L-DOPA AND AMBLYOPIA

SUMMARY

For about 10 years now we have known that oral L-Dopa medicine has an effect on the vision in eyes that are amblyopic. Initially the work was done on adults with amblyopia. More recently the work has been done in children.

Similar work has been done in Europe with a similar (injectable) medicine called Citicholine, with similar results.

It will be some years before the exact effect of L-Dopa in amblyopia will be known in a predictable and practical way. We unfortunately cannot reliably predict in your case (or your child's case) if L-Dopa will be useful and how useful. We only know that when we treat numbers of patients the L-Dopa produces a visual improvement greater than dummy pills in some.

L-Dopa is used in very much higher doses for the treatment of Parkinson's disease. In the low doses it has been used for treatment of amblyopia the commonest side effect is nausea. Some patients have a small drop in body temperature. I have had one patient who demonstrated "behavioural disturbance" for the first week of L-Dopa treatment (which was continued). A colleague of mine had one 9 year old who had depression which cleared within 24 hours of stopping the L-Dopa. No side-effects of this sort were recognised in the large Ohio series (see inside).

The duration of treatment is uncertain. It should probably be used for about 6 weeks to begin with.

This is being offered to you outside of a research protocol because Dr Kowal believes that sufficient research has been done on this medicine to show that it is probably effective. The research that remains to be done includes:

1. In which subgroups of amblyopes is it more likely to be more effective?
2. What is the ideal dose?
3. What is the ideal duration of treatment?

We have provided the information from the Sydney and Ohio groups for your interest and invite discussion.

We point out that there is absolutely no compulsion to use this medicine. It has been recommended as being probably effective. As far as it is known the medicine is safe in the doses given for the duration given.

This information handout is protected by the laws of Copyright and must not be reprinted, copied or otherwise disclosed in whole or in part to any person without the written consent of Dr. Lionel Kowal.

LEVODOPA AMBLYOPIA STUDY
Stephen Hing and Kim Johnson
New Children's Hospital

Protocol
Aim
To determine whether the results of standard occlusion treatment (patching) can be improved by the addition of Levodopa in children 4-8 yrs with amblyopia.

Description
Children aged 4-8 yrs who present with reduced vision in one eye to a level of 6/18 or worse, and who have not undergone any form of amblyopia treatment before, will be randomly allocated to one of two groups.

i) Control group - Traditional amblyopia treatment, patching of the sound eye
4 hrs/day, 5 days a week & placebo t.d.s.

ii) Treatment group - Oral Levodopa (sinemet) t.d.s. as well as the same occlusion regimen.

Double blind study.
VA will be tested at 1 month, at 2 months and 1 month after cessation of Levodopa. Patching will be continued in both groups up until the last month (3rd month). VA will be measured using the Logmar chart (log Minimum Angle of Resolution).

Parents are provided with an information sheet and informed consent must be obtained for each child.

Eligibility
- From NCH eye clinic or private Ophthalmology rooms.
- Worn gls for at least one month prior to starting study.
- VA 6/18 or worse and normal VA in the other eye.
- No previous amblyopia treatment.
- VA reduced due to refractive or strabismic amblyopia only. Children with occlusion amblyopia (eg cataract, haemangioma) and myopic anisometropic amblyopia are ineligible.
- Patients taking any form of medication will be excluded.

Dosage
Levodopa 0.5mg per kilo, Carbidopa 0.12mg per kilo t.d.s. (Levodopa to Carbidopa ratio
4 : 1).
Patients divided into three groups:-
1) 14 - 20kg 8mg
2) > 20 - 26kg 11.5mg
3) > 26 - 32kg 14.5mg

CHILDREN'S HOSPITAL RESEARCH FOUNDATION
Columbus, Ohio 43205

ABSTRACT OF THE PROPOSED STUDY

THE TITLE OF THE STUDY IS: L-Dopa Augmentation of Occlusion Therapy for Amblyopia

PRINCIPAL INVESTIGATOR(S): Lawrence E Leguire, Ph.D

1. GOAL(S)/SIGNIFICANCE:
The goal of the present study is to determine whether Levodopa/carbidopa (L-dopa) can be used to augment standard occlusion therapy for newly diagnosed amblyopic children in order to; 1) speed the recovery of vision; 2) improve compliance with occlusion; and 3) shorten the duration of occlusion therapy.

2. BACKGROUND INFORMATION
For the past nine years, Leguire et al have pioneered the use of L-dopa to augment occlusion therapy in older amblyopic children who were no longer helped by occlusion alone. Overall, they have found that seven-weeks of L-dopa + occlusion therapy can improve visual acuity by about 37% in children who were no longer helped by occlusion therapy alone (Leguire et al 1992, 1993a, b, 1995, 1998a). These results have recently received national/international attention and news reports have appeared in numerous newspapers in the U.S.A. and Canada. Investigators from around the world are starting to evaluate the use of L-dopa as an adjunct to occlusion therapy in children with amblyopia (Proianoy et al, 1999, Basmak et al, 1999; Gottlob et al, 1995). Ophthalmologists from around the world have started treating certain amblyopic patients and numerous paediatric ophthalmologists in the U.S.A. have expressed a keen interest in a multicentre clinical trial.

To date, most of the L-dopa studies undertaken by Leguire et al have been directed at amblyopic children who are no longer helped by standard occlusion therapy, between 4 and 15 years of age. This work has lead to the finding that the major metabolite of L-dopa, dopamine, has a major effect on retinal function. As a consequence Leguire et al have also investigated the effects of L-dopa on visual function in children with untreatable retinal degenerations (Leguire et al, 1998b).

The present study deals with newly diagnosed amblyopic children between 4 and 9 years of age (inclusive).

An integral part in all of the L-dopa studies undertaken to date by Leguire et al has been the assessment of possible side effects. In the standard protocol in longitudinal dosing studies, Leguire et al have periodically measured vital signs (heart rate, respiration, oral body temperature, blood pressure), weight, height and the subjects were questioned about how they feel. At baseline and at the end of the dosing regime, blood samples were performed including CHEM 20 and CBC with differential. Overall, the subjects tolerated the L-dopa very well. No changes have been observed, following seven-weeks of L-dopa oral administration, in the CHEM 20 or CBC with differential. The only statistically significant change during L-dopa dosing that was observed was a change in oral body temperature (Leguire et al 1995), which returned to baseline following the end of the dosing regimen. In subsequent studies (Leguire et al, unpublished data), dosage was for 12 weeks. The Leguire et al research group is considered the world leader in terms of assessing potential side-effects and tolerance of L-dopa in a paediatric population. In addition, Leguire and colleagues have developed a liquid formation of L-dopa (Nahada et al, under review) so that younger children do not have to take the L-dopa in pill or capsule form.

3. STUDY POPULATION:
The study population will consist of newly diagnosed amblyopic children between 4 and 9 years of age, inclusive. Subjects will be in otherwise good health, except for their amblyopia. Subjects will be randomized into placebo or L-dopa group based on visual acuity.

4. METHOD:
The study is a double masked, placebo controlled, pseudo-randomized 12-week longitudinal dosing study. The total duration of participation, with follow-up, is 48 weeks. Three standard vision tests are proposed; monocular visual acuity in each eye, stereoacuity and binocular fusion. These are non invasive behavioral (psychophysical) tests that take about 15 minutes to complete at each of the test sessions. Health status and tolerance/side effects will be assessed by subjective questionnaire (at baseline and weeks 2,4, 8 and 12 after the onset of the study). Occlusion compliance and occlusion tolerance will be assessed by parent questionnaire. Drug compliance will be assessed by measuring the remaining amount of drug in the bottle following the end of the 12 weeks dosage regimen.

Subjects will start in the study at the onset of their standard therapy for amblyopia, which is full-time occlusion (FTO). FTO usually lasts at least 12 weeks. At the onset of FTO, subjects will be randomized based on visual acuity in the amblyopic eye into an L-dopa or placebo group. Subjects will receive L-dopa based on body weight and will average 75mg/kg body weight t.i.d. for 12 weeks in liquid form. This dosage is the same or about 25% less than that used in the previous L-dopa studies, and is known to be an effective and well tolerated dosage. Subjects will be seen periodically for the vision tests and health status questionnaire and long-term follow up will last 48 weeks (total of seven test sessions). The test sessions occur at baseline (0), and at weeks 4, 8, 12, 24, 36 and 48 after the start of FTO.

Based on a power analysis, it is estimated that between 120 and 240 subjects will have to be run in the present study, depending on the specific parameter estimates. It is estimated that it will take two years to complete the present study with an N=240 and assuming a 10% drop-out rate. Drop-out rates in the previous longitudinal studies have been less than 10%.

5. RISKS:
Risks of the present study are limited to the L-dopa. Risks related to the L-dopa in decreasing prevalence include (from date compiled by Leguire et al from 5 studies) headaches, tiredness, mood changes, nausea, dizziness, dry mouth, emesis (once per 1500 ingested capsules), restlessness and nightmares. Other side effects with L-dopa ingestion occur rarely or with much larger doses as reported in the adult (Parkinson's disease) literature. Leguire et al have not observed any changes in the standard laboratory tests of the 41 paediatric subjects tested to date.

6. RISK MINIMISATION:
L-dopa dosage is based on body weight and is considered to be in the effective therapeutic range based on previous studies. Subjects are instructed to take the individual dose with a meal or snack
to minimize nausea and emesis. The liquid formulation will be used in the present study to ease dosing requirements. Subjects are given two cans of Sustacal or Ensure, a high protein drink, and instructed to drink one can in the event of possible adverse side effects. Based on case reports, high protein substances (e.g. Sustacal) compete for transport with L-dopa in the gut and at the blood-brain barrier and reduce the pharmacodynamics of L-dopa and presumably the adverse side-effects.

7. BENEFITS:
Occlusion therapy is a very traumatic therapy for the patient and family, and leads to family stress, peer teasing and poor treatment compliance (Leguire et al, under revision). Occlusion therapy is also very long; it may last several months to several years! Based on the Leguire et al research to date, we hypothesize that if we combine standard occlusion therapy with L-dopa therapy that it may be possible to facilitate the recovery of vision, which would improve occlusion compliance and lead to a shorter occlusion treatment duration. A shorter occlusion duration would also reduce the need for office visits and thereby reduce health care costs.

8. CONSENT:
fully informed, signed consent will be obtained from the parent(s) and, if possible, assent from the child after the study protocol and consent forms are reviewed with the parent(s) and child. The study coordinator at each site will obtain consent. Informed consent will be obtained usually in the Eye Clinic or in the private practice offices of the project paediatric ophthalmologists.

9. IMPORTANCE:
About 3% of children develop amblyopia (120,000/yr in the USA) and many never regain normal vision in the amblyopic eye or regain binocular vision. Occlusion has been the standard therapy for amblyopia for over 200 years, and the L-dopa research with older amblyopic children is the first new therapy that has been shown to be effective against amblyopia in older children. If the present proposed project is successful, occlusion + L-dopa treatment could become the new standard for the treatment of childhood amblyopia.

10. PREGNANCY:
Not applicable.

11. DATE/SITE:
June 1, 2000 - May 30, 2003.
Sites: Children's Hospital, Columbus, OH; Other sites to be arranged.

12. JUSTIFICATION FOR THE USE OF "WELL SUBJECTS"
Not applicable.

13. ADVERTISING:
Not applicable.

14. MONETARY COMPENSATION:
None. Parents will receive a box of patches/week for the 12 weeks dosing and occlusion portion of the study (12 boxes/patient with estimated value of $60.00). Parents will also receive two cans of a high protein drink (either Sustacal or Ensure) (estimated value of $2.00/can) with option of free additional cans as needed.

References (L-dopa Protocol)

Basmak H, Yildirim N, Erdinc), Yurdakul S, Ozdemir G: Effect of Levodopa therapy on visual evoked potentials and visual acuity in amblyopia.
Ophthalmologica, 1999; 213(2):110-3. German.

Gottlob I: The detection, prevention and rehabilitation of amblyopia.
Curr Opin Opthalmol. 1999 Oct; 10(5):300-4. Review.

Gottlob 1, Wizov SS, Reinecke RD: Visual acuities and scotomas after 3 week' Levodopa administration in adult amblyopia.
Graefes Arch Clin Exp Ophthalmol. 1995 Jul; 233(7):407-13.

Campos EC, Schiavi C, Benedetti P, Bolzani R, Porciatti V: Effect of citicoline on visual acuity in amblyopia: preliminary results. Graefes Arch Clin Exp Ophthalmol. 1995 May;233(5):307-12.

Leguire, L.E., Rogers, G.L., Bremer, D.L., Walson, P., Neff, M: Levodopa and Childhood Amblyopia. Journal of Paediatric Ophthalmology and strabismus, 29:290-298, 1992.

Leguire, L.E., Rogers, G.L., Bremer, D.L., Walson, P.D., and McGregor, M.L.:
Levodopa/Carbidopa for Childhood Amblyopia. Investigative Ophthalmology and Visual Science, 34: 3090-3095, 1993a.

Leguire, L.E., Walson, P., Rogers, G.L., Bremer, D.L. and McGregor, M.L.: Longitudinal Study of Levodopa/Carbidopa for Childhood Amblyopia J Ped Ophthalmol & Strab, 30:354-360, 1993b.

Leguire, L.E., Nairus, T and Walson, P.: Influence of Levodopa/Carbidopa on Body Temperature in Children. Current Therapeutic Research, 56:333-340, 1995a.

Leguire L.E., Walson, P., Rogers, G.L., Bremer, D.L. and McGregor, ML.: Levodopa/Carbidopa Treatment for Amblyopia in Older Children. Journal of Paediatric Ophthalmology and Strabismus, 32:143-151, 1995b.

Leguire L.E., Treating Older Children with Intractable Lazy Eye. A compilation of papers presented at the 13th Biennial Eye Research Seminar. Research to Prevent Blindness, p37-39, 1995.

Leguire, L.E., Rogers G.L., Walson, P.D., Bremer, D.L., McGregor, M.L.: Occlusion and Levodopa - Carbidopa Treatment for Childhood Amblyopia. Journal of the AAPOS, 2(5): 1-7, 1998a.

Leguire, L.E., Jende D.L., Nairus, T.M., Walson, P.D., Rogers, G.L., Bremer, D.L. and McGregor, M.L.: Levodopa - Carbidopa and Childhood Retinal Disease. Journal of the AAPOS, 2(2): 79-85, 1998b.

Procianoy E, Fuchs FD, Procianoy L, Procianoy F.: The effect of increasing doses of Levodopa on children with strabismic amblyopia. J AAPOS. 1999 Dec; 3(6): 337 - 40.

Porciatti V, Schiavi C, Benedetti P, Baldi A, Campos EC.: Cytidine - 5 - diphosphocholine improves visual acuity, contrast sensitivity and visually-evoked potentials of amblyopic subjects.
Curr Eye Res. 1998 Feb; 17(2):141-8.

 

PREPARING SOLUTION OF L-DOPA

Need: - A measuring jug marked at 500ml

- Ascorbic acid (vitamin C) powder (Bioglan brand)

- Freshly boiled and cooled water

- Sinemet 100/25 tablets

Method: - Prepare fresh solution daily

- Measure 500ml of water in jug

- Add ¼ teaspoon (1 gram) ascorbic acid powder

- Stir to dissolve

- Add five Sinemet 100/25 tablets. This produces a concentration of 1 mgm/ml

- Stir to dissolve

- Store with lid on or transfer to a covered container

- Shake the bottle or stir mixture before taking a dose. Doses should be:

1. Weight 14-20 kg:8 ml
2. Weight 20-26 kg:12 ml
3. Weight 26-32 kg:14 ml

These should be measured out in a measuring cup or with a syringe and taken 3 times a day.

At the end of the day discard any remaining solution.