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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by AIDS Clinical Trials Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01969058
First received: August 21, 2013
Last updated: April 29, 2014
Last verified: April 2014
  Purpose

This phase II study is being done in HIV-infected subjects 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. Your immune system helps your body fight infections. When your immune system is not working well, you 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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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 from baseline in CD8+ T-cell activation at week 14/16 [ Time Frame: baseline, week 14/16 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Markers of gut microbial translocation [ Time Frame: baseline, week 14/16, week 28 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 81
Study Start Date: April 2014
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A: isotretinoin
Participants will receive 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
No Intervention: Arm B: No isotretinoin treatment

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01969058

Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Douglas Kwon, MD, PhD Massachusetts General Hospital
Study Chair: Nina Lin, MD Harvard Medical School
  More Information

No publications provided

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01969058     History of Changes
Other Study ID Numbers: ACTG A5325, UM1AI068636
Study First Received: August 21, 2013
Last Updated: April 29, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Isotretinoin
Dermatologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 21, 2014