Clinical trial NCT01969058: Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Keywords: Isotretinoin
HIV-1
immunology markers
immune activation
viral suppression
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2013-10-25
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: Change in CD8+ T-cell Activation From Baseline to Week 14/16
timeFrame: baseline, week 14/16
Secondary outcomes:
measure: Change in CD8+ T-cell Activation
timeFrame: baseline, week 14/16, week 28
measure: Change in sCD14
timeFrame: baseline, week 14/16, week 28
measure: Change in I-FABP
timeFrame: baseline, week 14/16, week 28
measure: Change in IL-6
timeFrame: baseline, week 14/16, week 28
measure: Change in hsCRP
timeFrame: baseline, week 14/16, week 28
measure: Change in sTNF-r1
timeFrame: baseline, week 14/16, week 28
measure: Change in sTNF-r2
timeFrame: baseline, week 14/16, week 28
measure: Change in D-dimer
timeFrame: baseline, week 14/16, week 28
measure: Change in TF
timeFrame: baseline, week 14/16, week 28
measure: Change in sCD163
timeFrame: baseline, week 14/16, week 28
measure: Change in CD4+ T-cell Count
timeFrame: baseline, week 14/16, week 28
measure: Change in Cell-associated HIV-1 RNA
timeFrame: baseline, week 14/16, week 28
measure: Cell-associated HIV-1 DNA
timeFrame: baseline, week 14/16, week 28
measure: Change in Treg Frequency (%FoxP3+/CD25hi+/CD39+/CD127-(CD4+))
timeFrame: baseline, week 14/16, week 28
measure: Change in Th17 Frequency (%IFNg-/IL17+(CD161+/CCR6+))
timeFrame: baseline, week 14/16, week 28
measure: Pharmacokinetics - Endogenous Levels of Retinoid Metabolites for Isotretinoin Arm
timeFrame: weeks 0, 20, 28
measure: Pharmacokinetics - Steady-state Trough Concentrations of Isotretinoin for Isotretinoin Arm
timeFrame: weeks 8, 12, 16
measure: Pharmacokinetics - Trough Concentrations of TDF for Isotretinoin Arm
timeFrame: weeks 0, 8, 12, 16, 20
measure: Pharmacokinetics - 12-hour Levels of EFV for Isotretinoin Arm
timeFrame: weeks 0, 8, 12, 16, 20
measure: Primary Targeted Adverse Events
timeFrame: from study entry to end of study (week 28)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: 601 University of California, Los Angeles CARE Center CRS
state: California
city: San Francisco
country: United States
facility: 801 University of California, San Francisco HIV/AIDS CRS
state: California
city: Boston
country: United States
facility: 101 Massachusetts General Hospital (MGH) CRS
state: Massachusetts
city: Boston
country: United States
facility: 107 Brigham and Women's Hosp. ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: 2101 Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: 31786 New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Rochester
country: United States
facility: 31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Chapel Hill
country: United States
facility: 3201 Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: 3203 Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: 2401 Cincinnati CRS
state: Ohio
city: Providence
country: United States
facility: 2951 The Miriam Hospital (TMH) ACTG CRS
state: Rhode Island
city: Nashville
country: United States
facility: 3652 Vanderbilt Therapeutics (VT) CRS
state: Tennessee
city: Houston
country: United States
facility: 31473 Houston AIDS Research Team (HART) CRS
state: Texas
city: San Juan
country: Puerto Rico
facility: 5401 Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: Massachusetts General Hospital
name: Douglas Kwon, MD, PhD
role: STUDY_CHAIR
affiliation: Harvard Medical School (HMS and HSDM)
name: Nina Lin, MD
role: STUDY_CHAIR
References: