A Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of PGDM1400LS Alone and in Combination With VRC07-523LS and PGT121.414.LS in Healthy, HIV-uninfected Adult Participants

HIV Infections Clinical Trial

Official title:

A Phase 1 Dose-escalation Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of PGDM1400LS Alone and in Combination With VRC07-523LS and PGT121.414.LS in Healthy, HIV-uninfected Adult Participants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05184452
• Other study ID #: HVTN 140/HPTN 101
• Secondary ID: DAIDS DOCUMENT I
• Status: Completed
• Phase: Phase 1
• Start date: November 15, 2021
• Est. completion date: July 19, 2023

Study information

• Verified date: February 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Part A: The purpose of this part of the study is to understand how the body's immune system responds to a new lab-made antibody against HIV. The study is looking to see if the way the antibody is given affects the immune response. The study will also look at whether the antibody is safe to give to people and does not make them too uncomfortable. Part B: The purpose of this part of the study is to understand how the body's immune system responds to lab-made antibodies against HIV when they are given in combination at different doses. The study also wants to see if the way the antibodies are given affects the immune response.

Description:

The HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) are conducting this study to test a combination of different antibodies against HIV. HIV is the virus that causes AIDS. Antibodies are made by the body as one way to respond to or fight infection. Researchers can also make antibodies in laboratories and give them to people by infusions into a vein or under the skin. There are 2 parts of this study, Part A and Part B. About 15 people will take part in Part A of this study to test one study antibody. After early safety results from Part A are obtained, a decision will be made as to whether or not to do Part B of the study. Part B of the study would test a combination of 3 antibodies. If it is decided to move forward with Part B, 80 more people will join.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: July 19, 2023
• Est. primary completion date: July 19, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Age of 18 through 50 years

2. Access to a participating CRS and willingness to be followed for the planned duration of the study

3. Ability and willingness to provide informed consent

4. Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first study product administration with verbal demonstration of understanding of all questionnaire items answered incorrectly

5. Agrees not to enroll in another study of an investigational research agent until completion of the last required protocol clinic visit.

6. Good general health as shown by medical history, physical exam, and screening laboratory tests

7. Willingness to receive HIV test results

8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling.

9. Assessed by the clinic staff as being at "low risk" for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit (see Appendix J and Appendix K).

10. Hemoglobin

• = 11.0 g/dL for volunteers who were assigned female sex at birth
• = 13.0 g/dL for volunteers who were assigned male sex at birth and transgender males who have been on hormone therapy for more than 6 consecutive months
• = 12.0 g/dL for transgender females who have been on hormone therapy for more than 6 consecutive months
• For transgender volunteers who have been on hormone therapy for less than 6 consecutive months, determine hemoglobin eligibility based on the sex assigned at birth

11. White blood cell count = 2,500 to 12,000 cells/mm3

12. WBC differential either within institutional normal range or with site clinician approval

13. Platelets = 125,000 to 550,000 cells/mm3

14. Chemistry panel: alanine aminotransferase (ALT) < 1.25 times the institutional upper limit of normal (ie, < 1.25 times the reference range upper limit) and creatinine < 1.1 times the institutional upper limit of normal (ie, <1.1 times the reference range upper limit)

15. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA). Non-US sites may use locally available assays that have been approved by HVTN and HPTN Laboratory Operations

16. Negative Hepatitis B surface antigen (HBsAg)

17. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the anti-HCV is positive

18. Negative or trace urine protein

19. Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (ß-HCG) pregnancy test(s) performed within 48 hours prior to initial study product administration. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing.

20. A volunteer who was assigned female sex at birth must:

• Agree to use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through the last required protocol visit. Effective contraception is defined as using one of the following methods: Condoms (internal and external) with or without a spermicide, Diaphragm or cervical cap with spermicide, Intrauterine device (IUD), Hormonal contraception, Tubal ligation, or Any other contraceptive method approved by the HVTN 140/HPTN 101 PSRT, Successful vasectomy in any partner assigned male sex at birth (considered successful if a volunteer reports that a male partner has [1] documentation of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy); or,
• Not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy or bilateral oophorectomy; or,
• Be sexually abstinent.

21. Volunteers who were assigned female sex at birth must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit

Exclusion Criteria:

1. Weight < 35kg or > 115 kg

2. Blood products received within 120 days before first study product administration, unless eligibility for earlier enrollment is determined by the HVTN 140/HPTN 101 PSRT

3. Investigational research agents received within 30 days before first study product administration

4. Intent to participate in another study of an investigational research agent or any other study that requires non-Network HIV antibody testing during the planned duration of the HVTN 140/HPTN 101 study

5. Pregnant or breastfeeding

6. HIV vaccine(s) received in a prior HIV vaccine trial. Volunteers who have received control/placebo in an HIV vaccine trial are not excluded.

7. SARS-CoV-2 vaccine(s) received within 7 days prior to HVTN 140/HPTN 101 enrollment or planned within 7 days after enrollment.

8. Receipt of humanized or human mAbs, whether licensed or investigational.

9. Previous receipt of mAbs VRC01, VRC01LS, VRC07-523LS, PGDM1400, PGT121, PGT121.414.LS.

10. Immunosuppressive medications received within 30 days before first study product administration (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatological condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses < 20 mg/day and length of therapy < 14 days)

11. Serious adverse reactions to PGDM1400LS, VRC07-523LS, or PGT121.414.LS formulation components (see Section 8.2) including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.

12. Immunoglobulin received within 60 days before first study product administration (for mAb see criterion 8 above)

13. Autoimmune disease (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require immunosuppressive medication and that, in the judgment of the CRS investigator, is likely not subject to exacerbation and likely not to complicate Solicited and Unsolicited AE assessments.)

14. Immunodeficiency

15. Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or

process includes but is not limited to:

• Symptoms consistent with COVID-19 or known SARS-CoV-2 infection,
• A process that would affect the immune response,
• A process that would require medication that affects the immune response,
• Any contraindication to repeated infusions, or blood draws, including inability to establish venous or subcutaneous access,
• A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period,
• A condition or process (eg, chronic urticaria or recent injection or infusion with evidence of residual inflammation) for which signs or symptoms could be confused with reactions to the study product, or
• Any condition specifically listed among the exclusion criteria.

16. Any medical, psychiatric, or skin condition (eg, tattoos), or occupational responsibility that, in the judgment of the investigator, would interfere with or serve as a contraindication to protocol adherence, assessment of safety or Solicited AEs, or a participant's ability to give informed consent.

17. Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.

18. Current anti-tuberculosis (TB) therapy

19. Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as defined in the most recent National Asthma Education and Prevention Program (NAEPP) Expert Panel report).

Exclude a volunteer who:

• Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or
• Uses moderate/high-dose, inhaled corticosteroids, or
• In the past year has had either of the following: Greater than 1 exacerbation of symptoms treated with oral/parenteral corticosteroids; Emergency care, urgent care, hospitalization, or intubation for asthma.

20. Diabetes mellitus type 1 or type 2 (Not excluded: type 2 cases controlled with diet alone or a history of isolated gestational diabetes.)

21. Hypertension:

• If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined in this protocol as consistently = 140 mm Hg systolic and = 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be = 150 mm Hg systolic and = 100 mm Hg diastolic. For these volunteers, blood pressure must be = 140 mm Hg systolic and = 90 mm Hg diastolic at enrollment.
• If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure = 150 mm Hg at enrollment or diastolic blood pressure = 100 mm Hg at enrollment.

22. Bleeding disorder diagnosed by a clinician (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions)

23. Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study)

24. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

25. Asplenia: any condition resulting in the absence of a functional spleen

26. History of generalized urticaria, angioedema, or anaphylaxis (Not exclusionary:

angioedema or anaphylaxis to a known trigger with at least 5 years since last reaction to demonstrate satisfactory avoidance of trigger).

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• PGDM1400LS (5mg/kg, IV)
5 mg/kg to be administered via IV infusion
• PGDM1400LS (20mg/kg, IV)
20 mg/kg to be administered via IV infusion
• PGDM1400LS (20mg/kg, SC)
20 mg/kg to be administered via SC infusion
• PGDM1400LS (40mg/kg, IV)
40 mg/kg to be administered via IV infusion
• PGDM1400LS (40mg/kg, SC)
40 mg/kg to be administered via SC infusion
• PGDM1400LS (1.4g, IV)
1.4gram to be administered via IV infusion
• PGDM1400LS (1.4g, SC)
1.4gram to be administered via SC infusion
• VRC07-523LS (20mg/kg, IV)
VRC07-523LS 20mg/kg administered via IV infusion
• VRC07-523LS (20mg/kg, SC)
VRC07-523LS 20mg/kg administered via SC infusion
• VRC07-523LS (1.4g, IV)
VRC07-523LS 1.4g administered via IV infusion
• VRC07-523LS (1.4g, SC)
VRC07-523LS 1.4g administered via SC infusion
• VRC07-523LS (40mg/kg, IV)
VRC07-523LS 40mg/kg administered via IV infusion
• PGT121.414.LS (20mg/kg, IV)
PGT121.414.LS 20mg/kg administered via IV infusion
• PGT121.414.LS (20mg/kg, SC)
PGT121.414.LS 20mg/kg administered via SC infusion
• PGT121.414.LS (1.4g, IV)
PGT121.414.LS 1.4g administered via IV infusion
• PGT121.414.LS (1.4g, SC)
PGT121.414.LS 1.4g administered via SC infusion
• PGT121.414.LS (40mg/kg, IV)
PGT121.414.LS 40mg/kg administered via IV infusion

Locations

Country	Name	City	State
Kenya	Kenya Medical Research Institute (KEMRI)	Kericho
South Africa	CAPRISA eThekweni Clinical Research Site	Berea	Durban
South Africa	Groote Schuur Hospital	Cape Town	Western Cape Province
South Africa	Ward 21 Clinical Research Site	Hillbrow	Johannesburg
South Africa	Soweto HVTN CRS	Soweto
United States	The Hope Clinic of the Emory Vaccine Center	Atlanta	Georgia
United States	Vanderbilt Vaccine (VV)	Nashville	Tennessee
United States	New Jersey Medical School Clinical Research Center CRS	Newark	New Jersey
United States	Bridge HIV CRS	San Francisco	California
United States	George Washington University	Washington	District of Columbia
Zimbabwe	Seke South Clinical Research Site	Chitungwiza	Harare
Zimbabwe	Milton Park CRS	Milton Park	Harare
Zimbabwe	Spilhaus CRS	Milton Park	Harare

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Department of Health and Human Services, National Institutes of Health (NIH)

Countries where clinical trial is conducted

United States,  Zimbabwe,  Kenya,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of participants who experience local solicited adverse events (AEs) in Part A	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Day 3
Primary	Percentage of participants who experience local solicited adverse events (AEs) in Part B	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Week 24
Primary	Percentage of participants who experience systemic solicited AEs in Part A	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Day 3
Primary	Percentage of participants who experience systemic solicited AEs in Part B	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Day 24
Primary	Percentage of participants who experience unsolicited AEs in Part A	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Week 24
Primary	Percentage of participants who experience unsolicited AEs in Part B	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol.	Week 40
Primary	Percentage of participants who experience unsolicited severe adverse events (SAEs) Part A	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this study.	Week 24
Primary	Percentage of participants who experience unsolicited severe adverse events (SAEs) Part B	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, except as noted in the study protocol. The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this study.	Week 40
Primary	Percentage of participants who discontinue study product administration early in Part A		Day 0
Primary	Percentage of participants who discontinue study product administration early in Part B		Week 16
Primary	Percentage of participants who terminate the study early in Part A		Week 24
Primary	Percentage of participants who terminate the study early in Part B	Measured at prespecified timepoints among participants who received all scheduled product administrations	Week 40
Primary	Serum concentrations of PGDM1400LS in Part A	Measured at prespecified timepoints among participants who received all scheduled product administrations	Week 24
Primary	Serum concentrations of PGDM1400LS in Part B		Week 40
Primary	Serum concentrations of PGT121.414.LS for participants in Part B	Measured at prespecified timepoints among participants who received all scheduled product administrations	Week 40
Primary	Serum concentrations of VRC07-523LS for participants in Part B	Measured at prespecified timepoints among participants who received all scheduled product administrations	Week 40
Primary	Magnitude of serum neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) measured with monoclonal antibody mAb-specific Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part A	Measured from samples obtained at prespecified timepoints among participants who received all scheduled product administrations for participants in Part A	Week 24
Primary	Magnitude of serum neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) measured with monoclonal antibody mAb-specific Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part B	Measured from samples obtained at prespecified timepoints among participants who received all scheduled product administrations for participants in Part B	Week 40
Secondary	Serum concentrations of PGDM1400LS for participants in Part A	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 24
Secondary	Serum concentrations of PGDM1400LS for participants in Part B	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 40
Secondary	Serum concentrations of PGT121.414.LS for participants in Part B	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 40
Secondary	Serum concentrations of VRC07-523LS for participants in Part B	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 40
Secondary	Magnitude of neutralizing activity (ie, neutralizing antibody titers, including ID50, ID80) against Env-pseudotyped viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for Part A and clinical product assayed at same time.	Measured at selected timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 24
Secondary	Magnitude of neutralizing activity (i.e., neutralizing antibody titers, including ID50 and ID80) against a panel of Env-pseudotyped reference viruses in TZM-bl cells (in the validated TZM-bl pseudovirus neutralization assay) for participants in Part B	Measured at selected timepoints for all participants in all groups regardless of how many product administrations and how much product they received and for the clinical product assayed at the same time.	Week 40
Secondary	Anti-drug antibodies (ADA) titers for participants in Part A	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 24
Secondary	Anti-drug antibodies (ADA) titers for participants in Part B	Measured at prespecified timepoints for all participants in all groups regardless of how many product administrations and how much product they received	Week 40