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MMF for HIV Reservoir Reduction

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ClinicalTrials.gov Identifier: NCT03262441
Recruitment Status : Active, not recruiting
First Posted : August 25, 2017
Last Update Posted : September 9, 2019
Sponsor:
Collaborator:
University of Washington
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE August 23, 2017
First Posted Date  ICMJE August 25, 2017
Last Update Posted Date September 9, 2019
Actual Study Start Date  ICMJE January 1, 2018
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2017)
  • Change in frequency of cells containing integrated HIV DNA [ Time Frame: 22 months ]
    Change in cell-associated HIV DNA (ca-DNA) reservoir size as measured by multiplexed digital droplet PCR in study participants on versus off MMF (historical controls)
  • Change in HIV plasma viral load [ Time Frame: 22 months ]
    Change in HIV replication by single copy viral load (scVL) in study participants on versus off MMF (historical controls).
  • Change of HIV reactivation [ Time Frame: 22 months ]
    Change of viral reactivation by cell-associated HIV mRNA in study participants on versus off MMF (historical controls)
  • Change of inducible HIV reservoir size [ Time Frame: 22 months ]
    Change of the inducible HIV reservoir size by quantitative viral outgrowth assay (QVOA) in study participants on versus off MMF (historical controls).
  • Change of the cellular composition of the HIV DNA reservoir [ Time Frame: 22 months ]
    Change of the cellular composition of the HIV DNA reservoir in study participants on versus off MMF (historical controls).
Original Primary Outcome Measures  ICMJE
 (submitted: August 23, 2017)
Change in frequency of cells containing integrated HIV DNA [ Time Frame: 22 months ]
Change in cell-associated HIV DNA (ca-DNA) reservoir size as measured by multiplexed digital droplet PCR in study participants on versus off MMF (historical controls)
Change History Complete list of historical versions of study NCT03262441 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2017)
  • Blood CD4+ T cells [ Time Frame: 22 months ]
    Blood CD4+ T cell count
  • Thymic generation of new CD4+ T cells [ Time Frame: 22 months ]
    CD4+ T cell numbers that recently emigrated from the thymus
  • Complete blood cell count [ Time Frame: 22 months ]
    Complete blood cell count, comprehensive metabolic panel
  • Incidence of opportunistic infection [ Time Frame: 22 months ]
    Incidence of opportunistic infection
  • Antibody response to annual influenza vaccination [ Time Frame: 22 months ]
    Antibody response to annual influenza vaccination
Original Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2017)
  • Change in HIV plasma viral load [ Time Frame: 22 months ]
    Change in HIV replication by single copy viral load (scVL) in study participants on versus off MMF (historical controls)
  • Change of HIV reactivation [ Time Frame: 22 months ]
    Change of viral reactivation by cell-associated HIV mRNA in study participants on versus off MMF (historical controls)
  • Change of inducible HIV reservoir size [ Time Frame: 22 months ]
    Change of the inducible HIV reservoir size by quantitative viral outgrowth assay (QVOA) in study participants on versus off MMF (historical controls)
  • Blood CD4+ T cells [ Time Frame: 22 months ]
    Blood CD4+ T cell count
  • Thymic generation of new CD4+ T cells [ Time Frame: 22 months ]
    CD4+ T cell numbers that recently emigrated from the thymus
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MMF for HIV Reservoir Reduction
Official Title  ICMJE Mycophenolate Mofetil Therapy for Reduction of the HIV Reservoir
Brief Summary

This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir.

In addition to primary safety endpoints, the following hypotheses regarding drug efficacy will be tested:

  1. MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of ART.
  2. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during treatment with MMF and ART.
  3. There will be no excess risk of opportunistic infections in MMF-treated study participants.
  4. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of treatment.
  5. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily stem cell like memory (TSCM) and naïve (TN) CD4+ T cells.
  6. MMF will eliminate detectable measures of the HIV reservoir, including by cell-associated DNA/mRNA and quantitative viral outgrowth.
  7. MMF will not decrease the humoral immune response to routine annual influenza vaccination.
Detailed Description

This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir.

At the University of Washington in Seattle, investigators will enroll 5 study participants who have been on ≥2 years of suppressive ART. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A "go/no-go" decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.

All participants will be offered enrollment in a sub-study in which an anoscopy with rectum biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal lymphatic tissue (GALT).

Investigators will vaccinate study participants with the annual influenza vaccine and analyze their humoral response to this vaccine approximately one month later with a routine blood draw done in conjunction with a safety labs blood draw.

Investigators hypothesize that low doses of MMF will be well tolerated among healthy HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize that the incidence of opportunistic infections will not exceed that of comparable larger cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are much less common in this context. Therefore, in the event of an infection, Investigators will confer with the data safety management (DSM) panel to discuss whether this event is directly attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T cell counts will remain unchanged throughout MMF therapy, and that HIV replication will remain controlled on ART with addition of MMF.

Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at one-year intervals in study participants who have a demonstrated anti-proliferative response to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards to our sub-study, investigators predict that reservoir depletion will occur with equivalent rates in blood and GALT.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). "Go/no-go" decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Human Immunodeficiency Virus I Infection
Intervention  ICMJE Drug: Mycophenolate Mofetil 500Mg Tab
500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months
Other Name: Mycophenolate Mofetil Tablets USP Roxane Laboratories
Study Arms  ICMJE Experimental: Mycophenolate mofetil
Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months
Intervention: Drug: Mycophenolate Mofetil 500Mg Tab
Publications * Reeves DB, Duke ER, Hughes SM, Prlic M, Hladik F, Schiffer JT. Anti-proliferative therapy for HIV cure: a compound interest approach. Sci Rep. 2017 Jun 21;7(1):4011. doi: 10.1038/s41598-017-04160-3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 23, 2017)
5
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2021
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Confirmed HIV infection, by two different positive antibody tests and/or detectable plasma HIV RNA on two different dates
  2. ≥18 and ≤65 years of age
  3. Continuous ART during the last two years, with current ART preferably including an integrase inhibitor
  4. HIV RNA <40 copies / mL on four occasions during continuous ART of ≥ 2 years with no more than one blip of <1000 HIV RNA copies / mL
  5. CD4+ T cell count > 350/mm3 within the past 365 days
  6. Karnofsky score ≥80
  7. Plan to reside in area 2 years
  8. Consents to study
  9. Tolerability of MMF during one week dose escalation lead-in phase of 500 mg once daily
  10. Demonstrated anti-proliferative effect of MMF 500 mg twice daily

Exclusion Criteria:

  1. Active malignancy including skin cancer, myelodysplastic syndrome, or myeloproliferative disease within 24 weeks prior to study entry
  2. Prior organ or bone marrow transplantation
  3. Diagnosed autoimmune disease
  4. Medical need for ongoing treatment with an immunosuppressive drug
  5. Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or a history of blood CD4+ T cell count < 200/µL)
  6. Active opportunistic infection
  7. Using disallowed medications (see 4.3)
  8. Vomiting or diarrhea which prohibits consistent use of study drugs
  9. Pregnant, intention to become pregnant, or breastfeeding
  10. Woman of child bearing age who are NOT using two forms of birth control OR practicing complete abstinence
  11. Excessive ingestion of ethanol, determined by an AUDIT score of >8
  12. Substance abuse
  13. History of medical non-compliance
  14. Quantiferon TB positive
  15. The following laboratory values (< 30 days before enrollment):

    • Hemoglobin < 8.5 mg/dL
    • Absolute neutrophil count < 1000 cells/mm3
    • ALT > 2 x upper limit of normal
    • Platelet count < 100,000/uL
    • Creatinine clearance < 60 mL/min
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03262441
Other Study ID Numbers  ICMJE 8589
STUDY00002182 ( Other Identifier: University of Washington IRB )
109614-62-RGRL ( Other Grant/Funding Number: American Foundation for AIDS Research )
ACTU-2100 ( Other Identifier: University of Washington )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE University of Washington
Investigators  ICMJE
Principal Investigator: Joshua T Schiffer, MD MSc Fred Hutchinson Cancer Research Center
Principal Investigator: Florian Hladik, MD PhD University of Washington
PRS Account Fred Hutchinson Cancer Research Center
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP