HIV-1-infection
Conditions
Keywords
HIV, ibalizumab, Multi-drug Resistant (MDR) HIV
Brief summary
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
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 Data Safety Monitoring Board (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.
Interventions
DRUGibalizumab-uiyk
Ibalizumab-uiyk is an Immunoglobulin G4 (IgG4) monoclonal antibody targeting domain 2 of the extracellular portion of the Cluster of Differentiation 4 (CD4) protein. Ibalizumab-uiyk is FDA approved for the treatment of multi-drug resistant HIV in treatment experienced patients.
Sponsors
Westat
TaiMed Biologics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
- HIV-infected participants (all groups): 1. Are capable of understanding and have voluntarily signed the informed consent document 2. Currently receiving a stable Trogarzo-containing antiretroviral (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 3. 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 4. Are able and willing to comply with all protocol requirements and procedures 5. Are 18 years of age or older 6. Have a life expectancy that is \>6 months. 7. Have a viral load \<1,000 copies/mL at Screening 8. CD4+ T-cell count \> 50 cells/mm3 at Screening 9. 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): 1. Healthy volunteers born male and female as assessed by medical history and physical examination 2. Aged \>18 and \<50 years at the time of Screening 3. Ability and willingness to provide written informed consent 4. Willingness to comply with protocol schedule 5. Willingness to undergo HIV-1 testing 6. Non-reactive 4th generation point of care HIV-1 test at Screening 7. Hepatitis B Surface antigen negative 8. Hepatitis C antibody negative, or if reactive, Hepatitis C RNA undetectable in plasma 9. PT and PTT \<1.5 times the upper limit of normal (IM Group only) 10. 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): 1. 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 2. 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 3. Any significant acute illness within 1 week before the initial administration of study drug 4. 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 5. Any immunomodulating therapy (including interferon), systemic steroids, or systemic chemotherapy within 12 weeks before Enrollment 6. Any vaccination within 7 days before Day 1 7. Any female subject who either is pregnant, intends to become pregnant, or is currently breastfeeding 8. 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 9. Any radiation therapy during the 28 days before first administration of study medication 10. 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 11. History of coagulopathy that would preclude administration of IM injections (IM Group only) 12. Skin rashes or tattoos that would prevent ability to assess IM injection for injection-site reactions (IM Group only) 13. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Trogarzo Given as IV Push Over 30 Seconds | 12 weeks | Number of subjects who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol |
| Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Day 1 infusion versus Day 85 IV Push | Ratio of proportion of subjects with trough concentration (Ctrough) ≥ the threshold of 300 ng/mL given by 15 minute infusion (IVI) versus IV push (IVP) over 30 seconds |
| Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | Day 1 infusion versus Day 85 IV Push | 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 |
| Safety of Trogarzo Given as an Intramuscular Injection in the Intramuscular Injection Group | 10 weeks | Number of subjects in Intramuscular Injection Group who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol |
| Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion | Day 1 infusion versus Day 71 intramuscular injection | Ratio of proportion of subjects with trough concentration (Ctrough) ≥ the threshold of 300 ng/mL given by 15 minute infusion (IVI) versus intramuscular (IM) injection |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sentinel Group 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.
ibalizumab-uiyk: 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. | 5 |
| Core Group-HIV+ 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.
ibalizumab-uiyk: 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. | 4 |
| Core Group-HIV-uninfected 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.
ibalizumab-uiyk: 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. | 13 |
| Intramuscular Injection Group-HIV+ 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.
ibalizumab-uiyk: 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. | 7 |
| Intramuscular Injection Group-uninfected 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 IM injection.
ibalizumab-uiyk: 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. | 14 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 |
| Overall Study | non adherence to study | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Sentinel Group | Total | Intramuscular Injection Group-uninfected | Intramuscular Injection Group-HIV+ | Core Group-HIV-uninfected | Core Group-HIV+ |
|---|---|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 6 | 43 years STANDARD_DEVIATION 6 | 35 years STANDARD_DEVIATION 6 | 59 years STANDARD_DEVIATION 6 | 31 years STANDARD_DEVIATION 7 | 58 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 18 Participants | 6 Participants | 2 Participants | 8 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 24 Participants | 8 Participants | 4 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 38 Participants | 11 Participants | 6 Participants | 13 Participants | 4 Participants |
| Region of Enrollment United States | 5 participants | 43 participants | 14 participants | 7 participants | 13 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | 10 Participants | 6 Participants | 0 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 33 Participants | 8 Participants | 7 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 4 | 0 / 13 | 0 / 7 | 0 / 14 |
| other Total, other adverse events | 1 / 5 | 1 / 4 | 8 / 13 | 4 / 7 | 10 / 14 |
| serious Total, serious adverse events | 0 / 5 | 0 / 4 | 0 / 13 | 0 / 7 | 0 / 14 |
Outcome results
Primary
Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion
Ratio of proportion of subjects with trough concentration (Ctrough) ≥ the threshold of 300 ng/mL given by 15 minute infusion (IVI) versus intramuscular (IM) injection
Time frame: Day 1 infusion versus Day 71 intramuscular injection
Population: ITT population (HIV+ and HIV- participants pooled). Each HIV+ and HIV- participant received IV infusion and IM. Since the comparison between the two routes was conducted within the same participant (intra-individual comparison), data from both groups were pooled for the PK bridging statistical analysis. One HIV+ participant received only the IV infusion and discontinued prematurely without receiving the IM injection.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sentinel Group | Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion | Participants with Ctrough ≥ 300 ng/mL (IVI) | 5 Participants |
| Sentinel Group | Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion | Participants with Ctrough ≥ 300 ng/mL (IM) | 4 Participants |
| Core Group-HIV+ | Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion | Participants with Ctrough ≥ 300 ng/mL (IVI) | 14 Participants |
| Core Group-HIV+ | Pharmacokinetics Bridge Demonstrated for Intramuscular Injection of Trogarzo and IV Infusion | Participants with Ctrough ≥ 300 ng/mL (IM) | 12 Participants |
Comparison: The proportion of subjects with an average Ctrough ≥ 300 ng/mL is compared between IM and IV infusion.p-value: 0.3490% CI: [0.69, 1.08]Fisher Exact
Primary
Pharmacokinetics Bridge for IV Push and IV Infusion (AUC)
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
Time frame: Day 1 infusion versus Day 85 IV Push
Population: Intent to Treat (ITT) population (Sentinel and Core participants pooled). Each participant in both the Sentinel and Core groups received IV infusion and IV push. Since the comparison between the two routes was conducted within the same participant (intra-individual comparison), data from both groups were pooled for the pharmacokinetic (PK) bridging statistical analysis. Three Core Group HIV uninfected participants discontinued prematurely and did not have IVI or IVP data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sentinel Group | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVI) | 1232.86 day*mcg/mL | Standard Deviation 442.32 |
| Sentinel Group | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVP) | 1172.95 day*mcg/mL | Standard Deviation 442.73 |
| Core Group-HIV+ | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVI) | 1143.51 day*mcg/mL | Standard Deviation 629.16 |
| Core Group-HIV+ | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVP) | 1207.62 day*mcg/mL | Standard Deviation 515.46 |
| Core Group-HIV Uninfected | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVI) | 2772.35 day*mcg/mL | Standard Deviation 983.45 |
| Core Group-HIV Uninfected | Pharmacokinetics Bridge for IV Push and IV Infusion (AUC) | AUC (IVP) | 2812.55 day*mcg/mL | Standard Deviation 863.39 |
Comparison: The log transform of the ratio of the geometric means of the Area Under the Curve (AUC) for 30 second IV Push and 15 minute IV infusion is compared.p-value: 0.538990% CI: [0.9478, 1.1226]SAS PROC MIXED
Primary
Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough)
Ratio of proportion of subjects with trough concentration (Ctrough) ≥ the threshold of 300 ng/mL given by 15 minute infusion (IVI) versus IV push (IVP) over 30 seconds
Time frame: Day 1 infusion versus Day 85 IV Push
Population: Intent to Treat (ITT) population (Sentinel and Core participants pooled). Each participant in both the Sentinel and Core groups received IV infusion and IV push. Since the comparison between the two routes was conducted within the same participant (intra-individual comparison), data from both groups were pooled for the pharmacokinetic (PK) bridging statistical analysis. Three Core Group HIV uninfected participants discontinued prematurely and did not have IVI or IVP data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sentinel Group | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVI) | 5 Participants |
| Sentinel Group | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVP) | 5 Participants |
| Core Group-HIV+ | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVI) | 3 Participants |
| Core Group-HIV+ | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVP) | 3 Participants |
| Core Group-HIV Uninfected | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVI) | 10 Participants |
| Core Group-HIV Uninfected | Pharmacokinetics Bridge for IV Push and IV Infusion (Ctrough) | Participants with Ctrough ≥ 300 ng/mL (IVP) | 10 Participants |
Comparison: The proportion of subjects with an average Ctrough ≥ 300 ng/mL is compared between the 30-second IV push and the 15-minute IV infusion.p-value: 190% CI: [0.8299, 1.2049]Fisher Exact
Primary
Safety of Trogarzo Given as an Intramuscular Injection in the Intramuscular Injection Group
Number of subjects in Intramuscular Injection Group who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol
Time frame: 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sentinel Group | Safety of Trogarzo Given as an Intramuscular Injection in the Intramuscular Injection Group | 6 Participants |
| Core Group-HIV+ | Safety of Trogarzo Given as an Intramuscular Injection in the Intramuscular Injection Group | 13 Participants |
Primary
Safety of Trogarzo Given as IV Push Over 30 Seconds
Number of subjects who complete 100% of all Trogarzo administrations given as infusion/bolus/push as per protocol
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sentinel Group | Safety of Trogarzo Given as IV Push Over 30 Seconds | 5 Participants |
| Core Group-HIV+ | Safety of Trogarzo Given as IV Push Over 30 Seconds | 4 Participants |
| Core Group-HIV Uninfected | Safety of Trogarzo Given as IV Push Over 30 Seconds | 10 Participants |