safety and pharmacokinetics of administering Trogarzo 800 mg once every two weeks as an undiluted IV Push over 30 seconds, and as an intramuscular injection in clinically stable HIV-1 infected patients currently receiving treatment with a stable Trogarzo-containing regimen and in healthy volunteers. The first five (5) patients enrolled will comprise the Sentinel Group. Patients six (6) through twenty (20) (the Core Group) will not be screened until the Sentinel Group has completed Day 99 (14 weeks) of the study and the DSMB has reviewed the data accumulated and given approval for enrollment of the Core Group to proceed. The Sentinel Group will receive 2 successive doses of Trogarzo in accordance with the prescribing information. Safety and pharmacokinetic data from these administrations will serve as the comparator for each study participant. Beginning at Day 29 and continuing through Day 85, Sentinel Group participants will begin receiving the prescribed dosage of Trogarzo once every two weeks through Day 85 of the study on a schedule of increasing drug concentration and decreasing administration time at each visit to achieve an undiluted IV Push administration of Trogarzo over 30 seconds. After review of data from the Sentinel Group by a DSMB, if approved the study will continue with enrollment of the Core Group, which will enroll both clinically stable HIV-infected patients on a stable Trogarzo-containing treatment regimen and healthy volunteers. The HIV-infected participants in the Core Group will receive 2 successive doses of Trogarzo in accordance with the prescribing information. Safety and pharmacokinetic data from these administrations will serve as the comparator for each study participant. Thereafter, HIV-infected participants in the Core Group will receive the prescribed dosage of Trogarzo via undiluted IV Push over 30 seconds through Day 71 of the study. Healthy Volunteers in the Core Group will receive a single loading dose of 2000mg of Trogarzo, followed by three successive doses of 800mg Trogarzo in accordance with the prescribing information in order to reach steady state before pharmacokinetic data for analysis are collected. Thereafter, Healthy Volunteers in the Core Group will follow the same schedule of drug administration and assessments as the HIV-infected participants in the Core Group. HIV-infected participants in the Intramuscular Injection Group will receive 2 successive doses of Trogarzo in accordance with the prescribing information. Safety and pharmacokinetic data from these administrations will serve as the comparator for each study participant. Thereafter, HIV-infected Intramuscular Injection Group participants will receive the prescribed dosage of Trogarzo via intramuscular injection beginning at Day 29 and continuing through Day 71. Healthy Volunteers in the Intramuscular Injection Group will receive a single loading dose of 2000mg of Trogarzo, followed by three successive doses of 800mg Trogarzo in accordance with the prescribing information in order to reach steady state before pharmacokinetic data for analysis are collected. Thereafter, Healthy Volunteers in the Intramuscular Injection Group will follow the same schedule of drug administration and assessments as the HIV-infected participants in the Intramuscular Injection Group.

Official Title
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A Phase 3 Study of the Safety of Trogarzo® Administered as an Undiluted IV Push Over a Reduced Interval or as an Intramuscular Injection in Clinically Stable HIV-1 Infected Trogarzo® Experienced Patients and Healthy HIV-uninfected Volunteers

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: ibalizumab-uiyk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - HIV-infected participants (all groups): Are capable of understanding and have voluntarily signed the informed consent document Currently receiving a stable Trogarzo-containing ARV regimen for a minimum of 3 months, and no change in background ARVs anticipated over the period of study participation; a stable regimen is defined as having no changes in dose or frequency and no interruptions greater than or equal to 2 weeks during the 3 month period Have no acquired immunodeficiency syndrome (AIDS)-defining events in the 3 months before Screening, other than cutaneous Kaposi's sarcoma or wasting syndrome due to HIV Are able and willing to comply with all protocol requirements and procedures Are 18 years of age or older Have a life expectancy that is >6 months. Have a viral load <1,000 copies/mL at Screening CD4+ T-cell count > 50 cells/mm3 at Screening Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 times the upper limit of normal (IM Group only) Inclusion Criteria - Healthy Volunteers (all groups): Healthy volunteers born male and female as assessed by medical history and physical examination Aged >18 and <50 years at the time of Screening Ability and willingness to provide written informed consent Willingness to comply with protocol schedule Willingness to undergo HIV-1 testing Non-reactive 4th generation point of care HIV-1 test at Screening Hepatitis B Surface antigen negative Hepatitis C antibody negative, or if reactive, Hepatitis C RNA undetectable in plasma PT and PTT <1.5 times the upper limit of normal (IM Group only) Volunteers born female of reproductive potential who are sexually active with a male sex partner must agree to use one effective method of contraception from the time of signing the consent to completion of the study and agree to pregnancy testing as per the schedule of events. Volunteers born female with reproductive potential are defined as pre-menopausal volunteers born female who have not had a sterilization procedure (e.g., hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy). Volunteers born female are considered menopausal if they have not had a menses for at least 12 months and have a follicle-stimulating hormone (FSH) of greater than 40 IU/L or if FSH testing is not available, they have had amenorrhea for 24 consecutive months. Exclusion Criteria - HIV-infected participants (all groups): Any active AIDS-defining illness according to the Centers for Disease Control and Prevention (CDC) Revised Surveillance Case Definitions for HIV Infection 2008 (Morbidity and Mortality Weekly Report (MMWR) Vol.57/No. RR-10, Appendix A), or history of the same during the 3 months preceding Screening, with the following exceptions: cutaneous Kaposi's sarcoma and wasting syndrome due to HIV Any significant diseases (other than HIV-1 infection) or clinically significant findings, including psychiatric and behavioral problems, determined from Screening, medical history, and/or physical examination that, in the investigator's opinion, would preclude the subject from participating in this study Any significant acute illness within 1 week before the initial administration of study drug Any active infection secondary to HIV requiring acute therapy; however, subjects that require maintenance therapy (i.e., secondary prophylaxis for opportunistic infections) will be eligible for the study Any immunomodulating therapy (including interferon), systemic steroids, or systemic chemotherapy within 12 weeks before Enrollment Any vaccination within 7 days before Day 1 Any female subject who either is pregnant, intends to become pregnant, or is currently breastfeeding Any current alcohol or illicit drug use that, in the investigator's opinion, will interfere with the subject's ability to comply with the study schedule and protocol evaluations Any radiation therapy during the 28 days before first administration of study medication Any Grade 3 or 4 laboratory abnormality according to the Division of AIDS (DAIDS) grading scale, except for the following asymptomatic Grade 3 events: triglyceride elevation total cholesterol elevation or Grade 3 or 4 reductions in levels of CD4+ T cells History of coagulopathy that would preclude administration of IM injections (IM Group only) Skin rashes or tattoos that would prevent ability to assess IM injection for injection-site reactions (IM Group only) Use of high-dose aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole or other antiplatelet medication that would interfere with the ability to receive IM injections (IM Group only). Exclusion Criteria - Healthy Volunteers (all groups): Confirmed HIV-1 infection At high risk of severe COVID-19 disease as defined by one of the following: History of hypertension, atherosclerotic cardiovascular disease (ASCVD), coronary artery disease, diabetes mellitus History of asthma or chronic pulmonary disease History of renal disease and chronic renal insufficiency BMI over 35 Any acute or chronic medical condition that in the opinion of the investigator would preclude participation Chronic autoimmune disease Active IV drug use Excessive use of alcohol or recreational drugs that in the opinion of the investigator would preclude participation Decompensated psychiatric illness Need for chronic immunotherapy including systemic corticosteroids, other MAb therapy, or immunosuppressive drugs Volunteers born female who are pregnant, lactating, or planning on becoming pregnant over the study period Any of the following laboratory parameters: Hemoglobin <10.0 g/dL Absolute neutrophil count <1,000/mm3 Absolute lymphocyte count <500/mm3 Platelet count <100,000/mm3 Creatinine >1.25x upper limit of normal (ULN) Aspartate aminotransferase (AST) >1.5x ULN Alanine aminotransferase (ALT) >1.5x ULN Glucose (non-fasting) >160 mg/dL Proteinuria: 2+ or greater Hematuria: >10 red blood cells (RBCs) per high-power field Previous receipt of an experimental MAb for HIV-1treatment or prevention in a research study History of severe allergic reactions to drugs, vaccines, or drug infusion Participation in another investigational clinical trial within the past 12 weeks or anticipated during the course of the current study History of coagulopathy that would preclude administration of IM injections (IM Group only) Skin rashes or tattoos that would prevent ability to assess IM injection for injection-site reactions (IM Group only) Use of high-dose aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamoleor any other antiplatelet medication that would interfere with the ability to receive IM injections (IM Group only).

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sentinel Group<br>Five (5) participants will receive two successive doses of 800mg ibalizumab administered in accordance with the prescribing information followed by five (5) successive 800mg doses on a schedule gradually increasing drug concentration and decreasing administration time. | Drug: ibalizumab-uiyk<br>* Ibalizumab-uiyk is an IgG4 monoclonal antibody targeting domain 2 of the extracellular portion of the CD4 protein. Ibalizumab-uiyk is FDA approved for the treatment of multi-drug resistant HIV in treatment experienced patients.<br>* Other names: Trogarzo;|
| Experimental: Core Group<br>HIV-infected Core Group participants will receive two successive doses of 800mg ibalizumab (Trogarzo) administered in accordance with the prescribing information followed by four (4) successive 800mg doses via undiluted IV Push over 30 seconds. Healthy Volunteer Core Group participants will receive a single 2000mg loading dose followed by three successive doses of 800mg in accordance with the prescribing information in order to reach steady state. Thereafter, Healthy Volunteers will receive two successive doses of 800mg ibalizumab (Trogarzo) administered in accordance with the prescribing information followed by four (4) successive 800mg doses via undiluted IV Push over 30 seconds. | Drug: ibalizumab-uiyk<br>* Ibalizumab-uiyk is an IgG4 monoclonal antibody targeting domain 2 of the extracellular portion of the CD4 protein. Ibalizumab-uiyk is FDA approved for the treatment of multi-drug resistant HIV in treatment experienced patients.<br>* Other names: Trogarzo;|
| Experimental: Intramuscular Injection Group<br>HIV-infected Intramuscular Injection Group participants will receive two successive doses of 800mg ibalizumab (Trogarzo) administered in accordance with the prescribing information followed by four (4) successive 800mg doses via Intramuscular Injection. Healthy Volunteer Intramuscular Injection Group participants will receive a single 2000mg loading dose followed by three successive doses of 800mg in accordance with the prescribing information in order to reach steady state. Thereafter, Healthy Volunteers will receive two successive doses of 800mg ibalizumab (Trogarzo) administered in accordance with the prescribing information followed by four (4) successive 800mg doses via intramuscular injection. | Drug: ibalizumab-uiyk<br>* Ibalizumab-uiyk is an IgG4 monoclonal antibody targeting domain 2 of the extracellular portion of the CD4 protein. Ibalizumab-uiyk is FDA approved for the treatment of multi-drug resistant HIV in treatment experienced patients.<br>* Other names: Trogarzo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Trogarzo given as IV Push over 30 seconds in Sentinel Group | Percent of subjects in Sentinel Group who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol | 12 weeks | 
| Safety of Trogarzo given as IV Push over 30 seconds in Core Group | Percent of subjects in Core Group who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol | 10 weeks | 
| Pharmacokinetics(1) of Trogarzo infusion versus IV Push in Sentinel Group | Ratio of Area Under the Curve of Serum levels of Trogarzo given by 15 minute infusion versus Area Under the Curve of Serum levels of Trogarzo given by IV Push over 30 seconds | Day 1 infusion versus Day 85 IV Push | 
| Pharmacokinetics(2) of Trogarzo infusion versus IV Push in Sentinel Group | Ratio of Trough Serum levels of Trogarzo given by 15 minute infusion versus Trough Serum levels of Trogarzo given by IV Push over 30 seconds | Day 1 infusion versus Day 85 IV Push | 
| Pharmacokinetics(1) of Trogarzo infusion versus IV Push in Core Group | Ratio of Area Under the Curve of Serum levels of Trogarzo given by 15 minute infusion versus Area Under the Curve of Serum levels of Trogarzo given by IV Push over 30 seconds | Day 1 infusion versus Day 71 IV Push | 
| Pharmacokinetics(2) of Trogarzo infusion versus IV Push in Core Group | Ratio of Trough Serum levels of Trogarzo given by 15 minute infusion versus Trough Serum levels of Trogarzo given by IV Push over 30 seconds | Day 1 infusion versus Day 71 IV Push | 
| Safety of Trogarzo given as an intramuscular injection in the Intramuscular Injection Group | Percent of subjects in Intramuscular Injection Group who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol | 10 weeks | 
| Pharmacokinetics(1) of Trogarzo infusion versus intramuscular injection in the Intramuscular Injection Group | Ratio of Area Under the Curve of Serum levels of Trogarzo given by 15 minute infusion versus Area Under the Curve of Serum levels of Trogarzo given by intramuscular injection | Day 1 infusion versus Day 71 intramusuclar injection | 
| Pharmacokinetics(2) of Trogarzo infusion versus intramuscular injection in the Intramuscular Injection Group | Ratio of Trough Serum levels of Trogarzo given by 15 minute infusion versus Trough Serum levels of Trogarzo given by intramuscular injection | Day 1 infusion versus Day 71 intramusuclar injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects in the Sentinel Group who fail to maintain virologic control | Percent of subjects in the Sentinel group who experience a sustained increase in log HIV-1 RNA levels of greater than 0.5log from baseline | 99 days | 
| Percent of HIV-infected subjects in the Core Group who fail to maintain virologic control | Percent of subjects in the Core group who experience a sustained increase in log HIV-1 RNA levels of greater than 0.5log from baseline | 84 days | 
| Percent of HIV-infected subjects in the Intramuscular Injection Group who fail to maintain virologic control | Percent of HIV-infected subjects in the Intramuscular Injection Group who experience a sustained increase in log HIV-1 RNA levels of greater than 0.5log from baseline | 84 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, ibalizumab, MDR HIV