CClinicalTrials.gg
TerminatedNCT03308786IL2Updated Sep 28, 2022Results posted

HIV Reservoir Reduction With Interleukin-2

A Phase 2 interventional study of Recombinant Interleukin-2 in HIV Infection, sponsored by Case Western Reserve University. Terminated at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2022-09-28.

Sponsored by Case Western Reserve University · Phase 2, Interventional, and Basic science

Why this study was terminated
There were 3 instances of adverse events which were discussed with external safety monitoring committee and it was recommended that the study be terminated.
Phase
Phase 2
Study type
Interventional
Enrollment
9
Allocation
Not applicable
Ages
18 Years to 65 Years
Sex
All
01

Study summary

The purpose of this pilot study is to examine the effects of eight 4-day cycles of subcutaneous recombinant interleukin-2 (rIL-2) given every 8 weeks on levels of replication-competent HIV in CD4 cells and on the size of HIV viral reservoir in up to 20 participants with chronically suppressed HIV infection (viral load \<50 copies/mL).

Read the detailed description

Interleukin-2 (IL-2) has been extensively studied in HIV infected individuals with no demonstrated clinical benefit as far as improving survival or decreasing risk of progression to AIDS. The results of the two landmark, international, multicenter, phase III, randomized trials of IL-2 in HIV infected participants (SILCAAT and ESPRIT) have been recently published. These trials, which started more than a decade ago, enrolled over 5800 participants who were randomized to anti-retroviral therapy (ART) +/- IL-2 and showed no benefit to IL-2 treatment in survival or progression to AIDS. Many individuals with HIV infection can lead normal lives on ART but replication-competent virus remains within resting CD4+ cells, referred to as the "HIV reservoir". There is a renewed interest in strategies to decrease or eliminate the viral reservoir in an attempt to provide a sterilizing or a functional "cure" for HIV that would allow the discontinuation of ART, which currently must be taken life-long. These therapies have long-term metabolic and cardiovascular toxicities as well as substantial cost. More recent data suggest that IL-2 administration may decrease the size of the HIV reservoir, getting ART-treated participants closer to levels of HIV persistence that may ultimately allow for sterilizing or functional cure.

The purpose of this pilot study is to examine the effects of eight 4-day cycles of subcutaneous recombinant interleukin-2 (rIL-2) given every 8 weeks on levels of replication-competent HIV in CD4 cells and on the size of HIV viral reservoir in up to 20 participants with chronically suppressed HIV infection (viral load \<50 copies/mL).

02

Conditions studied

  • HIV Infection

Browse trials for

03

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Written informed consent signed and dated by study participant.
  2. Male or female, at least 18 years of age and not older than 65 years of age.
  3. HIV-1 infection, documented by and FDA-approved ELISA, EIA, or rapid antibody detection method, and confirmed by a second approved antibody-based test or by a positive approved HIV RNA detection assay.
  4. CD4+ T cell count ≥ 350 cells/mm3;
  5. HIV-1 RNA \< 50 copies/mL obtained within 60 days prior to study entry performed with an FDA-approved HIV-1 RNA assay.
  6. Adequate venous access and no other contraindications for leukapheresis
  7. Absolute neutrophil count (ANC) > 2000/mm3
  8. Hemoglobin level >10 g/dL (males); > 9.5 g/dL (females)
  9. Platelet count >150,000/mm3
  10. Serum creatinine \<1.5 mg/dL
  11. AST and ALT \<2.5 times the upper limit of normal
  12. TSH, T3, and T4 levels within the normal range of the processing laboratory.
  13. Anti-thyrosine peroxidase (TPO) within the normal range of the processing laboratory.
  14. Willing to comply with study-mandated evaluations; including not changing antiretroviral regimen (unless medically indicated) during the study period.
  15. All participants must have received HAART, and had viral loads below the limit of quantification of the assay for at least 1 year. Participants who had intermittent isolated episodes of detectable low-level viremia \< 500 copies RNA/mL flanked by viral loads below the limit of quantification of the assay will remain eligible.
  16. On a stable 3-drug combination antiretroviral regimen (no changes to treatment within 4 weeks of enrollment) and willing to continue on current antiretroviral therapy for the duration of the study, unless otherwise medically indicated. The study principal investigator can approve a 2-drug antiretroviral regimen on a case-by-case basis.

Exclusion criteria

Exclusion Criteria:

  1. Childbearing potential for female participants. For the purposes of this study, a woman is considered to be of childbearing potential if she is postmenarche, has not had a documented surgical sterilization procedure, has an intact uterus and at least 1 ovary, and has had a spontaneous menstrual period in the last 2 years.
  2. Acute or chronic hepatitis C infection, defined as a positive plasma HCV RNA using any FDA-approved qualitative or quantitative test in a participant with a positive HCV antibody (HCV RNA testing is not required in participants with a negative HCV antibody). Participants who have completed a course of a direct-acting antiviral agent for hepatitis C and have a confirmed plasma HCV RNA level below the limit of detection of the assay 12 weeks or longer after completion of therapy will be eligible.
  3. Acute or chronic hepatitis B infection, defined as a positive HBV surface antigen or a positive HBV DNA.
  4. History of advanced chronic liver disease, including cirrhosis, advanced liver fibrosis, severe portal hypertension, or manifestations or hepatic failure.
  5. History of malignant disease that is not considered to be surgically or medically eradicated or that has required any form of therapy in the past 5 years.
  6. Current diagnosis of congestive heart failure of any severity, uncontrolled angina or uncontrolled arrhythmias.
  7. History of chronic lung disease that has required pharmacologic treatment, oxygen supplementation, medical monitoring, or hospitalization in the previous year, or that is expected to cause persistent or recurrent pulmonary symptoms or impairment. Examples of the latter include but are not limited to chronic bronchitis, emphysema, and pulmonary fibrosis.
  8. History or any features on physical examination indicative of a bleeding diathesis.
  9. History or current diagnosis of thromboembolic disease, including deep vein thrombosis and pulmonary embolism, or family history of the same.
  10. History of hypersensitivity to radiological contrast media or anticipated need for exposure to radiological contrast media during the study period.
  11. Use of chronic corticosteroids, hydroxyurea, or immune-modulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to enrollment.

    NOTE: Use of inhaled or topical steroids is not exclusionary.

  12. Breast-feeding.
  13. Use of aspirin, warfarin or any other antithrombotic or antiplatelet agent during the 2-week period prior to leukapheresis.
  14. History of autoimmune disorders, including but not limited to Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, myasthenia gravis, glomerulonephritis, systemic lupus erythematous, and vasculitis.
  15. Type 1 diabetes mellitus.
  16. History of thyroid disease that has required antithyroid or thyroid hormone replacement therapy at any time in the past.
  17. Current continued use, or anticipated continued medical indication for nephrotoxic agents, including but not limited to aminoglycosides and other potentially nephrotoxic antimicrobials, indomethacin, high scheduled doses of other NSAIDs, and lithium salts.

    NOTE: Low doses or limited duration of these agents (i.e., ≤14 days) is not exclusionary.

  18. Current continued use, or anticipated continued medical indication for hepatotoxic agents, including but not limited to amiodarone, methotrexate, and anticonvulsants and antimicrobials with elevated hepatotoxic potential.

    NOTE: Low doses or limited duration of these agents (i.e., ≤14 days) is not exclusionary.

  19. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
  20. Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry that in the judgement of the investigator may compromise study participation or pose additional risks to the participant.
  21. Any other condition that, in the opinion of the clinical investigator or sponsor, might compromise any aspect of this trial.
04

Study design

Phase
Phase 2
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
9 participants (actual)

Study arms

  • Experimental
    IL2 treatment

    Subcutaneous recombinant interleukin-2 (rIL2), 5 MIU twice daily for four consecutive days(cycle) every 8 weeks for 8 cycles, in addition to combination antiretroviral therapy.

    Drug: Recombinant Interleukin-2

Interventions

  • DrugRecombinant Interleukin-2

    Subcutaneous recombinant interleukin-2 (rIL2), 5 MIU twice daily for four consecutive days(cycle) every 8 weeks for 8 cycles

    Also known as: IL2, IL-2, rIL2, aldesleukin

05

What researchers measure

Primary outcomes

  1. Latent HIV Reservoir Change by QVOA

    Change in the number of infectious units per million resting CD4+ T cells (IUPM) from baseline to the end of study treatment, as measured by the Quantitative Viral Outgrowth Assay (QVOA).

    Time frame: 15 months

Secondary outcomes

  1. Correlation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by Intact Proviral DNA.

    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the intact proviral DNA assay.

    Time frame: 15 months

  2. Correlation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by the Tat-rev Inducible Limiting Dilution Assay (TILDA).

    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Tat-rev inducible limiting dilution assay (TILDA).

    Time frame: 15 months

  3. Correlation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by the Envelope Detection by Induced Transcription-based Sequencing (EDITS)

    Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Envelope Detection by Induced Transcription-based Sequencing (EDITS).

    Time frame: 15 months

  4. In Vivo Induction of HIV Expression in Vivo as Measured by the Envelope Detection by Induced Transcription-based Sequencing (EDITS)

    Number of inducible cell-associated HIV mRNA copies per million CD4+ T cells at the beginning and end of rIL2 cycles 1, 4, and 8.

    Time frame: 15 months

  5. Plasma HIV RNA During rIL2 Exposure

    Plasma HIV RNA copies/mL by PCR at the beginning and end of rIL2 cycle 1.

    Time frame: baseline, day 7

  6. Natural Killer (NK) Cell Phenotype During rIL2 Exposure

    Change in the percent of NK cells expressing CD16+CD56+ by flow cytometry from baseline to the end of study treatment.

    Time frame: baseline, day 7

  7. Natural Killer (NK) Cell Phenotype During rIL2 Exposure

    Change in the percent of NK cells expressing CD56+CD16- by flow cytometry from baseline to the end of study treatment.

    Time frame: baseline, day 7

06

Results

Posted Sep 28, 2022
Limitations and caveats
On the basis of recommendation of the SMC, the study was terminated. Because of this, the primary objective could not be achieved and most of the secondary objectives could not be achieved.

Participant flow

Participant flow — Overall Study
MilestoneIL2 Treatment
Started9
Completed0
Not completed9
Withdrew: Study terminated after discussion with safety monitoring committee9

Outcome measures

PrimaryLatent HIV Reservoir Change by QVOA

Change in the number of infectious units per million resting CD4+ T cells (IUPM) from baseline to the end of study treatment, as measured by the Quantitative Viral Outgrowth Assay (QVOA).

Time frame:
15 months

No measurements were reported for this outcome.

SecondaryCorrelation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by Intact Proviral DNA.

Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the intact proviral DNA assay.

Time frame:
15 months

No measurements were reported for this outcome.

SecondaryCorrelation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by the Tat-rev Inducible Limiting Dilution Assay (TILDA).

Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Tat-rev inducible limiting dilution assay (TILDA).

Time frame:
15 months

No measurements were reported for this outcome.

SecondaryCorrelation of Latent Reservoir Measure by QVOA to Latent Reservoir Measure by the Envelope Detection by Induced Transcription-based Sequencing (EDITS)

Correlation coefficient between measures of the latent HIV reservoir by QVOA and measures of the latent HIV reservoir by the Envelope Detection by Induced Transcription-based Sequencing (EDITS).

Time frame:
15 months

No measurements were reported for this outcome.

SecondaryIn Vivo Induction of HIV Expression in Vivo as Measured by the Envelope Detection by Induced Transcription-based Sequencing (EDITS)

Number of inducible cell-associated HIV mRNA copies per million CD4+ T cells at the beginning and end of rIL2 cycles 1, 4, and 8.

Time frame:
15 months

No measurements were reported for this outcome.

SecondaryPlasma HIV RNA During rIL2 Exposure

Plasma HIV RNA copies/mL by PCR at the beginning and end of rIL2 cycle 1.

Time frame:
baseline, day 7
Reported as:
Mean · RNA copies/mL
Plasma HIV RNA During rIL2 Exposure
RNA copies/mLIL2 Treatment
baseline10 ± 0
day 7298 ± 522
SecondaryNatural Killer (NK) Cell Phenotype During rIL2 Exposure

Change in the percent of NK cells expressing CD16+CD56+ by flow cytometry from baseline to the end of study treatment.

Time frame:
baseline, day 7
Reported as:
Median · percentage of cells
Natural Killer (NK) Cell Phenotype During rIL2 Exposure
percentage of cellsIL2 Treatment
baseline28.8 (19.8 to 37.5)
day 735.8 (30.9 to 39.2)
SecondaryNatural Killer (NK) Cell Phenotype During rIL2 Exposure

Change in the percent of NK cells expressing CD56+CD16- by flow cytometry from baseline to the end of study treatment.

Time frame:
baseline, day 7
Reported as:
Median · percentage of cells
Natural Killer (NK) Cell Phenotype During rIL2 Exposure
percentage of cellsIL2 Treatment
baseline4.5 (3.1 to 5.2)
day 712.7 (8.3 to 17.1)

Adverse events

Collected over Adverse event data were collected until the study was terminated. This period was the time between enrollment into the study and study termination. The duration ranged from 8.3 months to 14.6 months,.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
IL2 Treatment0/9 (0%)1/9 (11.1%)2/9 (22.2%)
Most frequent serious events
Most frequent serious events
EventIL2 Treatment
suspected capillary leak syndromeVascular disorders1/9
Most frequent other events
Most frequent other events
EventIL2 Treatment
biochemical hypothyroidismEndocrine disorders2/9

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)IL2 Treatment
<=18 years0
Between 18 and 65 years9
>=65 years0
Age, Continuous
Age, Continuous(years)IL2 Treatment
Median49 (35 to 64)
Sex: Female, Male
Sex: Female, Male(Participants)IL2 Treatment
Female0
Male9
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)IL2 Treatment
Hispanic or Latino1
Not Hispanic or Latino8
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)IL2 Treatment
American Indian or Alaska Native0
Asian0
Native Hawaiian or Other Pacific Islander0
Black or African American2
White6
More than one race1
Unknown or Not Reported0
Region of Enrollment
Region of Enrollment(participants)IL2 Treatment
United States9
CD4+ T cell count ≥ 350 cells/mm^3
CD4+ T cell count ≥ 350 cells/mm^3(cells/mm^3)IL2 Treatment
Median808 (478 to 1230)
HIV-1 RNA < 50 copies/mL obtained within 60 days prior to study entry
HIV-1 RNA < 50 copies/mL obtained within 60 days prior to study entry(Participants)IL2 Treatment
Count of participants9

1 further baseline measures are reported on the registry.

07

Study locations

1 site
  • AIDS Clinical Trials Unit
    Cleveland, Ohio 44106, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Dec 17, 2019
  • Informed consent form · Apr 14, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03308786
Lead sponsor
Case Western Reserve University
Responsible party
Michael M. Lederman MD (Principal Investigator, Case Western Reserve University) — Principal investigator
First posted
Oct 13, 2017
Start date
Apr 1, 2019
Primary completion
Aug 20, 2020
Completion
Aug 20, 2020
Results posted
Sep 28, 2022
Last update
Sep 28, 2022

Study contacts

Benigno Rodriguez, MD
study chair · Case Western Reserve University
Michael Lederman, MD
study chair · Case Western Reserve University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Sep 2022. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Start the discussion