Reducing HIV Persistence in Lymph Nodes by Interleukin-15 (IL-15) Receptor Super-agonist (N-803) in Acute HIV Infection

• ClinicalTrials.gov Identifier: NCT04505501
• Recruitment Status: Recruiting
• First Posted: August 10, 2020
• Last Update Posted: October 6, 2021
• Sponsor: Thai Red Cross AIDS Research Centre
• Collaborators: Henry M. Jackson Foundation for the Advancement of Military Medicine; Walter Reed Army Institute of Research (WRAIR)
• Information provided by (Responsible Party): Thai Red Cross AIDS Research Centre

Study Description

Brief Summary:

Reducing HIV persistence in lymph nodes by Interleukin-15 (IL-15) Receptor super-agonist (N-803) in Individuals with Acute HIV Infection

Condition or disease	Intervention/treatment	Phase
HIV/AIDS	Drug: N-803	Phase 2

Detailed Description:

This is a phase II, randomized, unblinded, controlled trial to investigate the safety, tolerability and immunomodulation effect of combining N-803 with antiretroviral therapy (ART) during acute HIV infection (AHI). The study will be conducted at one study site, the Thai Red Cross AIDS Research Centre (TRCARC) in Bangkok, Thailand.

Eligible participants will be asked to undergo LN Bx at baseline (untreated AHI), prior to initiating dolutegravir-based ART. N-803 will be administered subcutaneously at weeks 0, 3, 6 (total 3 doses) and will be initiated together with ART. Participants will be asked to undergo a second inguinal LN Bx on the opposite groin approximately at week 6 (no later than 1 week after completion of study agents). They will be followed for safety parameters at weeks 8 and 12, after which they will roll over to the RV412, WRAIR#2178 safety monitoring protocol. The study duration for individual participants will be approximately 12 weeks. The study may include additional optional procedures at baseline and week 6 such as leukapheresis, brain MRI imaging and lumbar puncture, according to participants' consent.

It is hypothesized that N-803 initiated with ART during AHI, will be safe, and will lead to a reduction of HIV reservoir size in LN, demonstrated by decreased frequencies of vRNA+ and vDNA+ cells in the LNs, in comparison with ART alone.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: This study is unblinded.
• Primary Purpose: Treatment
• Official Title: Reducing HIV Persistence in Lymph Nodes by Interleukin-15 (IL-15) Receptor Super-agonist (N-803) in Individuals With Acute HIV Infection
• Actual Study Start Date: March 1, 2021
• Estimated Primary Completion Date: May 31, 2022
• Estimated Study Completion Date: August 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: N-803; N-803 at 6mcg/kg every 3 weeks for 3 doses plus ART (n=10)	Drug: N-803; N-803 is a novel IL-15 superagonist complex that enhances NK cell and CD8+ T-cell proliferation and activation.; Other Name: ALT-803
No Intervention: Control; ART alone (n=5)

Outcome Measures

Primary Outcome Measures :

1. Rate of occurrence of ≥ grade 3 adverse events determined to be related (Safety) [ Time Frame: at time of study completion at week 12 ]
   Rate of occurrence of ≥ grade 3 adverse events determined to be related
2. Frequency of vRNA+ and vDNA+ cells in LNs (Efficacy) [ Time Frame: at week 6 ]
   Frequency of vRNA+ and vDNA+ cells in LNs
3. levels of vDNA and vRNA in LNs (Efficacy) [ Time Frame: at week 6 ]
   levels of vDNA and vRNA in LNs
4. Frequency of CD8+ T cells in LNs (Efficacy) [ Time Frame: at week 6 ]
   Frequency of CD8+ T cells in LNs

Secondary Outcome Measures :

1. Frequency of Immune cells in LN and blood [ Time Frame: at week 6 ]
   Frequency of Immune cells in LN and blood
2. HIV-specific antibody levels [ Time Frame: at week 12 ]
   HIV-specific antibody levels
3. HIV-specific antibody function as measured by Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and Antibody-dependent cell-mediated viral inhibition (ADCVI) levels. [ Time Frame: at week 12 ]
   HIV-specific antibody function as measured by Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and Antibody-dependent cell-mediated viral inhibition (ADCVI) levels.
4. Frequency of cells harboring vDNA, vRNA, intact genome and replication competent HIV-1 in peripheral blood mononuclear cell (PBMC) [ Time Frame: at week 12 ]
   Frequency of cells harboring vDNA, vRNA, intact genome and replication competent HIV-1 in peripheral blood mononuclear cell (PBMC)
5. Differential expressed genes in LN and blood [ Time Frame: at week 12 ]
   Differential expressed genes in LN and blood
6. Immune activation markers in blood [ Time Frame: at week 12 ]
   Immune activation markers in blood
7. Immune activation markers in CSF [ Time Frame: at week 6 ]
   Immune activation markers in CSF
8. Extent of cerebral inflammation in MR Spectroscopy (MRS) [ Time Frame: at week 6 ]
   Extent of cerebral inflammation in MR Spectroscopy (MRS)
9. Viral load in the CSF [ Time Frame: at week 6 ]
   Viral load in the CSF

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18-40 years
2. Acute HIV infection (Fiebig I to V: Fiebig I: RNA+, p24 antigen-; Fiebig II: p24 antigen+, IgM-; Fiebig III: IgM+, Western Blot-; Fiebig IV: Western Blot indeterminate; Fiebig V: Western Blot+ without p31 protein band)
3. All female participants of childbearing potential must have a negative urine pregnancy test at the screening visit
4. Women of child bearing potential and men with partners of child bearing potential must agree to use effective contraception (as defined in section 8.1.2 Pregnancy Risks) during therapy and for 4 months after completion of therapy
5. Can read and write Thai and/or English language and must be able to understand and complete the informed consent process
6. Must successfully complete a Test of Understanding (TOU) prior to enrollment as described in Section 7.1
7. Willing to undergo inguinal LN Bx at two time points (baseline and week 6) and blood draws during each study visit
8. Willing to participate for the duration of the study visits and follow up.

Exclusion Criteria:

1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
2. Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months; minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) are not exclusionary
3. Receipt of any vaccine within 2 weeks prior to study enrollment and anticipated need for any vaccine within 2 weeks prior to or after any of the study agent administrations.
4. Current or anticipated use of systemic steroid medications.
5. Any clinically significant acute or chronic medical condition, including, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, that in the opinion of the investigator would preclude participation (e.g., history of seizure disorders, cardiac disease, bleeding/clotting disorder, autoimmune disease, active malignancy, poorly controlled asthma, active tuberculosis or other systemic infections, etc.)
6. Chronic liver disease
7. Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines, including a previous diagnosis of any of the following: (a) acute myocardial infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial revascularization, (e) stroke, (f) transient ischemic attack, or (g) peripheral arterial disease presumed to be of atherosclerotic origin
8. History of potential immune-mediated medical conditions
9. Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment
10. Major psychiatric illness and/or substance use during the past 12 months that in the opinion of the investigator would preclude participation
11. Concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment
12. Exposure to any experimental therapies within 90 days of study entry
13. Pre-exposure prophylaxis (PrEP) use within 90 days of study entry

Contacts and Locations

Contacts

Contact: Nitiya Chomchey, PhD; 6622542566; nitiya.c@ihri.org

Contact: Haoyu Qian; 301-500-3732; HQian@hivresearch.org

Locations

Thailand

Thai Red Cross AIDS Research Centre; Recruiting

Bangkok, Thailand, 10330

Contact: Nitiya Chomchey, RN, PhD 6622542566 nitiya.c@ihri.org

Contact: Kiat Ruxrungtham, MD 66863353655 kiat.r@chula.ac.th

Sponsors and Collaborators

Thai Red Cross AIDS Research Centre

Henry M. Jackson Foundation for the Advancement of Military Medicine

Walter Reed Army Institute of Research (WRAIR)

Investigators

• Study Chair: Denise C Hsu, MD PhD; Henry M. Jackson Foundation for the Advancement of Military Medicine

More Information

• Responsible Party: Thai Red Cross AIDS Research Centre
• ClinicalTrials.gov Identifier: NCT04505501
• Other Study ID Numbers: RV550
• First Posted: August 10, 2020
• Last Update Posted: October 6, 2021
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

HIV Infections; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases