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Study Description

Symptoms clearly attributable to inflammatory disease are controllable in the great majority of patients with vasculitis. However, most patients do not feel healthy despite effective immune-suppressive treatment. Among the residual symptoms that disrupt the lives of patients with vasculitis, fatigue, poor physical function, sleep disturbance, and satisfaction with social roles are the most common and have the greatest negative impact on quality of life. Although there are multiple potential sources of these symptoms – residual autoimmune/inflammatory disease, medication side effects, co-morbidities such as obstructive sleep apnea or depression – the cause(s) often defy identification and successful management in the individual patient. Chronic pain is also high on the list of important negative influences on quality of life of patients with vasculitis.

Naltrexone is an opioid antagonist that is used in high doses for emergency treatment of opioid overdose and is FDA approved in an oral daily dose of 50 mg to prevent recidivism in alcoholics. At much lower doses of 4 – 4.5 mg daily, however, it has been shown in small, blinded, randomized trials to improve pain in fibromyalgia, gastrointestinal symptoms in Crohn’s disease, and quality of life in patients with multiple sclerosis.  The mechanism is unclear, with proposals including not only modulation of central pain-processing pathways but also mitigation of inflammatory roles of microglia. In addition to blocking opioid receptors, naltrexone blocks TLR-4, and some studies suggest that the anti-inflammatory effects of low dose naltrexone are independent of opioid receptors.

This multi-center, randomized, double-blinded, cross-over, placebo-controlled trial aims to evaluate the efficacy of low-dose naltrexone (LDN) at 4.5 mg nightly in improving self-reported physical health in patients with vasculitis. The specific aims include 1) determining improvement in physical health during treatment with LDN, using different assessments; 2) determining the change in the severity from baseline during treatment with LDN vs. Placebo in 7 individual domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with social roles, and pain interferences, as well as with the pain intensity item; 3) determining change in self-reported mental health during treatment with LDN or placebo; 4) determining vasculitis disease activity during treatment with LDN or placebo; and 5) determining the safety of LDN in patients with vasculitis.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           18 Years and older   (Adult, Older Adult)

Sexes Eligible for Study:          All

Accepts Healthy Volunteers:  No

Inclusion Criteria:

1. Criteria for diagnosis of giant cell arteritis (GCA), Takayasu’s arteritis (TAK), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss)
   1. Giant cell arteritis: According to the American College of Rheumatology (ACR) criteria for classification of GCA, meeting at least 2 of the following 5 remaining criteria at the time of diagnosis of GCA:
      Age of disease onset >50 years (required)
      1. New onset or new type of localized pain in the head
      2. Temporal artery abnormality (i.e. temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries)
      3. ESR of >40 mm in the first hour by Westergren method
      4. Temporal artery biopsy showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells
      5. Large Vessel Vasculitis (LVV) by angiogram or biopsy not explained by something else
   2. Takayasu’s arteritis: According to an adaptation of the American College of Rheumatology criteria, meeting at least 2 of the following 5 remaining criteria at the time of inclusion of TAK: Arteriogram abnormalities compatible with TAK (includes conventional dye angiography or MR angiography or CT angiography) (required)
      1. Age at disease onset ≤50 years
      2. Claudication of extremities
      3. Decreased brachial artery pulse (one or both arteries)
      4. Blood pressure difference of >10mm Hg between the arms
      5. Bruit over subclavian arteritis or aorta
   3. Polyarteritis nodosa: An adaption of the America College of Rheumatology criteria will be used for the diagnosis of PAN. At the time of inclusion, one major and one minor criteria or two major criteria or isolated cutaneous PAN must be met.
      1. Major criteria (not explained by other causes):
         1. Arteriographic abnormality
         2. Presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy
         3. Mononeuropathy or polyneuropathy
      2. Minor criteria (not explained by other causes)
         1. Weight loss > 4 kg
         2. Livedo reticularis, cutaneous ulcerations, or skin nodules
         3. Testicular pain or tenderness
         4. Myalgias
         5. Diastolic blood pressure >90mm Hg
         6. Elevated BUN or serum creatinine levels
         7. Ischemic abdominal pain
      3. Isolated cutaneous polyarteritis nodosa
         1. Biopsy-proven cutaneous PAN VCRC5564 LoDoNaVasc
   4. Granulomatosis with polyangiitis: Participants can be enrolled if two of the five modified American College of Rheumatology criteria are met:
      1. Nasal or oral inflammation: painful or painless oral ulcers or purulent or blood nasal discharge
      2. Abnormal chest radiograph: nodules, fixed infiltrates, or cavities
      3. Urinary sediment: microhematuria or red cell casts
      4. Granulomatous inflammation on biopsy: granulomatous inflammation within the wall of an artery or in the perivascular area
      5. ANCA positivity by enzyme immunoassay for either PR3- or MPO-ANCA
   5. Microscopic polyangiitis: The following Chapel Hill Consensus Conference Definitions for MPA need to be met:
      1. Necrotizing vasculitis with few or no immune deposits affects small vessel (i.e., capillaries, venules, or arterioles)
      2. Necrotizing arteritis involving small and medium-sized arteritis may be present
      3. Necrotizing glomerulonephritis is very common
      4. Pulmonary capillaritis often occurs
   6. Eosinophilic granulomatosis with polyangiitis: An adaptation of the American College of Rheumatology criteria will be used for the diagnosis of EGPA. At the time of inclusion, four of the six items must have documented evidence:
      1. Asthma
      2. Peak peripheral blood eosinophilia of >10% of total WBC
      3. Peripheral neuropathy attributable to vasculitis
      4. Transient pulmonary infiltrates on chest imaging studies
      5. Paranasal sinus abnormalities or nasal polyposis
      6. Eosinophilic inflammation on tissue biopsy
         If patients have 4 of the above 6 criteria but lack clearcut documentation of small vessel vasculitis, they are also eligible for enrollment.
2. Baseline normalized score on PROMIS Global Physical Health of 40 or lower
3. Vasculitis in remission or very low disease activity (Physician Global Assessment 0-1) for at least 12 weeks
4. Stable immunosuppressive therapy (including prednisone) related to vasculitis for at least 12 weeks
5. No change in medications in the past 12 weeks made with the expectation of improving pain, fatigue, or mood
6. No plan to change medication or a non-pharmacologic treatment regimen likely to affect pain, fatigue, mood, or vasculitis activity during the next 12 weeks
7. Age of 18 years or older
8. Willingness and ability to comply with treatment and follow-up procedures, including receipt of weekly phone calls from the study coordinator
9. Willingness and ability to provide informed consent
   Exclusion Criteria:

• Change in any medication related to control of vasculitis, pain, fatigue, or mood within the past 12 weeks (medications taken as needed must be in a stable pattern per the patient's estimation)
• Use of another investigational agent as part of a clinical trial within 30 days of enrollment
• Current use of any opioid agonist including tramadol or suboxone
• Change in vasculitis activity in the past 12 weeks, as defined by a change in Physician Global Assessment greater than 1
• Baseline normalized score more than 40 on PROMIS Global Physical Health
• New major medical problem or surgery in past 12 weeks
• Pregnancy or breastfeeding
• Inability to provide informed consent or comply with study procedures
• Schizophrenia or bipolar disorder
• Poorly controlled depression or anxiety, as defined by a score of ≥ 20 on PHQ-9
• Liver cirrhosis
• Significant kidney disease, defined as glomerular filtration rate <30ml/min

Study Design:

Allocation: Randomized

Intervention Model: Crossover Assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Study Location(s):

Mayo Clinic, Rochester, Minnesota, United States, 55905

University of Pennsylvania, Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh, Pittsburgh, Pennsylvania, United States, 15260

University of Utah, Salt Lake City, Utah, United States, 84112

Study Website:

https://clinicaltrials.gov/ct2/show/NCT03482479?term=NCT03482479&rank=1