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Levocarnitine for Dry Eye in Sjogren's Syndrome (alLEViate)

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ClinicalTrials.gov Identifier: NCT03953703
Recruitment Status : Not yet recruiting
First Posted : May 16, 2019
Last Update Posted : May 22, 2019
Sponsor:
Information provided by (Responsible Party):
Leslie Crofford, Vanderbilt University Medical Center

Brief Summary:
This study evaluates the effectiveness of levocarnitine in the treatment of dry eye in adults with Sjogren's syndrome. Half of participants will receive levocarnitine while the other half will receive placebo.

Condition or disease Intervention/treatment Phase
Sjogren's Syndrome Keratoconjunctivitis Sicca Drug: Levocarnitine Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Placebo-controlled, Double Blind Phase 2 Clinical Trial of Levocarnitine for the Treatment of Keratoconjunctivitis Sicca in Sjogren's Syndrome
Estimated Study Start Date : July 17, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental: Levocarnitine
1000 mg once per day for two weeks followed by 1000 mg twice per day for 10 weeks
Drug: Levocarnitine
Levocarnitine 1000mg once per day for 2 weeks followed by 1000mg twice per day for 10 weeks

Placebo Comparator: Comparator: Placebo
1000 mg once per day for two weeks followed by 1000 mg twice per day for 10 weeks
Drug: Placebo
Placebo 1000mg once per day for 2 weeks followed by 1000mg twice per day to 10 weeks




Primary Outcome Measures :
  1. Ocular Surface Disease Index (OSDI) [ Time Frame: 12 weeks ]
    The Ocular Surface Disease Index (OSDI) was developed by the Outcomes Research Group (Allergan Inc.) in 1997 as an assessment of symptoms (functional, limitations, and environmental) of dry eye disease and their effect on vision. It is a 12-item list, with each item compromised of a five category Likert-like response option. of 24 different clinical and laboratory variables/disease descriptors, comprising nine organ systems. Scores of the descriptors range from 1 to 8, and the total possible score for all descriptors is 105. Regression models are applied to assign relative weights to each parameter


Secondary Outcome Measures :
  1. EULAR Sjogren's Disease Activity Index [ Time Frame: 12 weeks ]
    The EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SjS developed in 2009. It is a score than has been developed by consensus of experts from European and North American countries and it supported by the EULAR. The ESSDAI includes 12 domains (cutaneous, renal, articular, muscular, peripheral nervous system, hematological, glandular, constitutional, lymphadenopathic, biological) each of which is divided into 3-4 levels of activity.

  2. EULAR Sjogren's Syndrome Patient Reported Index [ Time Frame: 12 weeks ]
    The EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) is a patient-administered questionnaire to asses patients' symptoms. It was developed using the Patient Global Assessment of Disease as the 'gold standard" and measures symptoms of dryness, limb pain, and mental fatigue

  3. EULAR Sicca Score [ Time Frame: 12 weeks ]
    The EULAR sicca score is a measure of overall severity of dryness experienced by the patients. Ocular, oral, cutaneous, nasal, tracheal, and vaginal dryness is reported on a scale of 1-10. The final ESS score is calculated as follows: (2 x oral dryness + ocular dryness) / 3.

  4. Patient Global Assessment [ Time Frame: 12 weeks ]
    The Patient Global Assessment (PGA) is one of the most widely used patient reported outcomes in research. It is typically administered as a single question with either a 1-10 or 1-100 response

  5. Schirmer's tear test [ Time Frame: 12 weeks ]
    The Schirmer's tear test is used to determine if the tear glands produce enough tears to keep the eyes moist. Strips of filter paper are placed within the lower eyelid for a period of time. Wetting of the filter paper is measured in millimeters.

  6. Fluorescein staining [ Time Frame: 12 weeks ]
    Staining with fluorescein is used to characterize dry eye disease, assess severity, and monitor response to therapy. It is graded using the Oxford scale which consists of a chart containing a series of panels labeled A-E in order of increasing severity. Staining is represented by punctate dots, and the number of dots increases by one log unit from panel A to B and by 0.5 log units between panels B to E. To grade, comparisons are made between the panels and the appearance of staining on the conjunctiva and cornea of the patient.

  7. Lissamine green staining [ Time Frame: 12 weeks ]
    Staining with lissamine green is used to characterize dry eye disease, assess severity, and monitor response to therapy. It is graded using the Oxford scale which consists of a chart containing a series of panels labeled A-E in order of increasing severity. Staining is represented by punctate dots, and the number of dots increases by one log unit from panel A to B and by 0.5 log units between panels B to E. To grade, comparisons are made between the panels and the appearance of staining on the conjunctiva and cornea of the patient.

  8. Tear osmolarity [ Time Frame: 12 weeks ]
    Tear osmolarity is measured using nanoliter volumes of tears collected directly from the eyelid margin.

  9. Tear break-up time [ Time Frame: 12 weeks ]
    Tear break-up time is measured by adding fluorescein dye to the eye and observing the tear film using a slit lamp until dry spots occur.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  5. Tear osmolarity of 312mOsm/L or greater in at least 1 eye

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. Use of immunomodulatory (e.g. Restasis, Xiidra), anti-inflammatory (e.g. steroid containing) eye drops, or serum tears within 3 months prior to enrollment
  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

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Responsible Party: Leslie Crofford, Director, Division of Rheumatology and Immunology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03953703     History of Changes
Other Study ID Numbers: 124443
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: May 22, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Leslie Crofford, Vanderbilt University Medical Center:
Sjogren's syndrome, dry eye, sicca

Additional relevant MeSH terms:
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Sjogren's Syndrome
Keratoconjunctivitis
Keratoconjunctivitis Sicca
Dry Eye Syndromes
Syndrome
Disease
Pathologic Processes
Arthritis, Rheumatoid
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Xerostomia
Salivary Gland Diseases
Mouth Diseases
Stomatognathic Diseases
Lacrimal Apparatus Diseases
Eye Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Conjunctivitis
Conjunctival Diseases
Keratitis
Corneal Diseases