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Retinoids in ANCA Small Vessel Vasculitis: Silencing Autoantigens

This study has been withdrawn prior to enrollment.
(no subject enrolled in nearly 2 years)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01275274
First Posted: January 12, 2011
Last Update Posted: February 23, 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 Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
  Purpose
The purpose of this research study is to learn if adding all-trans retinoic acid (tretinoin) to conventional treatment of Anti- Neutrophil Cytoplasmic Autoantibodies (ANCA) vasculitis can decrease the level of disease activity.

Condition Intervention Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Drug: Retinoic acid Drug: Standard of care Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Retinoids in ANCA Small Vessel Vasculitis: Silencing Autoantigens

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • change in leukocyte Myeloperoxidase (MPO) and Proteinase 3 (PR3) message [ Time Frame: week 12 ]
    normalization of PR3 and MPO message at the end of treatment.


Secondary Outcome Measures:
  • Birmingham Vasculitis Activity Score (BVAS) [ Time Frame: 52 weeks ]
    (1) Change in BVAS at the end of treatment (week 12) and at week 52, compared to baseline (day 1); (2) Change in Treg and Th17 cells at weeks 12 and 52, compared to baseline (day 1); and (3) the frequency of relapse during the follow up period.


Enrollment: 0
Study Start Date: January 2012
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard of care
maintenance therapy with azathioprine or mycophenolate mofetil with or without small dose prednisone.
Drug: Standard of care
maintenance therapy with azathioprine or mycophenolate mofetil with or without small dose prednisone. Dose, frequency and duration depend on disease activity (partial or complete remission).
Other Names:
  • Imuran, Azasan
  • Cellcept
Experimental: Retinoic acid
Tretinoin in addition to standard of care
Drug: Retinoic acid
Patients will be started at half the recommended dose of retinoic acid for the treatment of acute promyelocytic leukemia (APL), i.e. 22.5mg/m2/day orally in two divided doses, to minimize the risk of adverse events. If there is no decrease in PR3/MPO gene expression to a fold change of < 2 by quantitative polymerase chain reaction(QT-PCR) technique for PR3 at the end of 4 weeks, the dose will be increased to 45 mg/m2/day in two divided doses for an additional 8 weeks. If the patient shows a decrease in PR3/MPO gene expression to < 2 at 4 weeks, the patient will remain on the same dose for the remainder of 12 weeks. All patients will be followed for a total of 12 months for safety evaluations and to assess changes in disease activity and the incidence of disease relapse.
Other Name: Tretinoin

Detailed Description:
Neutrophils are white blood cells that are the target of the ANCA antibodies. T cells are white blood cells that are involved in regulating the immune system. Laboratory research studies suggest that all-trans retinoic acid (tretinoin) can affect the neutrophils and the T lymphocytes in such a way that could decrease the abnormal immune response directed against the body own neutrophils.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with ANCA disease and no more than mild activity as determined by a BVAS score of 1 to 4. These are patients who will have undergone induction with cyclophosphamide and corticosteroids in the past, and will be in partial remission on maintenance therapy with azathioprine or mycophenolate mofetil with or without small dose prednisone. We anticipated that most patients enrolled in the study will have low grade persistent ("grumbling") disease on stable immunosuppressants.
  • Documented 6-fold or greater elevation in PR3 and/or MPO gene expression by the RT-PCR technique. We estimate that approximately 25% of patients with a BVAS <5 will have an elevation in PR3 and/or MPO gene expression based on our previous studies. 2 Patients must be on stable maintenance therapy with prednisone (<10 mg/day or equivalent), cyclosporine A, mycophenolate mofetil or azathioprine for at least 8 weeks.

Exclusion Criteria:

  • Patients with severe, active vasculitis requiring institution or an increase in dose of corticosteroids, cyclophosphamide, azathioprine, mycophenolate mofetil or any new immunosuppressive medication within the previous 8 weeks or at the time of enrollment.
  • Pregnancy, breastfeeding, or unwillingness to use at least two contraceptive methods (at least one of which must be primary, including tubal ligation, partner vasectomy, oral contraceptives, implanted contraceptives, and intrauterine device). The rationale is that retinoids are teratogenic and are excreted in breast milk. Contraceptive methods must be instituted at least 1 month before starting tretinoin and continued at least 1 month after stopping the medication.
  • History of hepatitis, cirrhosis or abnormal liver tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase, Gamma-glutamyl transpeptidase (GGT), total bilirubin, or prothrombin time; unless the abnormality is due to a specific hepatotoxic medication, AND the liver test levels are l< 2 times the upper limit of the normal AND normalize upon holding the offending drug.
  • Hypertriglyceridemia (>500 mg/dL) despite statin/fibrate therapy.
  • Any medical conditions requiring concurrent use of tetracycline, minocycline, or doxycycline, due to enhanced risk of increased intracranial pressure.
  • Any medical conditions requiring concurrent use of rifampin, phenobarbital, pentobarbital, ketoconazole, cimetidine, erythromycin, verapamil, diltiazem, vitamin A and antithrombotic agents (Tranexamic Acid, Aminocaproic Acid or Aprotinin)due to the potential for interactions with tretinoin therapy.
  • Presence of unstable cardiovascular disease, uncontrolled diabetes with hemoglobin A1c > 8% g/dL, or chronic inflammatory or infectious conditions.
  • Glomerular Filtration Rate (GFR) <25 ml/min/1.73m^2 as estimated by the MDRD equation, as the metabolites of retinoids are excreted in part in urine, and there is a concern for increased toxicity.
  • Untreated depression, as retinoids have been associated with depression, suicidal ideation, and aggressive behavior.
  • Neutropenia (neutrophil count < 1000 cell/mm^3).
  • Known osteoporosis.
  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): NCT01275274


Locations
United States, North Carolina
UNC Kidney Center
Chapel Hill, North Carolina, United States, 27599-7155
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Patrick H Nachman, MD UNC Kidney Center
  More Information

Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01275274     History of Changes
Other Study ID Numbers: 10-2007
P01DK058335 ( U.S. NIH Grant/Contract )
First Submitted: January 10, 2011
First Posted: January 12, 2011
Last Update Posted: February 23, 2017
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: no data obtained.

Keywords provided by University of North Carolina, Chapel Hill:
ANCA
Vasculitis
Pauci-immune vasculitis

Additional relevant MeSH terms:
Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Systemic Vasculitis
Autoimmune Diseases
Immune System Diseases
Mycophenolic Acid
Tretinoin
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Keratolytic Agents
Dermatologic Agents