MMF for HIV Reservoir Reduction

NCT03262441 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: 8589STUDY00002182109614-62-RGRLACTU-2100
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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. 1.MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of ART.
2. 2.Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during treatment with MMF and ART.
3. 3.There will be no excess risk of opportunistic infections in MMF-treated study participants.
4. 4.MMF therapy will lead to a progressive decrease in reservoir size over 22 months of treatment.
5. 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. 6.MMF will eliminate detectable measures of the HIV reservoir, including by cell-associated DNA/mRNA and quantitative viral outgrowth.
7. 7.MMF will not decrease the humoral immune response to routine annual influenza vaccination.

Conditions

Human Immunodeficiency Virus I Infection

Keywords

HIV; Antiretroviral treatment; Mycophenolate mofetil; Cure; Latency; Reservoir; CD4 T cell; Anti-proliferation

Outcome Measures

Primary Outcomes (3)

• Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 T Cells Over 12 Months

  Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 \& 12 months

  12 months

• Change in Cell-associated HIV DNA (Ca-DNA) Levels Per 10^6 Effector Memory CD4+ T Cells Over 12 Months

  Regression slope of change in cell-associated HIV DNA (ca-DNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 3 time points between 0 \& 12 months

  12 months

• Change in Cell-associated Intact HIV DNA (Ca-iDNA) Levels Per 10^6 T Cells Over 12 Months

  Regression slope of change in cell-associated intact HIV DNA (ca-iDNA) as measured by multiplexed digital droplet PCR in study participants on MMF calculated from 4 time points between 0 \& 12 months

  12 months

Secondary Outcomes (2)

• Blood CD4+ T Cells Per mm^3 Blood

  12 months

• Incidence of Opportunistic Infection

  12 months

Study Arms (1)

Mycophenolate mofetil

EXPERIMENTAL

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

Interventions

Mycophenolate Mofetil 500Mg Tab DRUG

500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months

Also known as: Mycophenolate Mofetil Tablets USP Roxane Laboratories

Mycophenolate mofetil

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed HIV infection, by two different positive antibody tests and/or detectable plasma HIV RNA on two different dates
• ≥18 and ≤65 years of age
• Continuous ART during the last two years, with current ART preferably including an integrase inhibitor
• 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
• CD4+ T cell count \> 350/mm3 within the past 365 days
• Karnofsky score ≥80
• Plan to reside in area 2 years
• Consents to study
• Tolerability of MMF during one week dose escalation lead-in phase of 500 mg once daily
• Demonstrated anti-proliferative effect of MMF 500 mg twice daily

You may not qualify if:

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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• University of Washington: collaborator

Study Sites (1)

2 West Clinic at Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Related Publications (2)

• 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.

  PMID: 28638104 BACKGROUND

• Schiffer JT, Levy C, Hughes SM, Pandey U, Padullo M, Jerome KR, Zhu H, Puckett K, Helgeson E, Harrington RD, Hladik F. Stable HIV Reservoir Despite Prolonged Low-Dose Mycophenolate to Limit CD4+ T-cell Proliferation. Open Forum Infect Dis. 2022 Nov 19;9(12):ofac620. doi: 10.1093/ofid/ofac620. eCollection 2022 Dec.

  PMID: 36519118 DERIVED

MeSH Terms

Interventions

Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Limitations and Caveats

This was a small and uncontrolled study.

Results Point of Contact

• Title: Dr. Joshua Schiffer
• Organization: Fred Hutchinson Cancer Research Center

jschiffe@fredhutch.org

(206)667-7359

Study Officials

• Joshua T Schiffer, MD MSc

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Florian Hladik, MD PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: August 23, 2017
• First Posted: August 25, 2017
• Study Start: February 12, 2018
• Primary Completion: August 31, 2019
• Study Completion: August 31, 2019
• Last Updated: December 3, 2020
• Results First Posted: December 3, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)