Levodopa for the Treatment of Residual Amblyopia

Phase 3

Completed

Conditions: Amblyopia

Interventions: Drug: Levodopa/Carbidopa
Drug: Placebo
Other: Patching

Registration Number: NCT01190813

Lead Sponsor: Jaeb Center for Health Research

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of oral levodopa and patching versus oral placebo and patching as treatment for residual amblyopia in children 7 to \<13 years old with visual acuity of 20/50 to 20/400 in the amblyopic eye.

Detailed Description: Amblyopia is the most common cause of monocular visual impairment in both children and young and middle-aged adults. Both patching and atropine are accepted treatment modalities for the management of moderate amblyopia in children. Despite best efforts with conventional amblyopia treatment, many older children and teenagers with amblyopia fail to achieve normal visual acuity in the amblyopic eye. In a previous PEDIG study where children 7 to 12 years old were treated with atropine and patching, only 36% of the children with moderate amblyopia and only 23% of the children with severe amblyopia achieved 20/40 or better acuity.

Many clinicians have recognized that conventional therapies with patching and atropine have not been universally successful and have sought alternatives. PEDIG has discussed for several years the problem of residual amblyopia and how the remaining visual acuity deficit could be reduced. A number of research groups have evaluated the short term use of oral levodopa-carbidopa as an adjunct to patching therapy for older children.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 139

Inclusion Criteria

Age 7 to 12
Amblyopia associated with strabismus, anisometropia, or both
- Criteria for strabismus: One of the following criteria must be met: Heterotropia at distance and/or near fixation on examination (with or without spectacles); History of strabismus surgery; Documented history of strabismus which is no longer present (which in the judgment of the investigator could have caused amblyopia)
- Criteria for anisometropia: One of the following criteria must be met: ≥0.50 D difference between eyes in spherical equivalent; ≥1.50 D difference between eyes in astigmatism in any meridian
Visual acuity, measured in each eye (amblyopic eye without cycloplegia) within 7 days prior to enrollment using the E-ETDRS protocol by a study certified visual acuity tester as follows:
- Visual acuity in the amblyopic eye 18 to 67 letters inclusive (20/50 to 20/400)
- Visual acuity in the fellow eye ≥78 letters (20/25 or better)
Current amblyopia treatment (other than spectacles)
- 12 weeks of at least 2 hours of occlusion per day prescribed for the fellow eye during the immediate pre-enrollment period.
- While on current treatment, visual acuity has not improved one line (5 letters) or more since a non-study visit at least 6 weeks ago. Both acuity measurements to define no improvement must have been done using the same testing method.
- Treatment with atropine at any time during this pre-enrollment period is not allowed.
- Any treatment prior to the current patching episode with stable acuity is acceptable.
Spectacle correction (if applicable) for measurement of enrollment visual acuity must meet the following criteria and be based on a cycloplegic refraction that is no more than 6 months old:
1. Requirements for spectacle correction:
  - Spherical equivalent must be within 0.50 D of fully correcting the anisometropia.
  - Hypermetropia of 3.00D or more must be corrected.
  - Hypermetropia must not be under corrected by more than 1.50 D spherical equivalent, and reduction in plus sphere must be symmetric in the two eyes.
  - Cylinder power in both eyes must be within 0.50 D of fully correcting the astigmatism.
  - Cylinder axis in both eyes is within 6 degrees of the axis in the spectacles when cylinder power is ≥1.00 D.
  - Myopia of amblyopic eye greater than 0.50 D by spherical equivalent must be corrected, and the glasses must not under correct the myopia by more than 0.25 D or overcorrect it by more than 0.50 D.
2. Spectacles meeting above criteria must be worn :until visual acuity in amblyopic eye is stable (defined as 2 consecutive visual acuity measurements by the same testing method at least 4 weeks apart with no improvement of one line (5 letters) or more.
Eye examination within 6 months prior to enrollment
Parent available for at least one year of follow-up, has access to phone), and willing to be contacted by clinical site and Jaeb Center staff
In the investigator's judgment, the subject is likely to comply with prescribed treatment (e.g., no history of poor compliance with patching treatment) and unlikely to continue to improve by using 2 hours of patching per day alone.

Exclusion Criteria

Myopia more than -6.00 D (spherical equivalent) in either eye.
Current vision therapy or orthoptics
Ocular cause for reduced visual acuity
- nystagmus per se does not exclude the subject if the above visual acuity criteria are met
Prior intraocular or refractive surgery
History of narrow-angle glaucoma
Bronchial asthma or severe pulmonary disease
Strabismus surgery planned within 26 weeks
Known allergy to levodopa or carbidopa
History of dystonic reactions
Current use of oral iron supplements including multivitamins containing iron during treatment with levodopa-carbidopa
Current use of antihypertensive, anti-depressant medications, phenothiazines, butyrophenones, risperidone and isoniazid, non-specific monoamine oxidase inhibitors, or medication for the treatment of attention deficit hyperactivity disorder
Known liver disease
History of melanoma
Known psychological problems
Known skin reactions to patch or bandage adhesives
Prior levodopa treatment
Treatment with topical ophthalmic atropine within the past 12 weeks
A physician-prescribed diet high in protein
Females who are pregnant, lactating, or intend to become pregnant within the next 34 weeks.
- A negative urine pregnancy test will be required for all females who have experienced menarche.
- Requirements regarding pregnancy testing prior to enrollment may be further defined by each individual Institutional Review Board.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Levodopa/Carbidopa	Levodopa/Carbidopa	Levodopa 0.76 mg/kg with Carbidopa 0.17 mg/kg tid
Levodopa/Carbidopa	Patching	Levodopa 0.76 mg/kg with Carbidopa 0.17 mg/kg tid
Placebo	Placebo	Oral placebo tid
Placebo	Patching	Oral placebo tid

Primary Outcome Measures

Name	Time	Method
Distribution of Amblyopic Eye Visual Acuity Change From Baseline	18 weeks after enrollment	The primary outcome is the amblyopic eye visual acuity letter score measured at the 18-week primary outcome visit following a rapid taper of study medicine beginning at week 16. The primary analytic approach will be a treatment group comparison of the mean amblyopic eye visual acuity adjusted for baseline acuity. Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Amblyopic Eye Visual Acuity Change From Baseline	18 weeks after enrollment	The primary outcome is the amblyopic eye visual acuity letter score measured at the 18-week primary outcome visit following a rapid taper of study medicine beginning at week 16. The primary analytic approach will be a treatment group comparison of the mean amblyopic eye visual acuity adjusted for baseline acuity. Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.

Secondary Outcome Measures

Name	Time	Method
Amblyopic Eye Visual Acuity Improvement Treatment Group Comparison at 18 Weeks	18 weeks after enrollment	Treatment group comparisons of the proportion of subjects who have improved from baseline by 10 or more letters.
Distribution of Amblyopic Eye Visual Acuity at 18 Weeks	18 weeks after enrollment
Mean Amblyopic Eye Visual Acuity at 18 Weeks	18 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Amblyopic Eye Visual Acuity Improvement Treatment Group Comparison at 4 Weeks	4 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects who have improved from baseline by 10 or more letters.
Amblyopic Eye Visual Acuity Improvement Treatment Group Comparison at 10 Weeks	10 weeks after enrollment	Treatment group comparisons of the proportion of subjects who have improved from baseline by 10 or more letters.
Amblyopic Eye Visual Acuity Improvement Treatment Group Comparison at 16 Weeks	16 weeks after enrollment	Treatment group comparisons of the proportion of subjects who have improved from baseline by 10 or more letters.
Amblyopic Eye Visual Acuity Improvement Treatment Group Comparison at 26 Weeks	26 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects who have improved from baseline by 10 or more letters.
Amblyopia Resolutionat 4 Weeks	4 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects with 20/25 or better visual acuity.
Amblyopia Resolution at 10 Weeks	10 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects with 20/25 or better visual acuity.
Mean Fellow Eye Visual Acuity Change From Baseline at 18 Weeks	18 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Amblyopia Resolution at 16 Weeks	16 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects with 20/25 or better visual acuity.
Amblyopia Resolution at 18 Weeks	18 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects with 20/25 or better visual acuity.
Amblyopia Resolution at 26 Weeks	26 weeks after enrollment	Treatment group comparisons adjusted for baseline acuity scores using logistic regression of the proportion of subjects with 20/25 or better visual acuity.
Distribution of Amblyopic Eye Visual Acuity Change From Baseline at 4 Weeks	4 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Change in Amblyopic Eye Visual Acuity From Baseline at 4 Weeks	4 weeks after enrollment	A treatment group comparison of the mean amblyopic eye visual acuity at 4 weeks after enrollment, adjusted for baseline acuity.
Distribution of Amblyopic Eye Visual Acuity Change From Baseline at 10 Weeks	10 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Change in Amblyopic Eye Visual Acuity From Baseline at 10 Weeks	10 weeks after enrollment	A treatment group comparison of the mean amblyopic eye visual acuity at 10 weeks after enrollment, adjusted for baseline acuity. Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Distribution of Amblyopic Eye Visual Acuity Change From Baseline at 16 Weeks	16 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Change in Amblyopic Eye Visual Acuity From Baseline at 16 Weeks	16 weeks after enrollment	A treatment group comparison of the mean amblyopic eye visual acuity at 16 weeks after enrollment, adjusted for baseline acuity. Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Distribution of Amblyopic Eye Visual Acuity Change From Baseline at 26 Weeks	26 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Change in Amblyopic Eye Visual Acuity From Baseline at 26 Weeks	26 weeks after enrollment	A treatment group comparison of the mean amblyopic eye visual acuity at 26 weeks after enrollment, adjusted for baseline acuity. Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Distribution of Fellow Eye Visual Acuity at 18 Weeks	18 weeks after enrollment	Similar to the analysis for the amblyopic eye, the fellow eye visual acuity will be evaluated to determine if study treatment had an adverse effect on the occluded eye. The analysis will be a treatment group comparison of the mean fellow eye visual acuity at 18 weeks after enrollment, adjusted for baseline acuity.
Mean Fellow Eye Visual Acuity at 18 Weeks	18 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Distribution of Fellow Eye Visual Acuity Change From Baseline at 18 Weeks	18 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Child Symptom Survey Score at Enrollment	At enrollment	A treatment group comparison of symptom survey scores at enrollment. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Child Symptom Survey Score at 4 Weeks	4 weeks after enrollment	A treatment group comparison of symptom survey scores at the 4 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Child Symptom Survey Score at 10 Weeks	10 weeks after enrollment	A treatment group comparison of symptom survey scores at the 10 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Child Symptom Survey Score at 16 Weeks	16 weeks after enrollment	A treatment group comparison of symptom survey scores at the 16 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Child Symptom Survey Score at 18 Weeks	18 weeks after enrollment	A treatment group comparison of symptom survey scores at the primary outcome (18 week) visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Child Symptom Survey Score at 26 Weeks	26 weeks after enrollment	A treatment group comparison of symptom survey scores at the 26 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at Enrollment	At enrollment	A treatment group comparison of symptom survey scores at enrollment. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at 4 Weeks	4 weeks after enrollment	A treatment group comparison of symptom survey scores at the 4 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at 10 Weeks	10 weeks after enrollment	A treatment group comparison of symptom survey scores at the 10 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at 16 Weeks	16 weeks after enrollment	A treatment group comparison of symptom survey scores at the 16 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at 18 Weeks	18 weeks after enrollment	A treatment group comparison of symptom survey scores at the primary outcome (18 week) visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Parent Symptom Survey Score at 26 Weeks	26 weeks after enrollment	A treatment group comparison of symptom survey scores at the 26 week visit. The average of the overall item responses will be calculated and compared by treatment group with a t-test for difference in means. A higher number reflects a more negative response (5=always, 4=often, 3=sometimes, 2=rarely, 1=never).
Mean Systemic Adverse Events	Enrollment through 26 weeks
Distribution of Fellow Eye Visual Acuity at 26 Weeks	26 weeks after enrollment	Similar to the analysis for the amblyopic eye, the fellow eye visual acuity will be evaluated to determine if study treatment had an adverse effect on the occluded eye. The analysis will be a treatment group comparison of the mean fellow eye visual acuity at 26 weeks after enrollment, adjusted for baseline acuity.
Mean Fellow Eye Visual Acuity at 26 Weeks	26 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Distribution of Fellow Eye Visual Acuity Change From Baseline at 26 Weeks	26 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.
Mean Fellow Eye Visual Acuity Change From Baseline at 26 Weeks	26 weeks after enrollment	Visual acuity was measured in each eye (right eye first) by a study-certified VA tester using the Electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS©) visual acuity protocol. Five letters is equivalent to one logMAR line.