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MMF for HIV Reservoir Reduction

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ClinicalTrials.gov Identifier: NCT03262441
Recruitment Status : Recruiting
First Posted : August 25, 2017
Last Update Posted : November 20, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
Human Immunodeficiency Virus I Infection Drug: Mycophenolate Mofetil 500Mg Tab Phase 2

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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
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
Official Title: Mycophenolate Mofetil Therapy for Reduction of the HIV Reservoir
Anticipated Study Start Date : January 1, 2018
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : August 31, 2020


Arms and Interventions

Arm Intervention/treatment
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
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


Outcome Measures

Primary Outcome Measures :
  1. 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)

  2. 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).

  3. 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)

  4. 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).

  5. 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).


Secondary Outcome Measures :
  1. Blood CD4+ T cells [ Time Frame: 22 months ]
    Blood CD4+ T cell count

  2. Thymic generation of new CD4+ T cells [ Time Frame: 22 months ]
    CD4+ T cell numbers that recently emigrated from the thymus

  3. Complete blood cell count [ Time Frame: 22 months ]
    Complete blood cell count, comprehensive metabolic panel

  4. Incidence of opportunistic infection [ Time Frame: 22 months ]
    Incidence of opportunistic infection

  5. Antibody response to annual influenza vaccination [ Time Frame: 22 months ]
    Antibody response to annual influenza vaccination


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03262441


Contacts
Contact: Joshua T Schiffer, MD MSc 206-667-7359 jschiffe@fredhutch.org
Contact: Florian Hladik, MD PhD 206-667-6848 florian@uw.edu

Locations
United States, Washington
2 West Clinic at Harborview Medical Center Recruiting
Seattle, Washington, United States, 98104
Contact: Mel Padullo    206-744-8884      
Contact: Eric Helgeson    206-744-8883      
Principal Investigator: Joshua Schiffer, MD, MS         
Principal Investigator: Florian Hladik, MD, PhD         
Sub-Investigator: Robert Harrington, MD         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
University of Washington
Investigators
Principal Investigator: Joshua T Schiffer, MD MSc Fred Hutchinson Cancer Research Center
Principal Investigator: Florian Hladik, MD PhD University of Washington
More Information

Publications:
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03262441     History of Changes
Other Study ID Numbers: 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 )
First Posted: August 25, 2017    Key Record Dates
Last Update Posted: November 20, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Fred Hutchinson Cancer Research Center:
HIV
Antiretroviral treatment
Mycophenolate mofetil
Cure
Latency
Reservoir
CD4 T cell
Anti-proliferation

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Mycophenolic Acid
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action