Retinoids in ANCA Small Vessel Vasculitis: Silencing Autoantigens

This study has been withdrawn prior to enrollment.
(no subject enrolled in nearly 2 years)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Patrick Nachman, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01275274
First received: January 10, 2011
Last updated: December 4, 2013
Last verified: December 2013
  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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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 ] [ Designated as safety issue: No ]
    normalization of PR3 and MPO message at the end of treatment.


Secondary Outcome Measures:
  • Birmingham Vasculitis Activity Score (BVAS) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    (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
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (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

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
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
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: 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
Investigators
Principal Investigator: Patrick H Nachman, MD UNC Kidney Center
  More Information

No publications provided

Responsible Party: Patrick Nachman, MD, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01275274     History of Changes
Other Study ID Numbers: 10-2007, P01DK058335
Study First Received: January 10, 2011
Last Updated: December 4, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

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
Mycophenolate mofetil
Tretinoin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Therapeutic Uses
Keratolytic Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on September 18, 2014