Clinical trial NCT03953703: Levocarnitine for Dry Eye in Sjogren's Syndrome
Official title: A Randomized Placebo-controlled, Double Blind Pilot Crossover Trial of Levocarnitine for the Treatment of Keratoconjunctivitis Sicca in Sjogren's Syndrome
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Sjogren's Syndrome
Keratoconjunctivitis Sicca
Keywords: Sjogren's syndrome, dry eye, sicca
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2019-05-16
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Clinician diagnosis of primary or secondary SjS.
2. Positive anti-SSA
3. Diagnosis of keratoconjunctivitis sicca defined by OSDI ≥ 25 and Schirmer's test ≤ 5mm/5min in at least 1 eye.
4. Stable medications for past 4 weeks

Exclusion Criteria:

1. Age \<18 or \>75 at screening visit
2. Pregnant or nursing, or women of childbearing potential unwilling to use a medically acceptable form of birth control
3. Unwilling or unable to stop the use of any artificial tear formulations containing L-carnitine.
4. Taking any form of levocarnitine supplementation or nutritional supplements containing L-carnitine within 2 months prior to enrollment
5. 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
6. Unwilling to discontinue wearing contact lenses for 1 month prior and throughout the duration of the study
7. Planned occlusion of the lacrimal puncta with either punctal plugs or cauterization during the study
8. Laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), or radial keratectomy
9. Ocular surgery/trauma in the last 6 months or planned during the study
10. History of ocular infection, including severe blepharitis, in the last 3 months
11. Active ocular allergy that, in the opinion of the investigator, would compromise interpretation of the data
12. Elevated AST, ALT, alkaline phosphatase or bilirubin above the upper limit of normal at screening
13. Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula)
14. Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the screening visit
15. 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
16. Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product
17. The patient has a known defect in oxidative phosphorylation (such as a confirmed mitochondrial myopathy)
18. 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
19. Allogeneic BMT or chemotherapy in the past 3 months
20. The patient has a history of seizure activity.
21. History of a cornea transplant
22. Herpes simplex or herpes zoster infection in the eye
23. Eyelid tattooing (permanent eyelining)
24. Current diagnoses of any of the following conditions: acute allergic conjunctivitis, inflammation (e.g, retinitis macular inflammation, choroiditis, uveitis, scleritis, episcleritis, keratitis)
25. On glaucoma eye-drops or eye-drops for lowering eye pressure
26. 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
27. 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
28. Issues with closing eyelids completely or having eyelashes rub on surface of eye
29. Unwilling to discontinue oral supplements for dry eye like fish oil for 1 month prior and throughout study duration
30. Unwilling to discontinue use of Tyrvaya (varenicline) nasal spray for 1 month prior and throughout study duration

Primary outcomes:
measure: Mean change in tear inflammatory cytokine milieu
timeFrame: 14 weeks
Secondary outcomes:
measure: Ocular Surface Disease Index (OSDI)
timeFrame: 14 weeks
measure: Mean change in tear carnitine levels.
timeFrame: 14 weeks
measure: EULAR Sjogren's Disease Activity Index
timeFrame: 14 weeks
measure: EULAR Sjogren's Syndrome Patient Reported Index
timeFrame: 14 weeks
measure: EULAR Sicca Score
timeFrame: 14 weeks
measure: Patient Global Assessment
timeFrame: 14 weeks
measure: Schirmer's tear test
timeFrame: 14 weeks
measure: Fluorescein staining
timeFrame: 14 weeks
measure: Lissamine green staining
timeFrame: 14 weeks
measure: Tear break-up time
timeFrame: 14 weeks
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Christine Shieh, MD
role: PRINCIPAL_INVESTIGATOR
References: