Evaluation of Safety & Efficacy for the Prevention of Ocular GVHD With Ophthalmic Tacrolimus vs Cyclosporine in Allo-HSCT

April 4, 2024 updated by: David Gomez Almaguer, Hospital Universitario Dr. Jose E. Gonzalez

Evaluation of Safety and Efficacy for the Prevention of Ocular Graft-versus-host Disease With Ophthalmic Tacrolimus vs. Ophthalmic Cyclosporine in Non-myeloablative Allogeneic Hematopoietic Stem Cell Transplant Recipients

Chronic GVHD (cGVHD) is a predominant cause of mortality and disability not related to relapse; it occurs in 30 to 70% of patients. The majority of patients with cGVHD present with ocular involvement with a reported incidence of 40-60%. Symptoms can range from mild dry eye syndrome to severe epithelial defects that can generate corneal perforation and loss of vision. The most accepted pharmacological modality is the topical application of cyclosporine A; on the other hand, tacrolimus has shown greater immunosuppressive power when used in ocular GVHD. However, this effectiveness is limited since by the time the manifestations appear, there is already permanent damage to the lacrimal gland due to the lymphocytic infiltration; so it is necessary to use a prevention strategy before these manifestations appear. Previously, the employment of ocular cyclosporine drops as ocular GVHD prophylaxis was assessed to evaluate safety and effectiveness, showing that it is well tolerated and can limit the appearance of severe dry eye manifestations in a small group of patients. The purpose of this work is to compare the two modalities currently accepted for the treatment of the disease, but in a prophylactic way; topical ciclosporin A against topical tacrolimus, to determine the safety and efficiency of each of them as a preventive measure to limit the risk of developing the appearance of ocular cGVHD and the permanent consequences that this generates.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

After being informed about the study and potential risks, all patients giving written informed consent will be assigned a participant number to anonymize their data and collect information, including age, sex, diagnosis, stage of disease, type of procedure, and conditioning chemotherapy. Additionally, an ophthalmology evaluation will be conducted in the Ophthalmology Department of the University Hospital of the U.A.N.L. by the study team of ophthalmologists, following a standardized method and using a worksheet for dry eye and ocular surface evaluation.

Participants will be randomized to receive either treatment arm A (cyclosporine eye drops) or treatment arm B (tacrolimus ointment) through a stratified method. After the hematopoietic stem cell transplant (HSCT), information will be collected, such as the transplant details (e.g., number of cluster of differentiation 34 [CD34] cells infused, cell source, and any complications during the procedure) and medications used for the systemic GVHD prophylaxis, as well as the graft date. In addition to the standard systemic management protocol for GVHD prevention of the transplant program of the Hematology Service of the Hospital University U.A.N.L. cyclosporine or tacrolimus will be administered to participants once grafting is demonstrated, defined as the presence in the blood count of a neutrophil count that is equal to or greater than to 500/mm3 and platelet count equal to or greater than 20,000/mm3.

  • Treatment arm A: topical cyclosporine 0.1% ocular drops, twice daily, one drop in each eye, with a 12-hour difference between each dose, for 12 continuous months. The commercial presentation that we will use has the following formula: Each milliliter of 0.1% solution contains Cyclosporine A 10 mg, c.b.p 1.0 ml.
  • Treatment arm B: tacrolimus ointment, to be applied approximately 1cm or the amount to cover the lower fornix twice a day in each eye, with a difference of 12 hours between each dose, for 12 continuous months. The presentation of the medicine in ointment has a 10 gr tube with 0.03% drug.

Ophthalmological evaluations will be carried out at the initial visit (before the bone marrow transplant) and scheduled subsequent visits: at the time of transplant graft (variable depending on the type of transplant, between days +10 and +21 approximately), and 3, 6, 9, and 12 months from the start of treatment (day of graft). Also, they will be evaluated during all follow-up visits to the transplant department of the Hematology Service, assessing adherence and tolerance to the medication through direct questioning. The severity of ocular GVHD will be established based on the NIH criteria and the severity criteria of the international consensus on the severity of chronic ocular GVHD (ICCGVHD)

Ophthalmological variables to be evaluated

  • Tear breakup time, Schirmer's test, esthesiometry, Keratograph 5M Topographer Dry Eye Assessment, upper and lower tarsus Meibomian Gland imaging (Keratograph 5M), tear osmolarity, metalloproteinase 9 levels in tears.
  • Corneal and conjunctival staining measured with the Oxford Scale and the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Scale and SICCA Ocular Staining Score (OSS).

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Mexico
    • Monterrey
      • Nuevo León, Monterrey, Mexico, 66640
        • Recruiting
        • Hospital Universitario de la U.A.N.L.
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patients undergoing allogeneic HSCT.
  2. Patients 18 years of age or older.
  3. Patients who agree to participate in the study and sign the informed consent document.

Exclusion Criteria:

  1. Patients undergoing HSCT who do not continue their evaluation and follow-up in the Hematology Service of the University Hospital.
  2. Patients under 18 years of age.
  3. Patients who do not agree to participate in the study.
  4. Patients diagnosed with previous rheumatic disease.
  5. Patients with dermatological conditions undergoing systemic treatment.
  6. Patients with uncontrolled thyroid disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Topical cyclosporine

Topical cyclosporine ophthalmic solution 0.1%, with a dosage of 1 drop in each eye every 12 hours, continued for a duration of 12 continuous months.

Composition: Each ml contains Cyclosporine A 0.1% w/v (1 mg/ml) in a sterile aqueous vehicle q.s.
Drug: Cyclosporine ophthalmic solution 0.1%
Ophthalmic prophylaxis begins once engraftment is documented, with a dose of 1 drop in each eye every 12 hours, continued for a duration of 12 continuous months
Experimental: Topical tacrolimus
Topical tacrolimus ophthalmic ointment 0.03%, with a dosage of approximately 1 cm or the necessary amount to cover the lower fornix, every 12 hours, continued for a duration of 12 continuous months Composition: Each gram contains Tacrolimus 0.03% w/w (0.3 mg/g) in a sterile ointment base q.s.
Drug: Tacrolimus ophthalmic ointment 0.03%
Ophthalmic prophylaxis begins once engraftment is documented, with a dose of approximately 1 cm or the necessary amount to cover the lower fornix, every 12 hours, continued for a duration of 12 continuous months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of ocular graft-versus-host disease in patients undergoing allo-HSCT receiving topical prophylaxis with Cyclosporine A or Tacrolimus as assessed by the International Consensus Criteria on chronic ocular graft-versus-host disease.
Time Frame: 2.5 years
Severity based on an aggregate of scores of the following parameters: Schirmer's test [mm] (0, >15; 1, 11-15; 2, 6-10; 3, ≤5), Corneal fluorescein staining [points] (0, 0; 1, <2; 2, 2-3; 3, ≥4), Ocular Surface Disease Index [points] (0, <13; 1, 13-22; 2, 23-32; 3, ≥33), Conjunctival injection [points] (0, None; 1, Mild/Moderate; 2, Severe). Graded as none (0-4 points), mild/moderate (5-8 points) and severe (9-11 points), where higher scores mean a worse outcome.
2.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of ocular graft-versus-host disease in patients undergoing allo-HSCT receiving topical prophylaxis with Cyclosporine A or Tacrolimus as assessed by the National Institutes of Health Consensus Development Projects on Chronic GVHD scoring system.
Time Frame: 2.5 years
Severity graded from 0 to 3 as follows: 0: No symptoms; 1: mild dry eye symptoms not affecting activity of daily living (requiring eye drops ≤3 x per day); 2: Moderate dry eye symptoms partially affecting activity of daily living (requiring eye drops >3 x per day or punctal plugs) WITHOUT new vision impairment due to keratoconjunctivitis sicca; 3: Severe dry eye symptoms significantly affecting activity of daily living (special eyewear to relieve pain) OR unable to work because of ocular symptoms OR loss of vision due to keratoconjunctivitis sicca. Note: higher scores mean a worse outcome.
2.5 years
Prevalence of ocular GVHD based on historical records in the hematology service of the University Hospital U.A.N.L. in patients without prophylactic treatment as assessed by the International Consensus Criteria on chronic ocular graft-versus-host disease
Time Frame: 10 years
Severity based on an aggregate of scores of the following parameters: Schirmer's test [mm] (0, >15; 1, 11-15; 2, 6-10; 3, ≤5), Corneal fluorescein staining [points] (0, 0; 1, <2; 2, 2-3; 3, ≥4), Ocular Surface Disease Index [points] (0, <13; 1, 13-22; 2, 23-32; 3, ≥33), Conjunctival injection [points] (0, None; 1, Mild/Moderate; 2, Severe). Graded as none (0-4 points), mild/moderate (5-8 points) and severe (9-11 points), where higher scores mean a worse outcome.
10 years
Severity of ocular GVHD based on historical records in the hematology service of the University Hospital U.A.N.L. in patients without prophylactic treatment, as assessed by the International Consensus Criteria on chronic ocular graft-versus-host disease.
Time Frame: 10 years
Severity based on an aggregate of scores of the following parameters: Schirmer's test [mm] (0, >15; 1, 11-15; 2, 6-10; 3, ≤5), Corneal fluorescein staining [points] (0, 0; 1, <2; 2, 2-3; 3, ≥4), Ocular Surface Disease Index [points] (0, <13; 1, 13-22; 2, 23-32; 3, ≥33), Conjunctival injection [points] (0, None; 1, Mild/Moderate; 2, Severe). Graded as none (0-4 points), mild/moderate (5-8 points) and severe (9-11 points), where higher scores mean a worse outcome.
10 years
Prevalence of ocular GVHD based on historical records in the hematology service of the University Hospital U.A.N.L. in patients without prophylactic treatment, as assessed by the National Institutes of Health Consensus on Chronic GVHD scoring system.
Time Frame: 10 years
Severity graded from 0 to 3 as follows: 0: No symptoms; 1: mild dry eye symptoms not affecting activity of daily living (requiring eye drops ≤3 x per day); 2: Moderate dry eye symptoms partially affecting activity of daily living (requiring eye drops >3 x per day or punctal plugs) WITHOUT new vision impairment due to keratoconjunctivitis sicca; 3: Severe dry eye symptoms significantly affecting activity of daily living (special eyewear to relieve pain) OR unable to work because of ocular symptoms OR loss of vision due to keratoconjunctivitis sicca. Note: higher scores mean a worse outcome.
10 years
Severity of ocular GVHD based on historical records in the hematology service of the University Hospital U.A.N.L. in patients without prophylactic treatment, as assessed by the National Institutes of Health Consensus on Chronic GVHD scoring system.
Time Frame: 10 years
Severity graded from 0 to 3 as follows: 0: No symptoms; 1: mild dry eye symptoms not affecting activity of daily living (requiring eye drops ≤3 x per day); 2: Moderate dry eye symptoms partially affecting activity of daily living (requiring eye drops >3 x per day or punctal plugs) WITHOUT new vision impairment due to keratoconjunctivitis sicca; 3: Severe dry eye symptoms significantly affecting activity of daily living (special eyewear to relieve pain) OR unable to work because of ocular symptoms OR loss of vision due to keratoconjunctivitis sicca. Note: higher scores mean a worse outcome.
10 years
Number of participants requiring adjuvant treatment for ocular GVHD in patients receiving prophylactic tacrolimus or cyclosporine for ocular GVHD.
Time Frame: 2.5 years
e.g topical corticosteroids
2.5 years
Number of participants requiring adjuvant treatments for the Dry Eye Disease
Time Frame: 2.5 years
e.g.eye lubricant, artificial tears, autologous serum or autologous platelet-rich plasma in drops.
2.5 years
Incidence of other manifestations of acute and chronic GVHD, local or systemic, in patients receiving prophylactic treatment for ocular GVHD.
Time Frame: 2.5 years
With The National Institutes of Health (NIH) consensus criteria used to diagnose GVHD
2.5 years
Number of participants with topical tacrolimus related adverse events as assessed by a questionnaire for evaluation of adverse drug events
Time Frame: 1 year
Variables: frequency and severity (0-100) of burning sensation, pain, itching, discomfort, blurred vision, foreign body sensation, others.
1 year
Number of participants with topical cyclosporine related adverse events as assessed by a questionnaire for evaluation of adverse drug events
Time Frame: 1 year
Variables: frequency and severity (0-100) of burning sensation, pain, itching, discomfort, blurred vision, foreign body sensation, others.
1 year
Prevalence of Dry Eye Disease prior to the HSCT.
Time Frame: 2.5
Evaluation of dry eye symptoms with the ocular surface disease index (OSDI), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), tear breakup time, schirmer test.
2.5
Subtypes of Dry Eye Disease prior to the HSCT
Time Frame: 2.5
Evaluation of dry eye symptoms with the ocular surface disease index (OSDI), National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), tear breakup time, schirmer test.
2.5

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of ocular GVHD in patients receiving prophylactic treatment for ocular GVHD.
Time Frame: 2.5 years
Assessed by the Ocular Graft Versus Host Disease diagnostic criteria and grading scale according to the NIH criteria 2014 and the International Consensus Criteria on chronic ocular graft versus host disease (ICCGVHD)
2.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital Universitario Dr. Jose E. Gonzalez

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2023

Primary Completion (Estimated)

December 31, 2025

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

October 30, 2023

First Submitted That Met QC Criteria

March 28, 2024

First Posted (Actual)

April 4, 2024

Study Record Updates

Last Update Posted (Actual)

April 8, 2024

Last Update Submitted That Met QC Criteria

April 4, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PI23-00201

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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