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About
This is a phase I, randomized, open-label trial to investigate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-Bavarian Nordic (BN)-HIV and A244d11gp120/ALFQ vaccination, and the impact on time to sustained viral rebound of ≥1000 copies/mL for 4 consecutive weeks during analytic treatment interruption (ATI) in people living with human immunodeficiency virus-1 (HIV-1, PLWH) who initiated antiretroviral therapy (ART) during acute HIV-1 infection (AHI).
Full description
This is a phase 1 study. The study duration is approximately 134 weeks. The primary objectives are:
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Step 1 Inclusion Criteria
Participants are eligible to be included in the protocol Step 1 only if all of the following criteria are met:
Thai National
Age ≥18 and ≤50 years of age
Can read and write Thai or English
Able and willing to provide written informed consent
Participant of the RV254 study
Confirmed HIV-1 infection (nucleic acid testing [NAT] and/or HIV serology positive with confirmatory quantitative HIV viral load) and started ART during acute infection (Fiebig stage I-V)
Uninterrupted treatment with ART (no interruption of ART for ≥7 consecutive days or longer) since ART initiation, for ≥ 48 weeks.
Currently on integrase inhibitor-based ART regimen (excluding long-acting injectable regimens) and no recent (≤8 weeks prior to screening) changes to ART regimen.
a. There must be at least one documented plasma HIV RNA <50 cps/mL after the last ART change prior to screening
Must be medically stable as confirmed by medical history, physical examination, vital signs, and clinical laboratory tests performed at screening, and as per the Investigator's discretion.
a. If the results of the screening laboratory panel (except those listed specifically in inclusion criterion) are outside the normal reference ranges, the participant may be included only if the Investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study after discussion with the Sponsor's Representative.
The following laboratory values at screening:
HIV RNA <50 copies/ml for ≥48 weeks at screening.
CD4 T-cell count ≥450 cells/mm3 at screening.
Sensitivity test demonstrating the lack of detection of resistant viruses to VRC07-523LS and PGDM1400LS
For persons of childbearing potential, negative pregnancy test at the screening visit.
Persons of childbearing potential must agree to not become pregnant and use two methods of contraception if engaging in sexual activity that could lead to pregnancy. One contraceptive method must be from the list of highly effective methods listed in section 7.5.3 of the protocol. The second method of contraception must be from the barrier methods also listed in section 7.5.3.Contraception must be used from the time of screening to the end of study .
Participants engaging in sexual activity that could lead to pregnancy in the partner and who are of reproductive potential must agree to use a condom to avoid pregnancy in a spouse or partner of childbearing potential and to avoid transmitting HIV to an uninfected partner. A condom must be used from the time of screening until the end of the study.
Willingness to abstain from sexual intercourse, or use a condom, or partner(s) using pre-exposure prophylaxis consistently during ATI and until plasma HIV-1 RNA is less than limit of detection after ART restart with all partners that are HIV-uninfected or serostatus unknown.
Passes Test of Understanding (Section 8.4)
Willing to interrupt and restart ART according to study schedule
Willing to participate and adhere to the prohibitions and restrictions specified in this protocol for the duration of the study visits and follow up.
Step 1 Exclusion Criteria
Participants who meet any of the following criteria will be excluded from the study:
Weight <50 kg or > 115 kg
Presence of HLA allele associated with viral control including HLA B*57:01 or HLA B*58:01 (based on archived data from RV254)
Anyone with contraindication to intramuscular injections, placement of intravenous lines, and blood draws
Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to entry.
Any clinically significant acute or chronic medical condition, that in the opinion of the investigator would preclude participation including cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological disorders, that in the opinion of the investigator would preclude participation (e.g., history of seizure disorders, cardiovascular disease, bleeding/clotting disorder, autoimmune disease, malignancy, poorly controlled asthma, active tuberculosis or other systemic infections, etc.)
Participants with acute illness (this does not include minor illnesses such as diarrhea or mild upper respiratory tract infection) including untreated syphilis, gonorrhea or chlamydia infection or temperature ≥38.0ºC within 24 hours prior to the first dose of IP will not enter baseline. Participant will be referred for treatment, and participant is eligible for repeat screening and potential study entry once treatment is successfully completed
Major surgery (per the Investigator's judgment) within 12 weeks before screening or plan to have major surgery during the time of study participation
• surgical procedures to be conducted under local or loco-regional anesthesia and not judged as major by the Investigator may participate.
Current or history of an HIV-associated malignancy (including Kaposi's sarcoma), and any type of lymphoma, or virus-associated cancers
Current or history of non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the 36 months prior to screening
• Minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) or carcinoma in situ of the cervix is not exclusionary
Current or history of clinical atherosclerotic cardiovascular disease, as defined by 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, including a previous diagnosis of any of the following: acute myocardial infarction, acute coronary syndromes, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), peripheral arterial disease presumed to be of atherosclerotic origin
Current or history of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with permanent sequelae, clinically significant arrhythmia (including any arrhythmia requiring medication, treatment, or clinical follow-up)
Current or history of advanced liver disease (non-alcoholic fatty liver disease, steatohepatitis, or alcoholic liver disease) with known or suspected cirrhosis or fibrosis score ≥F2.
Current or history of TTS, or heparin-induced thrombocytopenia and thrombosis syndrome.
Current or history of acute polyneuropathy e.g. Guillain-Barré syndrome
Current or history of CDC Category C event
Active or chronic hepatitis B virus infection (detectable HBsAg, HBV DNA, or both)
Hepatitis C infection (HCV antibody positive)
Receipt of a licensed or Emergency Use Authorization vaccine within 4 weeks prior to study screening or plans to receive live attenuated vaccines within 4 weeks or any other licensed or Emergency Use Authorization vaccine within 2 weeks prior to or 2 weeks after any of the study investigational product administrations.
Receipt of an investigational study agent within 12 months prior to study screening
Previous receipt of immunoglobulin (IgG) therapy Note: Individuals who received IgGs as prophylactic therapy (i.e., for HBV or rabies exposure) >12 months prior to screening will not be excluded.
Previous receipt of humanized or human monoclonal antibody whether licensed or investigational Note: Individuals who received monoclonal antibody for the prevention and/or treatment of SARS-CoV-2/COVID-19 >12 months prior to screening will not be excluded.
Previous participation in a candidate HIV vaccine study or immune prophylaxis for HIV-1 infection with confirmed receipt of active product or with unknown receipt of active product vs placebo (i.e. remains blinded to what was actually received).
History of use of any immunomodulatory medications within 6 months of study entry including systemic corticosteroids (>14 days), immunosuppressants, anti-cancer drugs, interleukins, systemic interferons, systemic chemotherapy, or other medications that the site investigator feels could have an immune modulatory effect Note: Topical or inhaled corticosteroids are not prohibited.
Known allergy or history of anaphylaxis or other serious adverse reactions to vaccines, vaccine products, neomycin, streptomycin, gentamicin or egg products
History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis in the 2 years prior to enrollment
History of chronic urticaria requiring daily treatment or a history of chronic or recurrent eczema and/or atopic dermatitis
History of splenectomy
EKG abnormality within 90 days prior to or at screening, including but not limited to second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (regardless of gender or sex), or clinically important arrhythmia that would interfere with the assessment of myocarditis/pericarditis or QTc interval.
QTc interval >440 ms within 90 days prior to or at screening
Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, offspring, or sibling).
Pregnant, breastfeeding or planning to become pregnant while enrolled in this study
Major psychiatric illness and/or substance use during the past 12 months that in the opinion of the investigator would preclude participation
Step 2 (ATI) Inclusion Criteria
Participants enrolled in the study may proceed with Step 2 if the meet all the following inclusion criteria:
Receipt at least 3 doses of N-803 and all doses of VRC07-523LS, PGDM1400LS, Ad26.Mos4.HIV with A244d11 gp120/ALFQ and MVA-BN HIV with A244d11 gp120/ALFQ in Step 1.
Plasma HIV-1 RNA <50 copies/mL at week 47 visit
CD4 T-cell count ≥450 cells/mm3 at week 47 visit
a. NOTE: The CD4 T-cell count can be repeated once, provided that the repeat is done within 4 weeks prior to Step 2 entry.
No CDC Category C event after study entry
Documented negative hepatitis B virus (HBV) surface antigen (HBsAg) at week 47 visit
Documented negative hepatitis C virus (HCV) antibody (anti-HCV) at week 47 visit
For persons of childbearing potential, negative pregnancy test at the week 50 visit
Persons of childbearing potential must agree to not become pregnant and use two methods of contraception if engaging in sexual activity that could lead to pregnancy. One contraceptive method must be from the list of highly effective methods listed in section 7.5.3. The second method of contraception must be from the barrier methods also listed in section 7.5.3.
Willingness to abstain from sexual intercourse, or use a condom, or partner(s) using pre-exposure prophylaxis consistently during ATI and until plasma HIV-1 RNA is less than limit of detection after ART restart with all partners that are HIV-uninfected or serostatus unknown.
Willingness to participate in ATI for up to 36 weeks.
Willingness to restart ART according to study guidelines.
Step 2 (ATI) Exclusion Criteria
Enrolled participants who meet any of the following criteria will be excluded from moving to Step 2:
Primary purpose
Allocation
Interventional model
Masking
0 participants in 2 patient groups
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Central trial contact
Kiat Ruxrungtham, M.D.; Somchai Sriplienchan, M.D., M.P.H.
Data sourced from clinicaltrials.gov
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