Retinoids in ANCA Small Vessel Vasculitis: Silencing Autoantigens

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.

Study Overview

• Status: Withdrawn
• Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Intervention / Treatment: Drug: Standard of care; Drug: Retinoic acid

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7155
      • UNC Kidney Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: Cellcept; Imuran, Azasan
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 Names: Tretinoin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in leukocyte Myeloperoxidase (MPO) and Proteinase 3 (PR3) message	normalization of PR3 and MPO message at the end of treatment.	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birmingham Vasculitis Activity Score (BVAS)	(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.	52 weeks

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Patrick H Nachman, MD, UNC Kidney Center

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: January 10, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (Estimate): January 12, 2011

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: February 17, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Vasculitis; ANCA; Pauci-immune vasculitis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Autoimmune Diseases; Systemic Vasculitis; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antineoplastic Agents; Dermatologic Agents; Keratolytic Agents; Tretinoin
• Other Study ID Numbers: 10-2007; P01DK058335 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: no data obtained.