Trial Outcomes & Findings for Nitisinone for Type 1B Oculocutaneous Albinism (NCT NCT01838655)

NCT ID: NCT01838655

Last Updated: 2019-02-26

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 5 participants
• Primary outcome timeframe: Baseline and 12 months
• Results posted on: 2019-02-26

Participant Flow

Five participants with OCA1B will be enrolled initially. However, up to an additional three participants may be enrolled to account for participants who withdraw from the study for any reason before the Month 12 visit.

Participant milestones

Measure	Nitisinone Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Overall Study STARTED	5
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Nitisinone for Type 1B Oculocutaneous Albinism

Baseline characteristics by cohort

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	38.8 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 12 months

Population: Right (OD) and left (OS) eyes

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.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
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. OD	1.2 scores on a scale Standard Deviation 1.68
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. OS	0.9 scores on a scale Standard Deviation 1.52

SECONDARY outcome

Timeframe: Baseline and 3 months

Population: Right (OD) and left (OS) eyes

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 3 months was calculated; these mean grades were then used to calculate absolute change from baseline at 3 months.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
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. OD	0.8 scores on a scale Standard Deviation 1.04
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. OS	0.9 scores on a scale Standard Deviation 1.23

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Right (OD) and left (OS) eyes

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 6 months was calculated; these mean grades were then used to calculate absolute change from baseline at 6 months.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 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. OD	0.6 scores on a scale Standard Deviation 0.39
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. OS	0.4 scores on a scale Standard Deviation 0.31

SECONDARY outcome

Timeframe: Baseline and 9 months

Population: Right (OD) and left (OS) eyes

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 9 months was calculated; these mean grades were then used to calculate absolute change from baseline at 9 months.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 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. OD	0.9 scores on a scale Standard Deviation 1.06
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. OS	0.6 scores on a scale Standard Deviation 0.60

SECONDARY outcome

Timeframe: Baseline and 3 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 3 months; these mean grades were then used to calculate absolute change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 3 Months as Compared to Baseline OD	1.2 scores on a scale Standard Deviation 1.04
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 3 Months as Compared to Baseline OS	0.6 scores on a scale Standard Deviation 0.82

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 6 months; these mean grades were then used to calculate absolute change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 6 Months as Compared to Baseline OD	0.4 scores on a scale Standard Deviation 0.55
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 6 Months as Compared to Baseline OS	0.1 scores on a scale Standard Deviation 0.22

SECONDARY outcome

Timeframe: Baseline and 9 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 9 months; these mean grades were then used to calculate absolute change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 9 Months as Compared to Baseline OD	0.8 scores on a scale Standard Deviation 0.76
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 9 Months as Compared to Baseline OS	0.7 scores on a scale Standard Deviation 0.84

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 12 months; these mean grades were then used to calculate absolute change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 12 Months as Compared to Baseline OD	1.4 scores on a scale Standard Deviation 1.39
Absolute Change in Semi-quantitative Iris Pigmentation for Each Eye at 12 Months as Compared to Baseline OS	1.2 scores on a scale Standard Deviation 1.15

SECONDARY outcome

Timeframe: Baseline and 3 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 3 months; these mean grades were then used to calculate percentage change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 3 Months as Compared to Baseline OD	66.7 percentage change Standard Deviation 51.37
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 3 Months as Compared to Baseline OS	29.0 percentage change Standard Deviation 41.29

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 6 months; these mean grades were then used to calculate percentage change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 6 Months as Compared to Baseline OD	23.3 percentage change Standard Deviation 32.49
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 6 Months as Compared to Baseline OS	4.0 percentage change Standard Deviation 8.94

SECONDARY outcome

Timeframe: Baseline and 9 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 9 months; these mean grades were then used to calculate percentage change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 9 Months as Compared to Baseline OD	42.0 percentage change Standard Deviation 42.66
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 9 Months as Compared to Baseline OS	34.0 percentage change Standard Deviation 42.19

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Right (OD) and left (OS) eyes

In Adobe Photoshop 7.0 the high resolution slit lamp image was divided into 4 quadrants with vertical and horizontal lines transecting the center of the iris. Using the elliptical marquee tool, a circle, approximately 0.25 times the diameter of the iris, was drawn in the center of each quadrant. Gaussian blur with radius of 50 was applied to the area enclosed in the 4 circles. With the dropper tool, the red pigment value corresponding to the degree of iris transillumination was sampled at the center of each circle. The 4 values were averaged to yield a composite transillumination score for each subject. Quantified values were then correlated to a scale score from 1 to 8 to generate an 8-point iris transillumination scale, with lower scores reflective of greater iris pigmentation (melanin content). The mean score across the 2 images for each participant's eye was calculated at baseline and 12 months; these mean grades were then used to calculate percentage change from baseline.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 12 Months as Compared to Baseline OD	77.7 percentage change Standard Deviation 91.94
Percent Change in Semi-quantitative Iris Pigmentation for Each Eye at 12 Months as Compared to Baseline OS	67.0 percentage change Standard Deviation 59.75

SECONDARY outcome

Timeframe: Baseline and 3 months

Population: Right (OD) and Left (OS) eyes

Visual acuity was measured using the Electronic ETDRS Visual Acuity Testing protocol. Acuity is measured as letters read using an electronic ETDRS program.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electronic Visual Acuity at 3 Months Compared to Baseline OD	1.8 ETDRS letters Standard Deviation 0.84
Absolute Change in Electronic Visual Acuity at 3 Months Compared to Baseline OS	6.0 ETDRS letters Standard Deviation 3.61

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Right (OD) and Left (OS) eyes

Visual acuity was measured using the Electronic ETDRS Visual Acuity Testing protocol. Acuity is measured as letters read using an electronic ETDRS program.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electronic Visual Acuity at 6 Months Compared to Baseline OD	4.2 ETDRS letters Standard Deviation 2.17
Absolute Change in Electronic Visual Acuity at 6 Months Compared to Baseline OS	4.8 ETDRS letters Standard Deviation 3.42

SECONDARY outcome

Timeframe: Baseline and 9 months

Population: Right (OD) and Left (OS) eyes

Visual acuity was measured using the Electronic ETDRS Visual Acuity Testing protocol. Acuity is measured as letters read using an electronic ETDRS program.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electronic Visual Acuity at 9 Months Compared to Baseline OD	2.8 ETDRS letters Standard Deviation 2.95
Absolute Change in Electronic Visual Acuity at 9 Months Compared to Baseline OS	5.6 ETDRS letters Standard Deviation 2.51

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Right (OD) and Left (OS) eyes

Visual acuity was measured using the Electronic ETDRS Visual Acuity Testing protocol. Acuity is measured as letters read using an electronic ETDRS program.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electronic Visual Acuity at 12 Months Compared to Baseline OD	5.4 ETDRS letters Standard Deviation 3.78
Absolute Change in Electronic Visual Acuity at 12 Months Compared to Baseline OS	5.0 ETDRS letters Standard Deviation 5.70

SECONDARY outcome

Timeframe: Baseline and 3 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. The minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity without glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 3 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity Without Glare at 3 Months Compared to Baseline Frequency 1.5	1.6 units Standard Deviation 1.52
Absolute Change in Contrast Sensitivity Without Glare at 3 Months Compared to Baseline Frequency 3	0.8 units Standard Deviation 0.84
Absolute Change in Contrast Sensitivity Without Glare at 3 Months Compared to Baseline Frequency 6	0.4 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity Without Glare at 3 Months Compared to Baseline Frequency 12	1.2 units Standard Deviation 2.17
Absolute Change in Contrast Sensitivity Without Glare at 3 Months Compared to Baseline Frequency 18	0.6 units Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline and 6 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. The minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity without glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 6 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity Without Glare at 6 Months Compared to Baseline Frequency 1.5	2.0 units Standard Deviation 2.83
Absolute Change in Contrast Sensitivity Without Glare at 6 Months Compared to Baseline Frequency 3	0.2 units Standard Deviation 0.45
Absolute Change in Contrast Sensitivity Without Glare at 6 Months Compared to Baseline Frequency 6	1.6 units Standard Deviation 1.52
Absolute Change in Contrast Sensitivity Without Glare at 6 Months Compared to Baseline Frequency 12	2.8 units Standard Deviation 2.95
Absolute Change in Contrast Sensitivity Without Glare at 6 Months Compared to Baseline Frequency 18	0.0 units Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline and 9 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. The minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity without glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 9 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity Without Glare at 9 Months Compared to Baseline Frequency 1.5	1.8 units Standard Deviation 2.49
Absolute Change in Contrast Sensitivity Without Glare at 9 Months Compared to Baseline Frequency 3	0.6 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity Without Glare at 9 Months Compared to Baseline Frequency 6	1.0 units Standard Deviation 1.00
Absolute Change in Contrast Sensitivity Without Glare at 9 Months Compared to Baseline Frequency 12	1.4 units Standard Deviation 2.19
Absolute Change in Contrast Sensitivity Without Glare at 9 Months Compared to Baseline Frequency 18	0.0 units Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline and 12 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. The minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity without glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 12 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity Without Glare at 12 Months Compared to Baseline Frequency 1.5	2.4 units Standard Deviation 2.51
Absolute Change in Contrast Sensitivity Without Glare at 12 Months Compared to Baseline Frequency 3	2.0 units Standard Deviation 2.55
Absolute Change in Contrast Sensitivity Without Glare at 12 Months Compared to Baseline Frequency 6	1.8 units Standard Deviation 1.92
Absolute Change in Contrast Sensitivity Without Glare at 12 Months Compared to Baseline Frequency 12	1.6 units Standard Deviation 2.19
Absolute Change in Contrast Sensitivity Without Glare at 12 Months Compared to Baseline Frequency 18	0.6 units Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline and 3 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with medium glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 3 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With Medium Glare at 3 Months Compared to Baseline Frequency 1.5	1.4 units Standard Deviation 1.14
Absolute Change in Contrast Sensitivity With Medium Glare at 3 Months Compared to Baseline Frequency 3	0.4 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity With Medium Glare at 3 Months Compared to Baseline Frequency 6	3.6 units Standard Deviation 3.78
Absolute Change in Contrast Sensitivity With Medium Glare at 3 Months Compared to Baseline Frequency 12	0.2 units Standard Deviation 0.45
Absolute Change in Contrast Sensitivity With Medium Glare at 3 Months Compared to Baseline Frequency 18	0.6 units Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline and 6 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with medium glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 6 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With Medium Glare at 6 Months Compared to Baseline Frequency 1.5	2.4 units Standard Deviation 2.88
Absolute Change in Contrast Sensitivity With Medium Glare at 6 Months Compared to Baseline Frequency 3	1.4 units Standard Deviation 1.67
Absolute Change in Contrast Sensitivity With Medium Glare at 6 Months Compared to Baseline Frequency 6	1.8 units Standard Deviation 1.79
Absolute Change in Contrast Sensitivity With Medium Glare at 6 Months Compared to Baseline Frequency 12	0.4 units Standard Deviation 0.89
Absolute Change in Contrast Sensitivity With Medium Glare at 6 Months Compared to Baseline Frequency 18	0.6 units Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline and 9 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with medium glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 9 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With Medium Glare at 9 Months Compared to Baseline Frequency 1.5	2.0 units Standard Deviation 2.35
Absolute Change in Contrast Sensitivity With Medium Glare at 9 Months Compared to Baseline Frequency 3	1.2 units Standard Deviation 0.84
Absolute Change in Contrast Sensitivity With Medium Glare at 9 Months Compared to Baseline Frequency 6	1.0 units Standard Deviation 1.00
Absolute Change in Contrast Sensitivity With Medium Glare at 9 Months Compared to Baseline Frequency 12	0.6 units Standard Deviation 1.34
Absolute Change in Contrast Sensitivity With Medium Glare at 9 Months Compared to Baseline Frequency 18	0.8 units Standard Deviation 1.30

SECONDARY outcome

Timeframe: Baseline and 12 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with medium glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 12 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With Medium Glare at 12 Months Compared to Baseline Frequency 1.5	1.4 units Standard Deviation 2.61
Absolute Change in Contrast Sensitivity With Medium Glare at 12 Months Compared to Baseline Frequency 3	1.8 units Standard Deviation 1.79
Absolute Change in Contrast Sensitivity With Medium Glare at 12 Months Compared to Baseline Frequency 6	2.6 units Standard Deviation 2.79
Absolute Change in Contrast Sensitivity With Medium Glare at 12 Months Compared to Baseline Frequency 12	0.4 units Standard Deviation 0.89
Absolute Change in Contrast Sensitivity With Medium Glare at 12 Months Compared to Baseline Frequency 18	1.2 units Standard Deviation 1.64

SECONDARY outcome

Timeframe: Baseline and 3 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with high glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 3 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With High Glare at 3 Months Compared to Baseline Frequency 1.5	1.2 units Standard Deviation 1.10
Absolute Change in Contrast Sensitivity With High Glare at 3 Months Compared to Baseline Frequency 3	1.8 units Standard Deviation 2.49
Absolute Change in Contrast Sensitivity With High Glare at 3 Months Compared to Baseline Frequency 6	0.2 units Standard Deviation 0.45
Absolute Change in Contrast Sensitivity With High Glare at 3 Months Compared to Baseline Frequency 12	0.2 units Standard Deviation 0.45
Absolute Change in Contrast Sensitivity With High Glare at 3 Months Compared to Baseline Frequency 18	0.0 units Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline and 6 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with high glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 6 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With High Glare at 6 Months Compared to Baseline Frequency 1.5	1.0 units Standard Deviation 1.00
Absolute Change in Contrast Sensitivity With High Glare at 6 Months Compared to Baseline Frequency 3	1.6 units Standard Deviation 1.67
Absolute Change in Contrast Sensitivity With High Glare at 6 Months Compared to Baseline Frequency 6	1.2 units Standard Deviation 2.17
Absolute Change in Contrast Sensitivity With High Glare at 6 Months Compared to Baseline Frequency 12	0.4 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity With High Glare at 6 Months Compared to Baseline Frequency 18	0.0 units Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline and 9 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with high glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 9 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With High Glare at 9 Months Compared to Baseline Frequency 1.5	1.4 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity With High Glare at 9 Months Compared to Baseline Frequency 3	0.6 units Standard Deviation 0.55
Absolute Change in Contrast Sensitivity With High Glare at 9 Months Compared to Baseline Frequency 6	1.0 units Standard Deviation 2.24
Absolute Change in Contrast Sensitivity With High Glare at 9 Months Compared to Baseline Frequency 12	1.6 units Standard Deviation 2.61
Absolute Change in Contrast Sensitivity With High Glare at 9 Months Compared to Baseline Frequency 18	0.6 units Standard Deviation 1.34

SECONDARY outcome

Timeframe: Baseline and 12 months

Gratings, images with alternating light and dark bars, assess contrast sensitivity via spatial frequency and contrast. Spatial frequency (SF), the number of pairs of bars (1 light, 1 dark) imaged within a given distance of the retina, is measured as the number of cycles per degree (cpd) of visual angle, where a cycle is 1 pair of bars. Grating of high SF corresponds to narrow bars; grating of low SF corresponds to wide bars. Contrast is the intensity difference between light and dark bars. Minimum contrast required to detect a given SF is the threshold contrast. The lower the threshold contrast, higher the contrast sensitivity. Contrast sensitivity with high glare was measured at frequencies of 1.5, 3, 6, 12, 18 cpd. Absolute change from baseline to 12 months was calculated. Raw values were used for the planned descriptive analysis; logarithmic transformation was not used as formal statistical analysis was not planned and was not appropriate as a majority of the raw values were 0.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Contrast Sensitivity With High Glare at 12 Months Compared to Baseline Frequency 1.5	1.6 units Standard Deviation 1.52
Absolute Change in Contrast Sensitivity With High Glare at 12 Months Compared to Baseline Frequency 3	2.2 units Standard Deviation 2.28
Absolute Change in Contrast Sensitivity With High Glare at 12 Months Compared to Baseline Frequency 6	2.6 units Standard Deviation 3.21
Absolute Change in Contrast Sensitivity With High Glare at 12 Months Compared to Baseline Frequency 12	1.8 units Standard Deviation 1.79
Absolute Change in Contrast Sensitivity With High Glare at 12 Months Compared to Baseline Frequency 18	0.0 units Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline and 3 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Adjusted Melanin Index at 3 Months Compared to Baseline Forehead	16.4 Adjusted Melanin Index*10^-5 Standard Deviation 14.95
Absolute Change in Adjusted Melanin Index at 3 Months Compared to Baseline Inner Bicep	4.8 Adjusted Melanin Index*10^-5 Standard Deviation 5.24
Absolute Change in Adjusted Melanin Index at 3 Months Compared to Baseline Lower Back	20.9 Adjusted Melanin Index*10^-5 Standard Deviation 18.91
Absolute Change in Adjusted Melanin Index at 3 Months Compared to Baseline Inner Forearm	10.7 Adjusted Melanin Index*10^-5 Standard Deviation 5.52
Absolute Change in Adjusted Melanin Index at 3 Months Compared to Baseline Outer Forearm	10.6 Adjusted Melanin Index*10^-5 Standard Deviation 5.60

SECONDARY outcome

Timeframe: Baseline and 6 Months

Population: Participant 005 did not have skin reflectometry measurements for any site at Month 6.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Adjusted Melanin Index at 6 Months Compared to Baseline Forehead	11.8 Adjusted Melanin Index*10^-5 Standard Deviation 4.57
Absolute Change in Adjusted Melanin Index at 6 Months Compared to Baseline Inner Bicep	8.2 Adjusted Melanin Index*10^-5 Standard Deviation 6.19
Absolute Change in Adjusted Melanin Index at 6 Months Compared to Baseline Lower Back	9.3 Adjusted Melanin Index*10^-5 Standard Deviation 7.60
Absolute Change in Adjusted Melanin Index at 6 Months Compared to Baseline Inner Forearm	12.1 Adjusted Melanin Index*10^-5 Standard Deviation 10.59
Absolute Change in Adjusted Melanin Index at 6 Months Compared to Baseline Outer Forearm	12.6 Adjusted Melanin Index*10^-5 Standard Deviation 6.71

SECONDARY outcome

Timeframe: Baseline and 9 Months

Population: Participant 002 did not have any skin reflectometry measurements for any site at Month 9.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Adjusted Melanin Index at 9 Months Compared to Baseline Forehead	10.3 Adjusted Melanin Index*10^-5 Standard Deviation 13.41
Absolute Change in Adjusted Melanin Index at 9 Months Compared to Baseline Inner Bicep	9.4 Adjusted Melanin Index*10^-5 Standard Deviation 5.85
Absolute Change in Adjusted Melanin Index at 9 Months Compared to Baseline Lower Back	5.5 Adjusted Melanin Index*10^-5 Standard Deviation 4.12
Absolute Change in Adjusted Melanin Index at 9 Months Compared to Baseline Inner Forearm	11.6 Adjusted Melanin Index*10^-5 Standard Deviation 7.82
Absolute Change in Adjusted Melanin Index at 9 Months Compared to Baseline Outer Forearm	1.5 Adjusted Melanin Index*10^-5 Standard Deviation 0.98

SECONDARY outcome

Timeframe: Baseline and 12 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Adjusted Melanin Index at 12 Months Compared to Baseline Forehead	8.3 Adjusted Melanin Index*10^-5 Standard Deviation 6.89
Absolute Change in Adjusted Melanin Index at 12 Months Compared to Baseline Inner Bicep	7.0 Adjusted Melanin Index*10^-5 Standard Deviation 7.74
Absolute Change in Adjusted Melanin Index at 12 Months Compared to Baseline Lower Back	4.2 Adjusted Melanin Index*10^-5 Standard Deviation 3.18
Absolute Change in Adjusted Melanin Index at 12 Months Compared to Baseline Inner Forearm	6.8 Adjusted Melanin Index*10^-5 Standard Deviation 4.20
Absolute Change in Adjusted Melanin Index at 12 Months Compared to Baseline Outer Forearm	8.6 Adjusted Melanin Index*10^-5 Standard Deviation 5.09

SECONDARY outcome

Timeframe: Baseline and 3 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Adjusted Melanin Index at 3 Months Compared to Baseline Forehead	50.1 Percentage change Standard Deviation 49.48
Percent Change in Adjusted Melanin Index at 3 Months Compared to Baseline Inner Bicep	40.1 Percentage change Standard Deviation 35.76
Percent Change in Adjusted Melanin Index at 3 Months Compared to Baseline Lower Back	201.0 Percentage change Standard Deviation 321.19
Percent Change in Adjusted Melanin Index at 3 Months Compared to Baseline Inner Forearm	83.3 Percentage change Standard Deviation 70.69
Percent Change in Adjusted Melanin Index at 3 Months Compared to Baseline Outer Forearm	42.1 Percentage change Standard Deviation 22.67

SECONDARY outcome

Timeframe: Baseline and 6 Months

Population: Participant 005 did not have skin reflectometry measurements for any site at Month 6.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Adjusted Melanin Index at 6 Months Compared to Baseline Forehead	35.4 Percentage change Standard Deviation 14.10
Percent Change in Adjusted Melanin Index at 6 Months Compared to Baseline Inner Bicep	123.0 Percentage change Standard Deviation 113.41
Percent Change in Adjusted Melanin Index at 6 Months Compared to Baseline Lower Back	117.4 Percentage change Standard Deviation 120.5
Percent Change in Adjusted Melanin Index at 6 Months Compared to Baseline Inner Forearm	91.1 Percentage change Standard Deviation 116.26
Percent Change in Adjusted Melanin Index at 6 Months Compared to Baseline Outer Forearm	67.9 Percentage change Standard Deviation 56.49

SECONDARY outcome

Timeframe: Baseline and 9 Months

Population: Participant 002 did not have skin reflectometry measurements for any site at Month 9.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Adjusted Melanin Index at 9 Months Compared to Baseline Forehead	33.2 Percentage change Standard Deviation 44.21
Percent Change in Adjusted Melanin Index at 9 Months Compared to Baseline Inner Bicep	94.5 Percentage change Standard Deviation 60.03
Percent Change in Adjusted Melanin Index at 9 Months Compared to Baseline Lower Back	39.6 Percentage change Standard Deviation 42.36
Percent Change in Adjusted Melanin Index at 9 Months Compared to Baseline Inner Forearm	81.0 Percentage change Standard Deviation 93.51
Percent Change in Adjusted Melanin Index at 9 Months Compared to Baseline Outer Forearm	6.0 Percentage change Standard Deviation 5.86

SECONDARY outcome

Timeframe: Baseline and 12 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Apparent absorbance (AA) at a given wavelength was determined as log10 (PR of blank/PR of object) at that wavelength. Adjusted Melanin (AM) index is calculated as the slope of AA levels from 650 to 700 nm. Lower values of AM index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites: forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Adjusted Melanin Index at 12 Months Compared to Baseline Forehead	24.7 Percentage change Standard Deviation 21.76
Percent Change in Adjusted Melanin Index at 12 Months Compared to Baseline Inner Bicep	104.5 Percentage change Standard Deviation 132.61
Percent Change in Adjusted Melanin Index at 12 Months Compared to Baseline Lower Back	32.7 Percentage change Standard Deviation 31.81
Percent Change in Adjusted Melanin Index at 12 Months Compared to Baseline Inner Forearm	47.4 Percentage change Standard Deviation 48.10
Percent Change in Adjusted Melanin Index at 12 Months Compared to Baseline Outer Forearm	30.5 Percentage change Standard Deviation 7.60

SECONDARY outcome

Timeframe: Baseline and 3 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Melanin Index at 3 Months Compared to Baseline Forehead	3.8 Melanin Index Standard Deviation 3.02
Absolute Change in Melanin Index at 3 Months Compared to Baseline Inner Bicep	1.4 Melanin Index Standard Deviation 0.69
Absolute Change in Melanin Index at 3 Months Compared to Baseline Lower Back	0.6 Melanin Index Standard Deviation 0.63
Absolute Change in Melanin Index at 3 Months Compared to Baseline Inner Forearm	1.8 Melanin Index Standard Deviation 1.12
Absolute Change in Melanin Index at 3 Months Compared to Baseline Outer Forearm	4.5 Melanin Index Standard Deviation 4.45

SECONDARY outcome

Timeframe: Baseline and 6 Months

Population: Participant 005 did not have skin reflectometry measurements for any site at Month 6.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Melanin Index at 6 Months Compared to Baseline Forehead	2.2 Melanin Index Standard Deviation 1.29
Absolute Change in Melanin Index at 6 Months Compared to Baseline Inner Bicep	2.7 Melanin Index Standard Deviation 1.68
Absolute Change in Melanin Index at 6 Months Compared to Baseline Lower Back	3.3 Melanin Index Standard Deviation 3.72
Absolute Change in Melanin Index at 6 Months Compared to Baseline Inner Forearm	2.1 Melanin Index Standard Deviation 1.43
Absolute Change in Melanin Index at 6 Months Compared to Baseline Outer Forearm	4.4 Melanin Index Standard Deviation 5.80

SECONDARY outcome

Timeframe: Baseline and 9 Months

Population: Participant 002 did not have skin reflectometry measurements for any site at Month 9.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Melanin Index at 9 Months Compared to Baseline Forehead	2.4 Melanin Index Standard Deviation 1.98
Absolute Change in Melanin Index at 9 Months Compared to Baseline Inner Bicep	1.9 Melanin Index Standard Deviation 1.60
Absolute Change in Melanin Index at 9 Months Compared to Baseline Lower Back	3.2 Melanin Index Standard Deviation 3.23
Absolute Change in Melanin Index at 9 Months Compared to Baseline Inner Forearm	2.1 Melanin Index Standard Deviation 1.33
Absolute Change in Melanin Index at 9 Months Compared to Baseline Outer Forearm	2.2 Melanin Index Standard Deviation 2.48

SECONDARY outcome

Timeframe: Baseline and 12 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Absolute change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Melanin Index at 12 Months Compared to Baseline Forehead	3.7 Melanin Index Standard Deviation 3.29
Absolute Change in Melanin Index at 12 Months Compared to Baseline Inner Bicep	2.3 Melanin Index Standard Deviation 1.90
Absolute Change in Melanin Index at 12 Months Compared to Baseline Lower Back	2.0 Melanin Index Standard Deviation 1.55
Absolute Change in Melanin Index at 12 Months Compared to Baseline Inner Forearm	2.2 Melanin Index Standard Deviation 1.96
Absolute Change in Melanin Index at 12 Months Compared to Baseline Outer Forearm	3.4 Melanin Index Standard Deviation 3.38

SECONDARY outcome

Timeframe: Baseline and 3 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Melanin Index at 3 Months Compared to Baseline Forehead	15.0 Percentage change Standard Deviation 12.90
Percent Change in Melanin Index at 3 Months Compared to Baseline Inner Bicep	6.7 Percentage change Standard Deviation 3.50
Percent Change in Melanin Index at 3 Months Compared to Baseline Lower Back	2.8 Percentage change Standard Deviation 3.34
Percent Change in Melanin Index at 3 Months Compared to Baseline Inner Forearm	8.6 Percentage change Standard Deviation 5.84
Percent Change in Melanin Index at 3 Months Compared to Baseline Outer Forearm	18.9 Percentage change Standard Deviation 19.90

SECONDARY outcome

Timeframe: Baseline and 6 Months

Population: Participant 005 did not have skin reflectometry measurements for any site at Month 6.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Melanin Index at 6 Months Compared to Baseline Forehead	8.4 Percentage change Standard Deviation 4.62
Percent Change in Melanin Index at 6 Months Compared to Baseline Inner Bicep	12.7 Percentage change Standard Deviation 8.31
Percent Change in Melanin Index at 6 Months Compared to Baseline Lower Back	17.0 Percentage change Standard Deviation 19.52
Percent Change in Melanin Index at 6 Months Compared to Baseline Inner Forearm	10.2 Percentage change Standard Deviation 7.50
Percent Change in Melanin Index at 6 Months Compared to Baseline Outer Forearm	19.2 Percentage change Standard Deviation 24.93

SECONDARY outcome

Timeframe: Baseline and 9 Months

Population: Participant 002 did not have skin reflectometry measurements for any site at Month 9.

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=4 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Melanin Index at 9 Months Compared to Baseline Forehead	9.2 Percentage change Standard Deviation 7.30
Percent Change in Melanin Index at 9 Months Compared to Baseline Inner Bicep	8.9 Percentage change Standard Deviation 7.89
Percent Change in Melanin Index at 9 Months Compared to Baseline Lower Back	15.8 Percentage change Standard Deviation 16.17
Percent Change in Melanin Index at 9 Months Compared to Baseline Inner Forearm	9.5 Percentage change Standard Deviation 6.15
Percent Change in Melanin Index at 9 Months Compared to Baseline Outer Forearm	8.8 Percentage change Standard Deviation 10.63

SECONDARY outcome

Timeframe: Baseline and 12 Months

Microflash 200D is a diffuse reflectance spectrophotometer that uses a prism photodiode to provide information at 10 nm increments along the visual spectrum from 400 to 700 nm. Percent reflectance (PR) at a specific wavelength was placed into context by relating it to the reflectance of a blank at the equivalent wavelength (i.e. relating the object's reflectance to the maximum reflectance possible). Melanin (M) index was calculated as follows:

Eqn 1= [ (PR at 650nm + PR at 660nm + 0.5*PR at 640nm + 0.5*PR at 670nm)/3 ]/100; M index = 100*log (1/Eqn 1) Higher values of M index correspond to higher melanin concentrations. Measurements were collected 5 times at each visit from each of the following sites:forehead, inner forearm, outer forearm, inner bicep and lower back. The mean of these five measurements was calculated at each visit. Percent change from baseline was calculated using these mean values.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Melanin Index at 12 Months Compared to Baseline Forehead	14.7 Percentage change Standard Deviation 14.11
Percent Change in Melanin Index at 12 Months Compared to Baseline Inner Bicep	10.9 Percentage change Standard Deviation 9.43
Percent Change in Melanin Index at 12 Months Compared to Baseline Lower Back	10.2 Percentage change Standard Deviation 7.92
Percent Change in Melanin Index at 12 Months Compared to Baseline Inner Forearm	10.4 Percentage change Standard Deviation 10.19
Percent Change in Melanin Index at 12 Months Compared to Baseline Outer Forearm	13.3 Percentage change Standard Deviation 13.44

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: Right eyes (OD) and left eyes (OS)

Amplitude for the ERG parameter, Dark Adaptation (DA) Comb B, was measured at each visit. Participants left and right eye will be analyzed.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electroretinogram (ERG) at Month 6 as Compared to Baseline. OD	38.6 µV Standard Deviation 27.93
Absolute Change in Electroretinogram (ERG) at Month 6 as Compared to Baseline. OS	76.2 µV Standard Deviation 29.06

SECONDARY outcome

Timeframe: Baseline and 12 months

Population: Right eyes (OD) and left eyes (OS)

Amplitude for the ERG parameter, Dark Adaptation (DA) Comb B, was measured at each visit. Participants left and right eye will be analyzed.

Outcome measures

Measure	Nitisinone n=10 eyes Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Electroretinogram (ERG) at Month 12 as Compared to Baseline. OD	27.8 µV Standard Deviation 16.66
Absolute Change in Electroretinogram (ERG) at Month 12 as Compared to Baseline. OS	85.8 µV Standard Deviation 83.83

SECONDARY outcome

Timeframe: Baseline and 3 months

Qualitative change in hair pigmentation was measured as a binary endpoint (no change vs. increase) at Month 3 compared to previous visit.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Hair Pigmentation at 3 Months Compared to Previous Visit. No change in hair pigmentation	1 Participants
Qualitative Change in Hair Pigmentation at 3 Months Compared to Previous Visit. Increase in hair pigmentation	4 Participants

SECONDARY outcome

Timeframe: 3 Months and 6 months

Qualitative change in hair pigmentation was measured as a binary endpoint (no change vs. increase) at Month 6 compared to Month 3

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Hair Pigmentation at 6 Months Compared to Previous Visit. No change in hair pigmentation	3 Participants
Qualitative Change in Hair Pigmentation at 6 Months Compared to Previous Visit. Increase in hair pigmentation	2 Participants

SECONDARY outcome

Timeframe: 6 Months and 9 months

Qualitative change in hair pigmentation was measured as a binary endpoint (no change vs. increase) at Month 9 compared to Month 6

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Hair Pigmentation at 9 Months Compared to Previous Visit. No change in hair pigmentation	4 Participants
Qualitative Change in Hair Pigmentation at 9 Months Compared to Previous Visit. Increase in hair pigmentation	1 Participants

SECONDARY outcome

Timeframe: 9 Months and 12 months

Qualitative change in hair pigmentation was measured as a binary endpoint (no change vs. increase) at Month 12 compared to Month 9

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Hair Pigmentation at 12 Months Compared to Previous Visit. No change in hair pigmentation	5 Participants
Qualitative Change in Hair Pigmentation at 12 Months Compared to Previous Visit. Increase in hair pigmentation	0 Participants

SECONDARY outcome

Timeframe: Baseline and 3 months

Qualitative change in skin pigmentation was measured as a binary endpoint (no change vs. increase) at Month 3 compared to previous visit.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Skin Pigmentation at 3 Months Compared to Previous Visit. No change in skin pigmentation	4 Participants
Qualitative Change in Skin Pigmentation at 3 Months Compared to Previous Visit. Increase in skin pigmentation	1 Participants

SECONDARY outcome

Timeframe: 3 Months and 6 months

Qualitative change in skin pigmentation was measured as a binary endpoint (no change vs. increase) at Month 6 compared to Month 3

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Skin Pigmentation at 6 Months Compared to Previous Visit. No change in skin pigmentation	5 Participants
Qualitative Change in Skin Pigmentation at 6 Months Compared to Previous Visit. Increase in skin pigmentation	0 Participants

SECONDARY outcome

Timeframe: 6 Months and 9 months

Qualitative change in skin pigmentation was measured as a binary endpoint (no change vs. increase) at Month 9 compared to Month 6

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Skin Pigmentation at 9 Months Compared to Previous Visit. No change in skin pigmentation	5 Participants
Qualitative Change in Skin Pigmentation at 9 Months Compared to Previous Visit. Increase in skin pigmentation	0 Participants

SECONDARY outcome

Timeframe: 9 Months and 12 months

Qualitative change in skin pigmentation was measured as a binary endpoint (no change vs. increase) at Month 12 compared to Month 9

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Skin Pigmentation at 12 Months Compared to Previous Visit. No change in skin pigmentation	5 Participants
Qualitative Change in Skin Pigmentation at 12 Months Compared to Previous Visit. Increase in skin pigmentation	0 Participants

SECONDARY outcome

Timeframe: Baseline and 3 months

Qualitative change in fundus pigmentation was measured as a binary endpoint (no change vs. increase) at Month 3 compared to previous visit.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Fundus Pigmentation at 3 Months Compared to Previous Visit. No change in fundus pigmentation	5 Participants
Qualitative Change in Fundus Pigmentation at 3 Months Compared to Previous Visit. Increase in fundus pigmentation	0 Participants

SECONDARY outcome

Timeframe: 3 Months and 6 months

Qualitative change in fundus pigmentation was measured as a binary endpoint (no change vs. increase) at Month 6 compared to Month 3

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Fundus Pigmentation at 6 Months Compared to Previous Visit. No change in fundus pigmentation	5 Participants
Qualitative Change in Fundus Pigmentation at 6 Months Compared to Previous Visit. Increase in fundus pigmentation	0 Participants

SECONDARY outcome

Timeframe: 6 Months and 9 months

Qualitative change in fundus pigmentation was measured as a binary endpoint (no change vs. increase) at Month 9 compared to Month 6

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Fundus Pigmentation at 9 Months Compared to Previous Visit. No change in fundus pigmentation	5 Participants
Qualitative Change in Fundus Pigmentation at 9 Months Compared to Previous Visit. Increase in fundus pigmentation	0 Participants

SECONDARY outcome

Timeframe: 9 Months and 12 months

Qualitative change in fundus pigmentation was measured as a binary endpoint (no change vs. increase) at Month 12 compared to Month 9

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Qualitative Change in Fundus Pigmentation at 12 Months Compared to Previous Visit. No change in fundus pigmentation	5 Participants
Qualitative Change in Fundus Pigmentation at 12 Months Compared to Previous Visit. Increase in fundus pigmentation	0 Participants

SECONDARY outcome

Timeframe: Baseline and 12 months

Hair melanin was assessed using pyrrole-2,3,5-tricarboxylic acid (PTCA), a marker of eumelanin and 4-amino-3-hydroxyphenylalanine (4-AHP), a marker of pheomelanin.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Absolute Change in Hair Melanin at 12 Months Compared to Baseline PTCA	8.38 ng/mg Standard Deviation 5.11
Absolute Change in Hair Melanin at 12 Months Compared to Baseline 4-AHP	5.92 ng/mg Standard Deviation 11.68

SECONDARY outcome

Timeframe: Baseline and 12 months

Hair melanin was assessed using pyrrole-2,3,5-tricarboxylic acid (PTCA), a marker of eumelanin and 4-amino-3-hydroxyphenylalanine (4-AHP), a marker of pheomelanin.

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Percent Change in Hair Melanin at 12 Months Compared to Baseline PTCA	50.30 percentage change Standard Deviation 45.92
Percent Change in Hair Melanin at 12 Months Compared to Baseline 4-AHP	27.23 percentage change Standard Deviation 23.22

OTHER_PRE_SPECIFIED outcome

Timeframe: Study duration, up to 18 months

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Number of Ocular Adverse Events	0 ocular adverse events

OTHER_PRE_SPECIFIED outcome

Timeframe: Study duration, up to 18 months

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Number of Non-ocular Adverse Events	10 non-ocular adverse events

OTHER_PRE_SPECIFIED outcome

Timeframe: Study duration, up to 18 months

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Severity of Adverse Events Mild	9 adverse events
Severity of Adverse Events Moderate	1 adverse events

OTHER_PRE_SPECIFIED outcome

Timeframe: Study duration, up to 18 months

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Number of Adverse Events Related to Investigational Product (IP)	0 adverse events related to IP

OTHER_PRE_SPECIFIED outcome

Timeframe: Study duration, up to 18 months

Outcome measures

Measure	Nitisinone n=5 Participants Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Number of Participants Withdrawn From Investigational Product (IP) Due to Safety and Abnormal Laboratory Results	0 participant withdrawals

Adverse Events

Nitisinone

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Nitisinone n=5 participants at risk Oral administration of nitisinone Nitisinone: Oral dose of 2mg daily for 12 months.
Blood and lymphatic system disorders Anaemia	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Cardiac disorders Palpitations	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
General disorders Dizziness	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Gastrointestinal disorders Dyspepsia	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Musculoskeletal and connective tissue disorders Pain in extremity	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Gastrointestinal disorders Gastrooesophageal reflux disease	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Vascular disorders Haemangioma	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Investigations Neurological examination abnormal	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Cardiac disorders Chest pain	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.
Respiratory, thoracic and mediastinal disorders Bronchitis	20.0% 1/5 • Number of events 1 • Up to 18 months Adverse events were collected on and after the baseline visit, and when investigational product (IP) began.

Additional Information

Brian Brooks, MD, PhD, Principal Investigator, NEI

National Institutes of Health

Phone: 301-451-2238

Email: brian.brooks@nih.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place