跳至主要内容
MedPath Trial logoMedPath TrialMedPath Trial Home
临床试验/NCT05769569
NCT05769569撤回1 期

Safety and Efficacy of Broadly Neutralizing Antibodies Followed by Innate Immune Stimulation and Therapeutic Vaccination for the Induction of HIV Remission

Henry M. Jackson Foundation for the Advancement of Military Medicine4 个研究点 分布在 1 个国家开始时间: 2023年9月1日最近更新:
Share to TwitterShare to FacebookShare to LinkedInShare to Reddit
适应症

试验速览

阶段
1 期
状态
撤回
发起方
试验地点
4
主要终点
To evaluate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination in PLWH who initiated ART during AHI.
研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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).

详细描述

This is a phase 1 study. The study duration is approximately 134 weeks. The primary objectives are:

  1. To evaluate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination in PLWH who initiated ART during AHI.
  2. To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to sustained viral rebound to ≥1000 copies/mL for 4 consecutive weeks AND has not declined by >0.2 log10 from the previous measurement during ATI.

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Parallel
主要目的
Treatment
盲法
None

入排标准

年龄范围
18 Years 至 50 Years（Adult）
性别
All
接受健康志愿者
是

入选标准

  • •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:
  • •Absolute neutrophil count (ANC) ˃1,000/mm3
  • •Hemoglobin >11.5 g/dL
  • •Platelet count ˃150,000/mm3
  • •Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2 using the re-expressed MDRD equation with Thai racial factor or the CKD-EPI Cystatin C equation.
  • •Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase (AP) ≤1 x ULN
  • •Total bilirubin ≤1 x ULN
  • •Troponin <1 x ULN
  • •HIV RNA <50 copies/ml for ≥48 weeks at screening.
  • •No history of virologic failure. Virologic failure is defined as having two consecutive HIV-1 RNA >1000 copies/mL at any time after achieving HIV-1 RNA <50 copies/mL.
  • •A single viral load measurement ≥50 but <1000 copies/mL, at any time from achieving HIV-1 RNA <50 copies/mL to > 48 weeks from screening, is allowed provided that it is bracketed by viral loads <50 copies/mL.
  • •A single viral load measurements ≥50 but <200 copies/mL, within 48 weeks of screening is allowed provided that each is bracketed by viral loads <50 copies/mL prior to 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.

排除标准

  • •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 ≥F
  • •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
  • •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.
  • •The second method of contraception must be from the barrier methods also listed in section 7.5.
  • •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.
  • 另有 9 项未显示

结局指标

主要结局

To evaluate the safety of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination in PLWH who initiated ART during AHI.

时间窗: Through month 31

Occurrence of ≥ grade 3 AE or SAE that are possibly, probably, or definitely related to the IPs during the study. Adverse events will be graded using "DAIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS (DAIDS AE SEVERITY GRADING TABLE) V2.1, JULY 2017" (https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf), where grade 1 is mild and grade 4 is potentially life threatening.

To evaluate the treatment combination on time to sustain viral rebound to ≥1000 copies/mL for 4 consecutive weeks AND has not declined by >0.2 log10

时间窗: Through month 31

Time (days) from ATI to sustained viral rebound of ≥1000 copies/mL for 4 consecutive weeks AND has not declined by \>0.2 log10 from the previous measurement.

次要结局

  • To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the number of participants with plasma HIV RNA <1000 copies/mL at 12 and 24 weeks of ATI.(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on effector function of T cell responses(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on HIV specific Antibody Dependent Cellular Cytotoxicity (ADCC):([Time Frame: Through month 31])
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on proliferation of T cell responses(Through month 31)
  • To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to first documented HIV-1 RNA viral rebound of ≥50 copies/mL following ATI.(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on magnitude of T cell responses(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on HIV specific Binding antibodies to HIV-1(Through month 31)
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the HIV reservoir prior to ATI using Total Virus Recovery([Time Frame: Through month 31])
  • To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to first documented HIV-1 RNA viral rebound of ≥1000 copies/mL following ATI.(Through month 31)
  • To evaluate the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on time to ART resumption for an HIV-related (virologic, immunologic, or clinical) reason during Step 2.(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on breadth of T cell responses(Through month 31)
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on cell-associated HIV RNA prior to ATI([Time Frame: Through month 31])
  • To measure the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on HIV RNA levels while on ART.(Through month 31)
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on total HIV DNA levels prior to ATI(Through month 31)
  • To assess the effects of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on HIV specific Antibody Dependent Cellular Phagocytosis (ADCP):([Time Frame: Through month 31])
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on cell-associated HIV DNA prior to ATI([Time Frame: Through month 31])
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the HIV reservoir prior to ATI using single copy HIV RNA([Time Frame: Through month 31])
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the HIV reservoir prior to ATI using Intact Proviral DNA:([Time Frame: Through month 31])
  • To assess the impact of VRC07-523LS, PGDM1400LS and N-803 in combination with Ad26.Mos4.HIV, MVA-BN-HIV and A244d11 gp120/ALFQ vaccination on the HIV reservoir prior to ATI using Quantitative Viral Outgrowth Assay (QVOA)([Time Frame: Through month 31])
  • To characterize the pharmacokinetics of VRC07-523LS and PGDM1400LS([Time Frame: Through month 31])

研究者

发起方
Henry M. Jackson Foundation for the Advancement of Military Medicine
申办方类型
Other
责任方
Sponsor

研究点 (4)

Loading locations...

相似试验

进行中（未招募）
1 期
A clinical study on safety, immune activation and the effect of treatment with histamine and IL- 2 in adult tyrosine kinase inhibitor-treated patients with chronic myeloid leukemia (CML )Chronic Myeloid Leukemia (CML)
EUCTR2016-002728-94-SESahlgrenska University Hospital15
已完成
1 期
Pausing Antiretroviral Treatment Under Structured EvaluationHIV-1-infection
NCT06031272Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections32
终止
1 期
Neoantigen Peptide Vaccine Strategy in Pancreatic Cancer Patients Following Surgical Resection and Adjuvant ChemotherapyPancreas CancerCancer of the PancreasPancreatic Cancer
NCT03956056Washington University School of Medicine12
进行中（未招募）
1 期
A study of a new vaccine against the MERS virus in adults aged 50 to 70 yearsMiddle East Respiratory Syndrome Coronavirus (MERS-CoV) infectionInfections and Infestations
ISRCTN17936606niversity of Oxford84
已完成
1 期
Safety Study of a Liposomal Vaccine to Treat Malignant Melanoma
ACTRN12610000149066ipotek Pty Ltd24