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Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01969058
First Posted: October 25, 2013
Last Update Posted: September 29, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
  Purpose
This phase II study was done in HIV-infected participants on antiretroviral therapy to evaluate the effects of isotretinoin (a drug that is approved for use in the treatment of severe acne) on the immune system. The immune system helps the body fight infections. When the immune system is not working well, one may be at greater risk for diseases that are common in aging, like heart disease, weaker bones, and kidney disease.

Condition Intervention Phase
HIV-1 Infection Drug: Isotretinoin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Participants were randomized 2:1 to Isotretinoin arm and no study treatment arm. The primary endpoints were compared between the 2 study arms.
Masking: None (Open Label)
Masking Description:
open label
Primary Purpose: Treatment
Official Title: A Prospective Randomized Controlled Study to Evaluate the Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery on Suppressive Antiretroviral Therapy (ART)

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Change in CD8+ T-cell Activation From Baseline to Week 14/16 [ Time Frame: baseline, week 14/16 ]

    Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38+ and Human leukocyte antigen (HLA)-DR+. The endpoint is measuring the change from baseline to week 14/16, where baseline is defined as the average of pre-entry and entry, and week 14/16 is defined as the average of week 14 and week 16.

    Change = (week 14/16 - baseline).



Secondary Outcome Measures:
  • Change in CD8+ T-cell Activation [ Time Frame: baseline, week 14/16, week 28 ]

    Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38+ and Human leukocyte antigen (HLA)-DR+.

    The endpoint is measuring the change from week 14/16 to week 28 (week 28 - week 14/16) and from baseline to week 28 (week 28 - baseline).

    Baseline is defined as the average of pre-entry and entry, and week 14/16 is defined as the average of week 14 and week 16.


  • Change in sCD14 [ Time Frame: baseline, week 14/16, week 28 ]

    sCD14 (soluble cluster of differentiation 14) is a marker of gut microbial translocation.

    The outcome measures are changes in log10 transformed sCD14 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in I-FABP [ Time Frame: baseline, week 14/16, week 28 ]

    I-FABP (intestinal-fatty acid binding protein) is a marker of gut microbial translocation. This marker is to replace the originally planned marker plasma LPS.

    The outcome measures are changes in log10 transformed I-FABP from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in IL-6 [ Time Frame: baseline, week 14/16, week 28 ]

    IL-6 (Interleukin-6) is a marker of systemic inflammation. The outcome measures are changes in log10 transformed IL-6 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in hsCRP [ Time Frame: baseline, week 14/16, week 28 ]

    hsCRP (high-sensitivity C-reactive protein) is a marker of inflammation. Change in log10 transformed hsCRP from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in sTNF-r1 [ Time Frame: baseline, week 14/16, week 28 ]

    sTNF-r1 (soluble tumour necrosis alpha receptor 1) is a marker of inflammation. Change in log10 transformed sTNF-r1 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in sTNF-r2 [ Time Frame: baseline, week 14/16, week 28 ]

    sTNF-r2 (soluble tumour necrosis alpha receptor 2) is a marker of inflammation. Change in log10 transformed sTNF-r2 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in D-dimer [ Time Frame: baseline, week 14/16, week 28 ]

    D-dimer (or D dimer) is a marker of coagulation activation. Change in log10 transformed D-dimer from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in TF [ Time Frame: baseline, week 14/16, week 28 ]

    TF (Tissue Factor) is a marker of Coagulation. Change in log10 transformed TF from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in sCD163 [ Time Frame: baseline, week 14/16, week 28 ]

    sCD163 (soluble CD 163) is a marker of macrophage activation Change in log10 transformed sCD163 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in CD4+ T-cell Count [ Time Frame: baseline, week 14/16, week 28 ]

    Change in peripheral total CD4 cell count from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.


  • Change in Treg Frequency [ Time Frame: baseline, week 14/16, week 28 ]

    Treg (T Regulatory) Cells are a subpopulation of T cells which modulate the immune system.

    The outcome measure is the change in Treg frequency from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

    Data for Treg frequency are not available as of August 2017. These data are based on immunology assays which are to be tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 3 months after the primary complete date. Please note that these secondary outcomes are not included in the primary analyses. There are many outcomes in this study and the immunology lab had to give priority to the assays planned to be included in the primary manuscript.


  • Change in Th17 Frequency [ Time Frame: baseline, week 14/16, week 28 ]

    Th17 (T-helper 17) cells are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17).

    The outcome is the change in Th17 frequency from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

    Th17 data are not available as of August 2017. These data are based on immunology assays which are to be tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 3 months after the primary complete date. Please note that these secondary outcomes are not included in the primary analyses. There are many outcomes in this study and the lab had to give priority to the assays planned to be included in the primary manuscript.


  • Change in Cell-associated HIV-1 DNA [ Time Frame: baseline, week 14/16, week 28 ]

    Change in genomic HIV-1 DNA in blood from baseline to week 14/16(week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

    Cell-assciated HIV-1 DNA data are not available as of August 2017. These data are based on virology assays which are to be tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 3 months after the primary complete date. Upon completion of the testing, the results will be reviewed for data completeness and quality. After resolution of any issues and finalization of the database, the analysis can be conducted and the results will then be posted to ClinicalTrials.gov. We anticipate to enter these results by December 2017.


  • Change in Cell-associated HIV-1 RNA [ Time Frame: baseline, week 14/16, week 28 ]

    Change in genomic HIV-1 RNA in blood from baseline to week 14/16(week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

    Cell-associated HIV-1 RNA data are not available as of August 2017. These data are based on virology assays which are to be tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 3 months after the primary complete date. Upon completion of the testing, the results will be reviewed for data completeness and quality. After resolution of any issues and finalization of the database, the analysis can be conducted and the results will then be posted to ClinicalTrials.gov. We anticipate to enter these results by December 2017.


  • Change in Endogenous Retinoid Metabolite Profiles [ Time Frame: baseline, week 14/16, week 28 ]

    Change in endogenous retinoid metabolite profiles from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline).

    Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

    Data for endogenous retinoid metabolite profiles is not available as of August 2017. Pharmacokinetics assays were batched to minimize variability. Sample shipment could not begin until after the study follow-up completion, which was 3 months after the primary completion date. Given that this was a multi-center study, shipment of samples took several months to complete. Upon completion of the testing, the results will be reviewed for data completeness and quality. We expect to complete analysis and post results to ClinicalTrials.gov by December 2017.


  • Pharmacokinetics - Trough Concentrations of Isotretinoin and Antiviral Treatment (ART) [ Time Frame: study entry, weeks 8, 12, 16, 20 and 24 ]

    Isotretinoin arm only, trough concentrations of isotretinoin at weeks 8, 12, 16, and trough concentrations of ART at study entry and weeks 8, 12, 16, 20 and 24.

    Pharmacokinetics data are not available as of August 2017. To minimize variability, pharmacokinetics assays were batched. Due to batching, sample shipment could not begin until after the study follow-up completion, which was 3 months after the primary completion date. Given that this was a multi-center study, shipment of samples took several months to complete. Therefore, samples are in the process of being tested. Upon completion of the testing, the results will be reviewed for data completeness and quality. After resolution of any issues and finalization of the database, the analysis can be conducted and the results will then be posted to ClinicalTrials.gov. We expect to complete analysis and post results to ClinicalTrials.gov by December 2017.


  • Primary Targeted Adverse Events [ Time Frame: from study entry to end of study (week 28) ]
    Targeted events for A5325 include: events that meet the International Conference on Harmonization (ICH) definitions for a serious adverse event, post-entry signs/symptoms and laboratory abnormalities of Grade ≥3 or that lead to a change in treatment regardless of grade, and any diagnoses.


Enrollment: 76
Study Start Date: July 2014
Study Completion Date: November 2016
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Isotretinoin Arm
Participants received Isotretinoin at approximately 0.5 mg/kg orally once daily for 4 weeks, then increased to approximately 1.0 mg/kg orally once daily for 12 weeks.
Drug: Isotretinoin
Isotretinoin is a drug that is approved for use in the treatment of severe acne. The aim of this study is to evaluate the role of Isotretinoin on immune activation and inflammation.
Other Name: 13-cis-retinoic acid
No Intervention: No study treatment Arm
No Isotretinoin treatment

Detailed Description:
Isotretinoin was administered to participants in the Isotretinoin arm at approximately 0.5 mg/kg PO once daily for 4 weeks, then increased to approximately 1.0 mg/kg PO once daily for 12 weeks. Follow-up continues to week 28 to evaluate the duration of effect. Randomization was stratified by willingness to participate in the gut biopsy substudy, A5330s. The study population included HIV-1 infected adults whose virus was suppressed on ART, excluding women of child bearing potential.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all IND studies.

CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

  • Receiving ART therapy for at least 12 months prior to study entry.
  • No plans to change the ART regimen in the 6 months after study entry.
  • HIV-1 RNA below the lower limit of detection using an FDA-approved assay obtained within 30 days prior to study entry by any laboratory that has a CLIA certification or its equivalent (eg, <50 copies/mL on Roche Amplicor HIV-1 Monitor assay, <75 copies/mL on the Versant HIV-1 RNA assay by branched DNA, <40 copies/mL on the Abbott m2000sp/m2000rt real-time PCR test, < 20 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1 assay).
  • All measurements of HIV-1 RNA within the 12 months prior to study entry must be below the limit of detection with the following exception:

NOTE A: 1 viral blip (<200 copies/mL) is permitted if it is preceded and followed by viral loads below the limits of detection.

NOTE B: The virologic assay must have a lower limit of detection of ≤ 75 copies/mL.

  • CD4+ cell count <350 cells/mm3 obtained at screening within 30 days prior to entry at any laboratory that has a CLIA (Clinical Laboratory Improvement Amendments) certification or its equivalent.
  • The following laboratory values obtained within 30 days prior to entry by any laboratory that has a CLIA certification or its equivalent:

    1. Hemoglobin A1c (HgbA1c) levels ≤ 6.5%
    2. Hemoglobin ≥ 9.0 g/dL
    3. Platelet count ≥ 50,000/mm3
    4. Creatinine ≤1.5 mg/dl
    5. CrCl ≥ 60 mL/min, calculated by the Cockcroft-Gault method
    6. Aspartate aminotransferase (AST) (SGOT) ≤1.5x upper limit of normal (ULN)
    7. Alanine aminotransferase (ALT) (SGPT) ≤1.5x ULN
    8. Serum lipase ≤1.5x ULN
    9. Fasting triglyceride level ≤200 mg/dL
    10. Fasting glucose <126mg/dL
  • Karnofsky performance score >/=70 within 30 days prior to entry.
  • Men and post-menopausal females aged ≥ 18 years and ≤ 80 years at entry.

Note: Post-menopausal is defined as having either:

  1. Appropriate medical documentation (see note) of prior complete bilateral oophorectomy (i.e., surgical removal of the ovaries, resulting in "surgical menopause" and occurring at the age at which the procedure was performed), OR
  2. Permanent cessation (12 consecutive months or more of amenorrhea) of previously occurring menses as a result of ovarian failure with documentation of hormonal deficiency by a certified healthcare provider (i.e., "spontaneous menopause").

Hormonal deficiency should be properly documented (see note) in the case of suspected spontaneous menopause as follows:

  1. If age >54 years and with the absence of normal menses: Serum FSH (Follicle Stimulating Hormone) level elevated to within the post-menopausal range based on the laboratory reference range where the hormonal assay is performed.
  2. If age ≤ 54 years and with the absence of normal menses: Negative serum or urine HCG with concurrently elevated serum FSH (follicle stimulating hormone) level in the post-menopausal range, depressed estradiol (E2) level in the post-menopausal range, and absent serum progesterone level, based on the laboratory reference ranges where the hormonal assays are performed.

NOTE: "Appropriate documentation", and "properly documented" means written documentation or oral communication from a clinician or clinician's staff documented in source documents of an operative report, discharge summary, or

  • No active hepatitis B or C infection. NOTE: For subjects who have documentation of prior infection, but no active hepatitis infection, evidence of clearance must be greater than 1 year.
  • Ability and willingness of subject to provide informed consent.
  • Willingness to adhere to the iPLEDGE program requirements.
  • Indication of willingness to participate in the substudy A5330s. NOTE: In the event that 12 or fewer subjects have enrolled into A5330s by the time enrollment in the main study has reached 50% of the accrual target, A5330s enrollment will be required.

Exclusion Criteria:

  • Pre-existing diagnosis of diabetes.
  • Currently receiving treatment with fibrate, nicotinic acid, tetracycline, fish oil >1g/d, or methotrexate.
  • Known active healing fracture or any severe bone disorders. NOTE: does not include healed fractures or history of old fractures.
  • Receipt of any of the following medications within 30 days prior to entry: systemic steroids (including intra-articular steroids; inhaled or nasal steroid therapy is permitted), interleukins, systemic interferons (including intra-articular steroid injection; local injection of interferon alpha for treatment of human papilloma virus is permitted), or systemic chemotherapy.
  • Known allergy/sensitivity or any hypersensitivity to vitamin A, retinoids, or any of their derivatives.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Acute or serious illness requiring systemic treatment and/or hospitalization within 60 days prior to entry.
  • Weight < 40 kg or > 150 kg.
  • History of major depression or suicide attempt requiring hospitalization, or psychotic episode requiring medication or hospitalization.
  • History of inflammatory bowel disease such as Crohn's disease, or Ulcerative colitis.
  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): NCT01969058


Locations
United States, Alabama
31788 Alabama CRS
Birmingham, Alabama, United States, 35294
United States, California
601 University of California, Los Angeles CARE Center CRS
Los Angeles, California, United States, 90035
801 University of California, San Francisco HIV/AIDS CRS
San Francisco, California, United States, 94110
United States, Massachusetts
101 Massachusetts General Hospital (MGH) CRS
Boston, Massachusetts, United States, 02114
107 Brigham and Women's Hosp. ACTG CRS
Boston, Massachusetts, United States, 02115
United States, Missouri
2101 Washington University Therapeutics (WT) CRS
Saint Louis, Missouri, United States, 63110
United States, New Jersey
31786 New Jersey Medical School Clinical Research Center CRS
Newark, New Jersey, United States, 07103
United States, New York
31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS
Rochester, New York, United States, 14642
United States, North Carolina
3201 Chapel Hill CRS
Chapel Hill, North Carolina, United States, 27516
3203 Greensboro CRS
Greensboro, North Carolina, United States, 27401
United States, Ohio
2401 Cincinnati CRS
Cincinnati, Ohio, United States, 45267-0405
United States, Rhode Island
2951 The Miriam Hospital (TMH) ACTG CRS
Providence, Rhode Island, United States, 02906
United States, Tennessee
3652 Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, United States, 37204
United States, Texas
31473 Houston AIDS Research Team (HART) CRS
Houston, Texas, United States, 77030
Puerto Rico
5401 Puerto Rico AIDS Clinical Trials Unit CRS
San Juan, Puerto Rico, 00931
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Douglas Kwon, MD, PhD Massachusetts General Hospital
Study Chair: Nina Lin, MD Harvard Medical School
  More Information

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01969058     History of Changes
Other Study ID Numbers: ACTG A5325
UM1AI068636 ( U.S. NIH Grant/Contract )
First Submitted: August 21, 2013
First Posted: October 25, 2013
Results First Submitted: August 4, 2017
Results First Posted: September 5, 2017
Last Update Posted: September 29, 2017
Last Verified: September 2017

Keywords provided by AIDS Clinical Trials Group:
Isotretinoin
HIV-1
immunology markers
immune activation
viral suppression

Additional relevant MeSH terms:
Isotretinoin
Dermatologic Agents