A Randomized Placebo-controlled, Double Blind Pilot Crossover Trial of Levocarnitine for the Treatment of Keratoconjunctivitis Sicca in Sjogren's Syndrome
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Mean change in tear inflammatory cytokine milieu
Study Overview
Brief Summary
This study evaluates the effectiveness of levocarnitine in the treatment of dry eye in adults with Sjogren's syndrome. This will be a crossover study design with all participants receiving both levocarnitine and placebo.
Detailed Description
A phenome wide association study (PheWAS) was conducted for variants in the SLC22A5 gene encoding the OCTN2 protein. OCTN2 is a cell membrane protein that transports carnitine into the cell. The carnitine supplement levocarnitine, FDA approved for human use and with a favorable safety profile, was identified for repurposing. SLC22A5/OCTN2 are a class of sodium ion dependent, high affinity transmembrane proteins expressed in the heart, liver, muscle, and kidney among other tissues. The screen identified "sicca syndrome" (OR 4.56; P = 5.6E-04) as well as various other eye diseases as the most significantly associated phenotypes. Sicca syndrome is defined as dryness of the exocrine glands, particularly the eyes (keratoconjunctivitis sicca) and mouth (xerostomia). This condition is most often caused by Sjogren's syndrome (SjS), a systemic autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands.
Interestingly, carnitine is present in considerable quantities in the tears of normal, healthy eyes, and studies have shown a decrease in the tear carnitine levels of dry eye patients. Furthermore, eyedrop preparations containing l-carnitine have shown benefit in dry eye disease. The overall hypothesis is that OCTN2 dysfunction underlies keratoconjunctivitis sicca in SjS patients and that oral supplementation with levocarnitine may be beneficial.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Clinician diagnosis of primary or secondary SjS.
- •Positive anti-SSA
- •Diagnosis of keratoconjunctivitis sicca defined by OSDI ≥ 25 and Schirmer's test ≤ 5mm/5min in at least 1 eye.
- •Stable medications for past 4 weeks
Exclusion Criteria
- •Age <18 or >75 at screening visit
- •Pregnant or nursing, or women of childbearing potential unwilling to use a medically acceptable form of birth control
- •Unwilling or unable to stop the use of any artificial tear formulations containing L-carnitine.
- •Taking any form of levocarnitine supplementation or nutritional supplements containing L-carnitine within 2 months prior to enrollment
- •Unwilling to discontinue immunomodulatory (e.g. Restasis, Xiidra), anti-inflammatory (e.g. steroid containing) eye drops, or serum tears for 1 month prior and throughout the duration of the study
- •Unwilling to discontinue wearing contact lenses for 1 month prior and throughout the duration of the study
- •Planned occlusion of the lacrimal puncta with either punctal plugs or cauterization during the study
- •Laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), or radial keratectomy
- •Ocular surgery/trauma in the last 6 months or planned during the study
- •History of ocular infection, including severe blepharitis, in the last 3 months
- •Active ocular allergy that, in the opinion of the investigator, would compromise interpretation of the data
- •Elevated AST, ALT, alkaline phosphatase or bilirubin above the upper limit of normal at screening
- •Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula)
- •Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the screening visit
- •Laboratory parameters at the pre-treatment visit showing any of the following abnormal results: neutrophil count < 1,500/mm3; platelet count < 100,000/mm3; hemoglobin < 9 g/dL
- •Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product
- •The patient has a known defect in oxidative phosphorylation (such as a confirmed mitochondrial myopathy)
- •Any medical or psychiatric condition, which in the opinion of the investigator, places the subject at unacceptable risk or which might compromise the validity of the collected data
- •Allogeneic BMT or chemotherapy in the past 3 months
- •The patient has a history of seizure activity.
- •History of a cornea transplant
- •Herpes simplex or herpes zoster infection in the eye
- •Eyelid tattooing (permanent eyelining)
- •Current diagnoses of any of the following conditions: acute allergic conjunctivitis, inflammation (e.g, retinitis macular inflammation, choroiditis, uveitis, scleritis, episcleritis, keratitis)
- •On glaucoma eye-drops or eye-drops for lowering eye pressure
- •Known diagnoses of: Hepatitis C infection, HIV infection, Sarcoidosis, Amyloidosis, Graft versus host disease, Cicatrizing conjunctivitis (e.g. from trachoma, Stevens-Johnson syndrome, pemphigoid, drug induced pseudo-pemphigoid, or chemical ocular burns), Pre-existing lymphoma in patients with no prior diagnosis of SS, Past head and neck radiation treatment
- •Condition that may compromise ocular surface integrity: trachoma, Stevens-Johnson syndrome, pemphigoid, graft versus host disease, prior chemical burn, recurrent corneal erosions, persistent corneal epithelial defects, prior ocular trauma
- •Issues with closing eyelids completely or having eyelashes rub on surface of eye
- •Unwilling to discontinue oral supplements for dry eye like fish oil for 1 month prior and throughout study duration
- •Unwilling to discontinue use of Tyrvaya (varenicline) nasal spray for 1 month prior and throughout study duration
Arms & Interventions
Experimental: Levocarnitine, Placebo
1000 mg of levocarnitine twice per day for six weeks, a two week washout period, 1000 mg of placebo twice per day for 6 weeks
Intervention: Levocarnitine (Drug)
Experimental: Levocarnitine, Placebo
1000 mg of levocarnitine twice per day for six weeks, a two week washout period, 1000 mg of placebo twice per day for 6 weeks
Intervention: Placebo (Drug)
Experimental: Placebo, Levocarnitine
1000 mg of placebo twice per day for six weeks, a two week washout period, 1000 mg of levocarnitine twice per day for 6 weeks
Intervention: Levocarnitine (Drug)
Experimental: Placebo, Levocarnitine
1000 mg of placebo twice per day for six weeks, a two week washout period, 1000 mg of levocarnitine twice per day for 6 weeks
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Mean change in tear inflammatory cytokine milieu
Time Frame: 14 weeks
Levels of inflammatory cytokines IFN-gamma, TNF-alpha, IL-17, IL-6 and IL-1beta will be measured by flow cytometric multiplexed bead assay.
Secondary Outcomes
- Schirmer's tear test(14 weeks)
- Tear break-up time(14 weeks)
- Mean change in tear carnitine levels.(14 weeks)
- Patient Global Assessment(14 weeks)
- Fluorescein staining(14 weeks)
- Lissamine green staining(14 weeks)
- Ocular Surface Disease Index (OSDI)(14 weeks)
- EULAR Sjogren's Syndrome Patient Reported Index(14 weeks)
- EULAR Sjogren's Disease Activity Index(14 weeks)
- EULAR Sicca Score(14 weeks)
Investigators
Christine Shieh
Assistant Professor of Ophthalmology
Vanderbilt University Medical Center