Nitisinone for Type 1B Oculocutaneous Albinism

NCT01838655 | Completed Phase 1 Results

• 2 other identifiers: 13012413-EI-0124
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Oculocutaneous albinism, type 1B (OCA1B) is a genetic disease caused by problems in the gene that makes tyrosine. Tyrosine is an amino acid needed to produce pigment in the skin, hair, and eyes. People with OCA1B have pale skin, white hair, and light-colored eyes. Pigment in the back of the eye helps vision, so people with OCA-1B often have visual problems. Researchers want to see if a drug called nitisinone can help improve eye pigmentation and vision in people with OCA1B. Nitisinone is approved for treating a related genetic disease that causes problems with tyrosine, so it may help people with OCA1B. Objectives: \- To see if nitisinone can help improve eye pigmentation and vision in people with OCA1B. Eligibility: \- Individuals at least 18 years of age who have OCA1B. Design:

• This study will last about 18 months. It requires eight outpatient visits, each about 3 months apart. Each visit will require 1 to 2 days of testing.
• Participants will be screened with a physical exam, eye exam, and medical history. They will have additional vision and neurological tests. They will be tested to see how their brain and retinas respond to light. They will also take hair and blood samples, and answer questions about diet.
• Participants will receive the study drug. They will take one pill a day for 1 year. They will keep track of the dose in a study diary.
• At the outpatient visits, participants will have the following tests:
• Medical history and physical exam
• Neurological and eye exams
• Retina function tests
• Tests of the skin and brain's response to light
• Blood and urine tests
• Dietary consultation
• Visual function questionnaire.
• After the end of the study, participants will return to the care of their regular eye doctor.

Conditions

Albinism; Vision Loss

Keywords

Albinism; Nitisinone; Melanin; Vision Loss

Outcome Measures

Primary Outcomes (1)

• Absolute Mean Change in Iris Pigmentation on an 8-point Iris Transillumination Scale at 12 Months as Compared to Baseline. Participants Left and Right Eyes Will be Analyzed.

  High-resolution (2544x1696) digital images of the anterior segment of both eyes were captured prior to pupil dilation using diffuse illumination and iris transillumination. An independent reviewer selected two transillumination images from each eye of each participant for each visit according to preset quality criteria. Images were coded, randomized and presented to a panel of 18 graders on a SHARP 90" HD LED TV. After instruction and a practice dataset, graders scored each image using an 8-point scale. Graders could score images with a single decimal place if they felt an image fell in between two of the standards. The iris transillumination scale ranged from 0 to 8, with lower scores reflective of greater iris pigmentation (melanin content). The mean across all graders and the two images for each participant's eye at baseline and 12 months was calculated; these mean grades were then used to calculate absolute change from baseline at 12 months.

  Baseline and 12 months

Secondary Outcomes (59)

• Absolute Mean Change in Iris Pigmentation on an 8-point Iris Transillumination Scale at 3 Months as Compared to Baseline. Participants Left and Right Eyes Will be Analyzed.

  Baseline and 3 months

• Absolute Mean Change in Iris Pigmentation on an 8-point Iris Transillumination Scale at 6 Months as Compared to Baseline. Participants Left and Right Eyes Will be Analyzed.

  Baseline and 6 months

• Absolute Mean Change in Iris Pigmentation on an 8-point Iris Transillumination Scale at 9 Months as Compared to Baseline. Participants Left and Right Eyes Will be Analyzed.

  Baseline and 9 months

• Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 3 Months as Compared to Baseline

  Baseline and 3 months

• Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 6 Months as Compared to Baseline

  Baseline and 6 months

Other Outcomes (5)

• Number of Ocular Adverse Events

  Study duration, up to 18 months

• Number of Non-ocular Adverse Events

  Study duration, up to 18 months

• Severity of Adverse Events

  Study duration, up to 18 months

Study Arms (1)

Nitisinone

EXPERIMENTAL

Oral administration of nitisinone

Drug: Nitisinone

Interventions

Nitisinone DRUG

Oral dose of 2mg daily for 12 months.

Also known as: Orfadin

Nitisinone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant must be 18 years of age or older.
• Participant must understand and sign the protocol s informed consent document.
• Participant must have normal renal function, liver function, and platelet counts or have mild abnormalities no greater than grade 1 as defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE).
• Any female participant of childbearing potential must have a negative pregnancy test at screening and must be willing to undergo pregnancy testing immediately prior to the start of the investigational product and while on the investigational product.
• Any female participant of childbearing potential and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or must agree to practice two effective methods of contraception while taking the investigational product and for at least two months following the last dose of investigational product. Acceptable methods of contraception include:
• Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch, or vaginal ring),
• Intrauterine device,
• Barrier methods (diaphragm, condom) with spermicide, or
• Surgical sterilization (tubal ligation).
• Participant must have OCA1B, as defined by ALL (a-d) of the following criteria:
• Participant has ophthalmic signs or symptoms of albinism, including:
• Bilateral visual acuity E-ETDRS EVA letter score of less than or equal to 83 (i.e., Snellen equivalent of 20/25 or worse) that is not attributable to any other pathology.
• Bilateral iris transillumination that can be seen in clinical photographs.
• Predominant contralateral decussation of ganglion cell axons, as determined by pattern visual evoked potential (VEP).
• Participant has at least one definitive mutation in the OCA1 gene (tyrosinase).

You may not qualify if:

• Participant is pregnant or breast-feeding.
• Participant is a male AND has a definitive mutation in the OA1 gene.
• Participant has any of the following abnormal laboratory test results:
• Serum potassium \< 3.0 mEq/L,
• Serum CK \> 500 U/L,
• Hemoglobin \< 10.0 g/dL,
• White blood cell (WBC) count \< 3.0 k/microL,
• Plasma tyrosine \> 150 microM,
• ESR \> 100 mm/h, and/or
• Serum T4 \> 15 microg/dL OR Serum T4 \< 4 microg/dL.
• Participant has keratopathy.
• Participant has a current malignancy.
• Participant has open skin lesions.
• Participant is on a diet that deliberately increases protein intake to disproportionate levels (e.g., Atkins diet). The diet must be reasonably balanced, as determined by a dietician.
• Participant has uncontrolled hypertension, defined as systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg.

Sponsors & Collaborators

• National Eye Institute (NEI): lead
• National Human Genome Research Institute (NHGRI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Hertle RW, Anninger W, Yang D, Shatnawi R, Hill VM. Effects of extraocular muscle surgery on 15 patients with oculo-cutaneous albinism (OCA) and infantile nystagmus syndrome (INS). Am J Ophthalmol. 2004 Dec;138(6):978-87. doi: 10.1016/j.ajo.2004.07.029.

  PMID: 15629289 BACKGROUND

• Giebel LB, Tripathi RK, King RA, Spritz RA. A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse. J Clin Invest. 1991 Mar;87(3):1119-22. doi: 10.1172/JCI115075.

  PMID: 1900309 BACKGROUND

• Giebel LB, Tripathi RK, Strunk KM, Hanifin JM, Jackson CE, King RA, Spritz RA. Tyrosinase gene mutations associated with type IB ("yellow") oculocutaneous albinism. Am J Hum Genet. 1991 Jun;48(6):1159-67.

  PMID: 1903591 BACKGROUND

• Adams DR, Menezes S, Jauregui R, Valivullah ZM, Power B, Abraham M, Jeffrey BG, Garced A, Alur RP, Cunningham D, Wiggs E, Merideth MA, Chiang PW, Bernstein S, Ito S, Wakamatsu K, Jack RM, Introne WJ, Gahl WA, Brooks BP. One-year pilot study on the effects of nitisinone on melanin in patients with OCA-1B. JCI Insight. 2019 Jan 24;4(2):e124387. doi: 10.1172/jci.insight.124387.

  PMID: 30674731 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Albinism; Vision Disorders

Interventions

nitisinone

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Skin Diseases, Genetic; Hypopigmentation; Pigmentation Disorders; Skin Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Brian Brooks, MD, PhD, Principal Investigator, NEI
• Organization: National Institutes of Health

brian.brooks@nih.gov

301-451-2238

Study Officials

• Brian P Brooks, M.D.

  National Eye Institute (NEI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2013
• First Posted: April 24, 2013
• Study Start: April 16, 2013
• Primary Completion: July 11, 2016
• Study Completion: February 7, 2017
• Last Updated: February 26, 2019
• Results First Posted: November 17, 2017

Record last verified: 2017-10

Locations

US (1)