Cyclosporine Implant for Ocular Graft-Versus-Host Disease
| Status: | Completed |
|---|---|
| Conditions: | Orthopedic, Hematology |
| Therapuetic Areas: | Hematology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 9 - Any |
| Updated: | 4/21/2016 |
| Start Date: | October 2004 |
| End Date: | March 2011 |
A Phase I Clinical Trial to Study the Safety of a Sustained-Release Subconjunctival Cyclosporine Implant for Ocular Graft-vs-Host Disease (GVHD1)
Graft-vs.-Host Disease (GVHD) is a major complication of allogeneic hematopoietic stem cell
transplantation (SCT) commonly affecting the skin, liver, gastrointestinal tract, and eye.
The most common clinical manifestations of ocular GVHD generally result from
involvement of the lacrimal gland and the conjunctiva. Lacrimal gland involvement can lead
to aqueous tear deficiency resulting in severe keratoconjunctivitis sicca (KCS) which can
significantly increase the morbidity of patients with chronic GVHD.
Systemic immunosuppressants such as cyclosporine (CsA) can be effective for treating ocular
GVHD including lacrimal gland dysfunction. However, systemic immunosuppression is not
generally prescribed for patients whose sole manifestation of GVHD is ocular complications
as it may negate the overall graft-vs.-tumor effect and decrease patient survival. Topical
CsA and corticosteroids are generally not effective for treating aqueous tear deficiency
possible due to epithelial barriers preventing penetration of the drugs to the lacrimal
gland. A sustained-release subconjunctival CsA implant was developed to bypass these
epithelial barriers and significantly increase the CsA concentrations in the lacrimal gland
to treat aqueous tear deficiency related to GVHD.
The objective of this randomized pilot study is to investigate the safety and potential
efficacy of a CsA implant in patients with lacrimal gland involvement and aqueous tear
deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to
the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia).
Secondary efficacy evaluation will include changes in corneal and conjunctival staining
grades, best-corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI),
changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.
Patients with active systemic GVHD with aqueous tear deficiency associated with lacrimal
gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older
are eligible for inclusion in this pilot study. The study will involve surgical placement of
the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in
each participant. Participants older than 12 years of age will be randomized to receive one
of two implant release rates. All participants under the age of 12 will receive the smaller,
lower dose implant. However, all participants under age 12 will not be randomized and will
only be eligible to receive the smaller, lower dose implant.
The implant will remain in place for up to two years and then be removed. IF the participant
has clinical success, they will be given the option of allowing the implant to remain in
place for an additional year. Clinical success is achieved if the participant meets any of
the following measures in either eye assessed at the 1-year visit:
Interval change from baseline characteristics
Decrease in corneal staining by greater than or equal to 2
Decrease in temporal or nasal conjunctival staining grades by greater than or equal to 2
Decrease in total staining grade by greater than or equal to 2
Decrease in OSDI calculated score by greater than or equal to 20%
Increase in Schirmer tear test measurement by greater than or equal to 3 mm
Meets mild-moderate KCS characteristics at 1 year
Corneal staining grade less than or equal to 3
Nasal or temporal conjunctival staining grades less than or equal to 3
OSDI calculated score less than or equal to 15
Schirmer tear test measurement greater than or equal to 5 mm
For participants with implant duration of one year, safety evaluations will be conducted at
baseline (pre-implantation) and monthly post-implantation for 13 months. Additional safety
assessments will be done at 1 day, and at 1 and 2 weeks post-operatively for implant
placement and removal procedures. Safety and efficacy evaluations will be conducted at
baseline, at 1, 3, 6, 9, and 12 months post-implantation, and at 3 months following implant
removal (15 months post-implantation). For participants with clinical success and who choose
the implant to remain for another year, visits will be held as described above then
conducted at 2-month intervals starting at month 14. Safety evaluations will be conducted
every 2 months until the end of the second year. Additional safety assessments will be done
at 1 day, and at 1 and 2 weeks post-operatively for implant removal procedures. Safety and
efficacy evaluations will be conducted at 16, 20, and 24 months post-implantation, and at 3
months following implant removal (27 months post-implantation).
transplantation (SCT) commonly affecting the skin, liver, gastrointestinal tract, and eye.
The most common clinical manifestations of ocular GVHD generally result from
involvement of the lacrimal gland and the conjunctiva. Lacrimal gland involvement can lead
to aqueous tear deficiency resulting in severe keratoconjunctivitis sicca (KCS) which can
significantly increase the morbidity of patients with chronic GVHD.
Systemic immunosuppressants such as cyclosporine (CsA) can be effective for treating ocular
GVHD including lacrimal gland dysfunction. However, systemic immunosuppression is not
generally prescribed for patients whose sole manifestation of GVHD is ocular complications
as it may negate the overall graft-vs.-tumor effect and decrease patient survival. Topical
CsA and corticosteroids are generally not effective for treating aqueous tear deficiency
possible due to epithelial barriers preventing penetration of the drugs to the lacrimal
gland. A sustained-release subconjunctival CsA implant was developed to bypass these
epithelial barriers and significantly increase the CsA concentrations in the lacrimal gland
to treat aqueous tear deficiency related to GVHD.
The objective of this randomized pilot study is to investigate the safety and potential
efficacy of a CsA implant in patients with lacrimal gland involvement and aqueous tear
deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to
the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia).
Secondary efficacy evaluation will include changes in corneal and conjunctival staining
grades, best-corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI),
changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.
Patients with active systemic GVHD with aqueous tear deficiency associated with lacrimal
gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older
are eligible for inclusion in this pilot study. The study will involve surgical placement of
the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in
each participant. Participants older than 12 years of age will be randomized to receive one
of two implant release rates. All participants under the age of 12 will receive the smaller,
lower dose implant. However, all participants under age 12 will not be randomized and will
only be eligible to receive the smaller, lower dose implant.
The implant will remain in place for up to two years and then be removed. IF the participant
has clinical success, they will be given the option of allowing the implant to remain in
place for an additional year. Clinical success is achieved if the participant meets any of
the following measures in either eye assessed at the 1-year visit:
Interval change from baseline characteristics
Decrease in corneal staining by greater than or equal to 2
Decrease in temporal or nasal conjunctival staining grades by greater than or equal to 2
Decrease in total staining grade by greater than or equal to 2
Decrease in OSDI calculated score by greater than or equal to 20%
Increase in Schirmer tear test measurement by greater than or equal to 3 mm
Meets mild-moderate KCS characteristics at 1 year
Corneal staining grade less than or equal to 3
Nasal or temporal conjunctival staining grades less than or equal to 3
OSDI calculated score less than or equal to 15
Schirmer tear test measurement greater than or equal to 5 mm
For participants with implant duration of one year, safety evaluations will be conducted at
baseline (pre-implantation) and monthly post-implantation for 13 months. Additional safety
assessments will be done at 1 day, and at 1 and 2 weeks post-operatively for implant
placement and removal procedures. Safety and efficacy evaluations will be conducted at
baseline, at 1, 3, 6, 9, and 12 months post-implantation, and at 3 months following implant
removal (15 months post-implantation). For participants with clinical success and who choose
the implant to remain for another year, visits will be held as described above then
conducted at 2-month intervals starting at month 14. Safety evaluations will be conducted
every 2 months until the end of the second year. Additional safety assessments will be done
at 1 day, and at 1 and 2 weeks post-operatively for implant removal procedures. Safety and
efficacy evaluations will be conducted at 16, 20, and 24 months post-implantation, and at 3
months following implant removal (27 months post-implantation).
The objective of this randomized pilot study is to investigate the safety and potential
efficacy of a CsA implant in participants with lacrimal gland involvement and aqueous tear
deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to
the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia).
Secondary efficacy evaluation will include changes in corneal and conjunctival staining
grades, best-corrected visual acuity (BCVA), the Ocular Surface Diseases Index (OSDI),
changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.
Participants with active systemic GVHD with aqueous tear deficiency associated with lacrimal
gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older
are eligible for inclusion in this pilot study. The study will involve surgical placement of
the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in
each participant. Participants older than 12 years of age will be randomized to receive one
of two implant release rates. However, all participants under age 12 will not be randomized
and will only be eligible to receive the smaller, lower dose implant. On each anniversary
study visit a participant will be given the opportunity to retain the implant on an annual
basis. This will be based upon the determination of clinical success (defined in the Study
Design section below) combined with a participant's report of symptom improvement. The
Implant will be removed if the Investigator believes the implant is harmful or if the
participant requests the implant to be removed.
efficacy of a CsA implant in participants with lacrimal gland involvement and aqueous tear
deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to
the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia).
Secondary efficacy evaluation will include changes in corneal and conjunctival staining
grades, best-corrected visual acuity (BCVA), the Ocular Surface Diseases Index (OSDI),
changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.
Participants with active systemic GVHD with aqueous tear deficiency associated with lacrimal
gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older
are eligible for inclusion in this pilot study. The study will involve surgical placement of
the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in
each participant. Participants older than 12 years of age will be randomized to receive one
of two implant release rates. However, all participants under age 12 will not be randomized
and will only be eligible to receive the smaller, lower dose implant. On each anniversary
study visit a participant will be given the opportunity to retain the implant on an annual
basis. This will be based upon the determination of clinical success (defined in the Study
Design section below) combined with a participant's report of symptom improvement. The
Implant will be removed if the Investigator believes the implant is harmful or if the
participant requests the implant to be removed.
- INCLUSION CRITERIA:
To be eligible for the study each participant must satisfy all of the following inclusion
criteria:
- Male or female greater than or equal to 9 years of age.
- Must be greater than or equal to 30 days post-hematopoietic stem cell transplantation
(SCT) and have systemic GVHD diagnosed by the transplant physician.
- Must have lacrimal gland dysfunction from GVHD following SCT as defined by Schirmer
tear test score (with anesthesia) of greater than or equal to 1 mm but less than or
equal to 9 mm in both eyes.
- Must have open puncta and no puncta plug placement at the time of enrollment.
- If using topical corticosteroids, must be equal dose in both eyes of less than or
equal to 4 drops per day.
- Topical lubrication using tear substitutes (includes eye drops, gels, and ointments)
are permitted with equal dosing in both eyes.
- Must understand and sign informed consent or assent.
- Must be willing and able to comply with study evaluation and testing schedule.
- Females of childbearing potential and all males must agree to use an effective form
of birth control for duration of the study.
- Females of childbearing potential must have a negative serum pregnancy test at
baseline evaluation.
EXCLUSION CRITERIA:
To be eligible for the study, participants must not satisfy any of the following exclusion
criteria.
- Use of a topical ophthalmic cyclosporine formulation less than or equal to 30 days
prior to enrollment.
- Diagnosed with active ocular infection.
- History of recurrent herpes keratitis or active disease less than or equal to 6
months prior to enrollment.
- Aqueous tear deficiency or KCS related to previous irradiation, Stevens-Johnson
syndrome, cicatricial pemphigoid, alkali burns, trachoma or Sjogren's syndrome.
- Seropositive for Hepatitis C (i.e. positive anti-HCV antibody) or seropositive for
HIV with testing performed no earlier than 4 months before the date of stem cell
transplantation.
- Diagnosis of active sarcoidosis.
- Use of a drug with anticholinergic activity within less than 4 times the half-life of
the drug prior to enrollment (e.g., carbamazepine [Tegretol (R)] has a half-life of
16-24 hours so must not be used within 4 days of enrollment).
- Use of an investigational drug for eye disease within 30 days of enrollment.
- Known allergy or hypersensitivity to cyclosporine, fluorescein, or lissamine green.
- Uncontrolled systemic disease or serious illness that could, in the investigator's
opinion, interfere with the participant's ability to comply with study therapy,
required follow-up testing, or interfere with interpretation of the study results.
- Pregnant or lactating female.
- Serum creatinine greater than 2.5 mg/dL, absolute neutrophil count (ANC) less than
750/MicroL Platelet count less than 25,000/MicroL, Partial Thromboplastin Time (PTT),
or International Normal Ratio (INR) or Prothrombin Time (PT) exceeding the
institutional upper limit of normal would require review by the Hematologist for
surgical clearance. Hematologist review of the abnormal coagulation value and
approval for surgery must be documented in the medical record prior to the surgical
procedure.
- Participants that have received total body irradiation or direct eye/orbital
radiation greater than 5000 cGy. (Potential participants will be assessed by a study
clinician to determine that the cause of the dry eye symptoms is due to GVHD and not
radiation. The clinician, in conjunction with the oncology staff as needed, will also
assess the participant's clinical exam and medical history).
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Click here to add this to my saved trials
