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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:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01969058
First received: August 21, 2013
Last updated: August 4, 2017
Last verified: August 2017
August 21, 2013
August 4, 2017
July 2014
August 2016   (Final data collection date for primary outcome measure)
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).

Change from baseline in CD8+ T-cell activation at 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. 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.
Complete list of historical versions of study NCT01969058 on ClinicalTrials.gov Archive Site
  • 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.
  • Markers of gut microbial translocation [ Time Frame: baseline, week 14/16, week 28 ]
    Change in levels of plasma LPS and sCD14 from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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.
  • Markers of systemic inflammation and coagulation [ Time Frame: baseline, week 14/16, week 28 ]
    Change in levels of IL-6, hsCRP, sTNFα receptor 1 and 2, D-dimer, and TF from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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.
  • Markers of macrophage activation (sCD163) [ Time Frame: baseline, week 14/16, week 28 ]
    Change in levels of sCD163 from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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.
  • Peripheral CD4+ T-cell count [ Time Frame: baseline, week 14/16, week 28 ]
    Change in total CD4 cell count from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. Levels measured at pre-entry and entry were averaged for baseline
  • Th17 and Treg frequency [ Time Frame: baseline, week 14/16, week 28 ]
    Change in Th17 and Treg frequency from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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 DNA and RNA [ Time Frame: baseline, week 14/16, week 28 ]
    Change in genomic HIV-1 DNA, 2-LTR circles and RNA in blood from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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.
  • Endogenous retinoid metabolite profiles [ Time Frame: baseline, week 14/16, week 28 ]
    Change in endogenous retinoid metabolite profiles from baseline to week 14/16, from baseline to week 14/16, and from baseline to week 28. 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.
  • Primary targeted adverse events [ Time Frame: from baseline to week 28 ]
    Primary targeted adverse events including all reportable SAEs, diagnoses, signs, symptoms or laboratory toxicities. Events reportable regardless of grade will be considered primary events if they are grade 3 or higher, except for adverse events related to biopsy procedure
  • Pharmacokinetics - Trough concentrations of Isotretinoin and ART [ Time Frame: study entry, weeks 8, 12, 16, 20 and 24 ]
    Arm A 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.
Not Provided
Not Provided
 
Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery
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)
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.
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.
Interventional
Phase 2
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
HIV-1 Infection
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
  • 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.
    Intervention: Drug: Isotretinoin
  • No Intervention: No study treatment Arm
    No Isotretinoin treatment
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
76
November 2016
August 2016   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years to 80 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Puerto Rico,   United States
 
 
NCT01969058
ACTG A5325
UM1AI068636 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Douglas Kwon, MD, PhD Massachusetts General Hospital
Study Chair: Nina Lin, MD Harvard Medical School
AIDS Clinical Trials Group
August 2017

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