Safety and Efficacy Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to BH4 Deficiency

• Sponsor: BioMarin Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00355264
• Collaborator: (none)
• Enrollment: 12
• Locations: 10
• Arm: 1
• Duration (Months): 34
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the ability of Phenoptin to control blood phenylalanine levels in subjects who have hyperphenylalaninemia due to a primary BH4 deficiency and to evaluate the safety of Phenoptin in this population. Some subjects were receiving non-registered formulations of BH4 at enrollment and this treatment was suspended after Part 1 and within one day the subjects started Phenoptin at approximately the same dose.

Condition or Disease	Intervention/Treatment	Phase
Tetrahydrobiopterin Deficiencies; Hyperphenylalaninemia, Non-Phenylketonuric	Drug: Phenoptin	Phase 2

Detailed Description

Within 4 weeks of completing screening assessments to determine eligibility, subjects will be enrolled in the study. The study will be conducted in two parts.

Part 1: After screening, all subjects will be followed for two weeks without modification of their baseline medical or dietary care.

Part 2: Beginning at Week 2, subjects who were receiving non-registered formulations of BH4 at enrollment will suspend this treatment and within one day will start Phenoptin at approximately the same dose of the non-registered BH4 formulation. Subjects not receiving BH4 at enrollment will begin treatment with Phenoptin at approximately 5 mg/kg/day, given orally, prior to meals.

At the discretion of the Investigator, the Phenoptin dose may be adjusted up or down at the Week 6 visit to control blood Phe levels (<360 µmol/L), or to optimize the clinical effect. The maximum dose allowed will be approximately 20 mg/kg/day. All subjects will receive Phenoptin for a total of 8 weeks. Subjects will be instructed to continue their usual diet without modification. Study visits will occur every other week.

Tyrosine, biopterin and neopterin will be analyzed at the following visits: Week 0 (enrollment), Week 2 (prior to dosing with Phenoptin), Week 8 (after 6 weeks of treatment with Phenoptin) and Week 10 (after 8 weeks of treatment with Phenoptin).During each visit, blood Phe level will be measured (2.5-5 hours after a meal), and safety evaluations will be performed. Safety will be assessed by monitoring adverse events and vital signs, performing physical examinations, assessing signs and symptoms of primary BH4 deficiency (i.e., neurological symptoms such as seizures, changes in muscle tone, weakness, etc.) and clinical laboratory tests (chemistry, hematology and urinalysis).

Extension: Upon completion of 8 weeks of treatment (i.e., at the Week 10 visit), subjects will be offered the option to continue treatment with Phenoptin in an extension of this study. Participation in the study extension will continue until one of the following occurs:

1. the subject withdraws consent and discontinues from the study,

2. the subject is discontinued from the study at the discretion of the investigator,

3. the study drug is available through the appropriate marketing approval, or

4. the study is terminated.

During the extension period, study drug will be dispensed to subjects monthly, and study visits will be required every 3 months. The Phenoptin dose may be adjusted at any visit during the study extension at the discretion of the Investigator. The maximum dose allowed will be approximately 20 mg/kg/day.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Outcomes were to be evaluated for all subjects with primary BH4 disease. Outcomes were also evaluated based on the type of BH4 deficiency either due to defects in the genes encoding the enzymes involved in BH4 biosynthesis, GTPcyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR); or defects in the genes encoding the enzymes involved in BH4 recycling, pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR)Outcomes were to be evaluated for all subjects with primary BH4 disease. Outcomes were also evaluated based on the type of BH4 deficiency either due to defects in the genes encoding the enzymes involved in BH4 biosynthesis, GTPcyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR); or defects in the genes encoding the enzymes involved in BH4 recycling, pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR)
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2, Multicenter, Open Label Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to Primary BH4 Deficiency
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm on Active Drug 5mg/kg/day orally, dose may be adjusted to between 5-20 mg/kg/day by investigator at week 6 to control blood Phe levels Outcomes were also evaluated by the subject's type of BH4 deficiency either defects in the genes encoding the enzymes involved in biosynthesis or defects in the genes encoding the enzymes involved in recycling.	Drug: Phenoptin; 5mg/kg/day orally, dose may be adjusted to between 5-20 mg/kg/day by investigator at week 6 to control blood Phe levels

Outcome Measures

Primary Outcome Measures

1. Blood Phenylalanine(Phe) Levels Measured at Specified Timepoints [At Baseline, Week 4 through Extension Week 130]

   Baseline blood phenylalanine(Phe) value is the latest measurement taken prior to initiation of Phenoptin treatment. The ideal range for blood Phe levels is approximately 120-360 µmol/L.

2. Percentage of Subjects With Blood Phenylalanine (Last Observation Carried Forward) < 360 μmol/L [At Baseline, Week 4 through Extension Week 130]

   Baseline blood phenylalanine(Phe) value is the latest measurement taken prior to initiation of Phenoptin treatment. The objective of this outcome was to compare to Phe levels achieved using previous treatment regimens.

Secondary Outcome Measures

1. Subjects Experiencing Adverse Events(AEs) [Up to 35 Months]

   Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities. Moderate = AE resulted in some limitation of usual activities. Severe = AE resulted in an inability to carry out usual activities. A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. Serious AE (SAE) resulted in death, was life-threatening, required in patient hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect; or was an important medical event.

Other Outcome Measures

1. AEs Consistent With Signs and/or Symptoms of BH4 Deficiency [Up to 35 months]

   Attention was paid to AEs that may be consistent with signs and/or symptoms associated with primary BH4 deficiency to determine if such signs and symptoms arose or increased in severity or frequency during the study. These included prematurity and low birth weight, inability to control body temperature, low muscle tone, decreased spontaneous movements, poor sucking, movement disorders, difficulty swallowing, hypersalivation, seizures or convulsions, behavioral problems, developmental delay, and mental retardation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented history of blood Phe level > 180 µmol/L on at least one occasion

• Established diagnosis of hyperphenylalaninemia (HPA) due to primary BH4 deficiency with a documented defect in biopterin metabolism with blood or urine tests

• Willing and able to provide written informed consent or, in the case of subjects under the age of 18 years, provide written assent (if required) and written informed consent by a parent or legal guardian

• Negative urine pregnancy test at screening for females of child-bearing potential

• Male and female subjects of childbearing potential (if sexually active and non-sterile) must be using acceptable birth control measures and be willing to continue to use acceptable birth control measures, as determined by the Investigator, and be willing to continue to use acceptable birth control measures while participating in the study

• Willing and able to comply with all study procedures

• Able to take medication orally

Exclusion Criteria:

• Perceived to be unreliable or unavailable for study participation or, if under the age of 18 years, have parents or legal guardians who are perceived to be unreliable or unavailable

• Use of any investigational agent (other than BH4) within 30 days prior to screening, or requirement for any investigational agent or vaccine prior to completion of all scheduled study assessments

• Positive urine pregnancy test at screening (non-sterile females of child bearing potential only), already known to be pregnant or breastfeeding or planning a pregnancy in self or partner during the study

• Female subjects of childbearing potential not using an effective method of birth control, as determined by the PI, or unwilling to continue to use acceptable birth control measures.

• Alanine aminotransferase (ALT) > 2 times the upper limit of normal (i.e., Grade 1 or higher based on World Health Organization Toxicity Criteria) at screening

• Concurrent disease or condition that would interfere with study participation or safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation)

• Serious neuropsychiatric illness (e.g., major depression) not currently under medical control

• Requirement for concomitant treatment with any drug known to inhibit folate synthesis (e.g., methotrexate)

• Clinical diagnosis of phenylketonuria (PKU) due to phenylalanine hydroxylase deficiency

• Any condition that, in the view of the PI, renders the subject at high risk from treatment compliance and/or completing the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90095
2		Chicago	Illinois	United States	60614
3		Minneapolis	Minnesota	United States	55455
4		New York	New York	United States	10029
5		Chapel Hill	North Carolina	United States	27599
6		Portland	Oregon	United States	97239
7		Salt Lake City	Utah	United States	84132
8		Seattle	Washington	United States	98105
9		Madison	Wisconsin	United States	53705
10		Düsseldorf		Germany	40225

Sponsors and Collaborators

• BioMarin Pharmaceutical

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• sponsor website

Publications

None provided.

• Responsible Party: BioMarin Pharmaceutical
• ClinicalTrials.gov Identifier: NCT00355264
• Other Study ID Numbers: PKU-007
• First Posted: Jul 21, 2006
• Last Update Posted: Sep 25, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Phenylketonurias

Study Results

Participant Flow

Recruitment Details	This study was a multicenter study, conducted at 8 sites in the United States of America and one site in Germany
Pre-assignment Detail	A sample size planned of 10 to 15 subjects considered adequate based on clinical considerations. Actual enrolled and treated are 12 subjects.

Arm/Group Title	Phenoptin
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of Tetrahydrobiopterin (BH4) at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half of the dose was administered orally twice daily, to achieve a full dose per day. In Part 3 (concurrent with Extension), subjects had the option of receiving 10 mg/kg/day Phenoptin administered orally twice daily for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects that completed Part 2 were offered the option of participating in Part 3. Among 12 subjects, 2 participated in Part 3 that took place concurrent with the Extension study.
Period Title: Part 1 (2 Weeks)
STARTED	12
COMPLETED	12
NOT COMPLETED	0
Period Title: Part 1 (2 Weeks)
STARTED	12
COMPLETED	12
NOT COMPLETED	0
Period Title: Part 1 (2 Weeks)
STARTED	2
COMPLETED	2
NOT COMPLETED	0
Period Title: Part 1 (2 Weeks)
STARTED	12
COMPLETED	10
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Phenoptin
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, administered orally twice for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin. The mean Phenoptin dose received during the study was 9.1 mg/kg/day with a minimum of 1.9 mg/kg/day and a maximum of 21 mg/kg/day. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 are offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.5 (9.6)
Age, Customized (Count of Participants)
<18 years of age	10 83.3%
>=18 and <65 years of age	2 16.7%
>=65 years of age	0 0%
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	10 83.3%
Other	2 16.7%
Region of Enrollment (participants) [Number]
North America	10 83.3%
Europe	2 16.7%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	142.1 (27.6)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	45.2 (27.1)
Type of Enzyme Defects (participants) [Number]
Synthesis	9 75%
Recycling	3 25%
Blood Phe at Screening Visit (µmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [µmol/L]	164.5 (186.8)

Outcome Measures

1. Primary Outcome

Title	Blood Phenylalanine(Phe) Levels Measured at Specified Timepoints
Description	Baseline blood phenylalanine(Phe) value is the latest measurement taken prior to initiation of Phenoptin treatment. The ideal range for blood Phe levels is approximately 120-360 µmol/L.
Time Frame	At Baseline, Week 4 through Extension Week 130

Outcome Measure Data

Analysis Population Description

Efficacy analysis population are the subjects received at least 1 dose of Phenoptin and has at least 1 post-treatment measurement of blood Phe.

Arm/Group Title	All Subjects	Subgroup: Subjects With Synthesis Enzymatic Defect	Subgroup: Subjects With Recycling Enzyme Defect
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, half a dose administered orally twice daily for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 are offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.	Subjects primary BH4 deficiency due to defects in the genes encoding the enzymes involved in BH4 biosynthesis, guanosine triphosphate (GTP) cyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).	Subjects with BH4 deficiency due to defects in the genes encoding the enzymes involved in BH4 recycling, pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR).
Measure Participants	12	9	3
Baseline	132.9 (134.7)	72.2 (13.4)	315.0 (180.9)
Part 2: Week 4	104.1 (66.7)	78.2 (28.4)	181.7 (96.1)
Part 2: Week 6	120.8 (119.0)	70.2 (17.2)	272.7 (175.1)
Part 2: Week 8	112.3 (106.8)	66.6 (13.6)	249.3 (156.2)
Part 2: Week 10	143.2 (147.3)	75.0 (11.5)	347.7 (187.7)
Extension: Week 22	94.3 (76.5)	63.8 (8.5)	185.7 (123.1)
Extension: Week 34	105.0 (95.3)	71.9 (16.6)	204.3 (170.8)
Extension: Week 46	144.8 (164.2)	78.8 (20.4)	343.0 (261.0)
Extension: Week 58	151.4 (173.1)	72.4 (17.7)	388.3 (226.6)
Extension: Week 70	106.7 (93.8)	72.0 (12.6)	210.7 (161.6)
Extension: Week 82	153.0 (223.2)	61.3 (12.1)	428.0 (349.4)
Extension: Week 94	186.2 (305.8)	63.8 (10.6)	553.3 (494.2)
Extension: Week 106	157.2 (159.8)	69.8 (21.7)	419.3 (33.0)
Extension : Week 118	124.3 (119.4)	73.1 (22.8)	277.7 (171.1)
Extension: Week 130	124.9 (118.2)	74.6 (14.9)	276.0 (173.9)

2. Primary Outcome

Title	Percentage of Subjects With Blood Phenylalanine (Last Observation Carried Forward) < 360 μmol/L
Description	Baseline blood phenylalanine(Phe) value is the latest measurement taken prior to initiation of Phenoptin treatment. The objective of this outcome was to compare to Phe levels achieved using previous treatment regimens.
Time Frame	At Baseline, Week 4 through Extension Week 130

Outcome Measure Data

Analysis Population Description

Efficacy analysis population are the subjects received at least 1 dose of Phenoptin and has at least 1 post-treatment measurement of blood Phe.

Arm/Group Title	All Subjects
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, administered orally twice for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin, either resumed with previously taken BH4 (tetrahydrobiopterin) formulations. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 are offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.
Measure Participants	12
Baseline	83.3 694.2%
Part 2: Week 4	100 833.3%
Part 2: Week 6	91.7 764.2%
Part 2: Week 8	91.7 764.2%
Part 2: Week 10	91.7 764.2%
Extension: Week 22	100 833.3%
Extension: Week 34	91.7 764.2%
Extension: Week 46	83.3 694.2%
Extension: Week 58	83.3 694.2%
Extension: Week 70	91.7 764.2%
Extension: Week 82	83.3 694.2%
Extension: Week 94	83.3 694.2%
Extension: Week 106	75 625%
Extension: Week 118	83.3 694.2%
Extension: Week 130	83.3 694.2%

3. Secondary Outcome

Title	Subjects Experiencing Adverse Events(AEs)
Description	Intensity was determined by the Investigator. For symptomatic AEs the following definitions were applied. Mild = AE did not limit usual activities. Moderate = AE resulted in some limitation of usual activities. Severe = AE resulted in an inability to carry out usual activities. A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. Serious AE (SAE) resulted in death, was life-threatening, required in patient hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect; or was an important medical event.
Time Frame	Up to 35 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenoptin
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, administered orally twice for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 are offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.
Measure Participants	12
Any Adverse Events	12 100%
Study Drug-Related Adverse Events	6 50%
Any Serious Adverse Events	2 16.7%
Withdrawal from study due to AE	1 8.3%
Withdrawal from Study due to SAE	0 0%
TEAE by severity: Mild	4 33.3%
TEAE by severity: Moderate	6 50%
TEAE by severity: Severe	2 16.7%

4. Other Pre-specified Outcome

Title	AEs Consistent With Signs and/or Symptoms of BH4 Deficiency
Description	Attention was paid to AEs that may be consistent with signs and/or symptoms associated with primary BH4 deficiency to determine if such signs and symptoms arose or increased in severity or frequency during the study. These included prematurity and low birth weight, inability to control body temperature, low muscle tone, decreased spontaneous movements, poor sucking, movement disorders, difficulty swallowing, hypersalivation, seizures or convulsions, behavioral problems, developmental delay, and mental retardation.
Time Frame	Up to 35 months

Outcome Measure Data

Analysis Population Description

AEs that are signs and symptoms of BH4 deficiency were reported for 3 subjects: One SAE of mild dyskinesia (required hospitalization) in one subject; events of severe dystonia and moderate Dyskinesia in one subject; and one event of mild vertigo in one subject. All events resolved and were considered unrelated to Phenoptin except mild vertigo.

Arm/Group Title	Phenoptin
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, administered orally twice for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 were offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.
Measure Participants	12
Subjects with Any Signs and/or Symptoms of BH4 Def	3 25%
Dystonia	1 8.3%
Dyskinesia	2 16.7%
Vertigo	1 8.3%

Adverse Events

Time Frame	Up to 35 months (from enrollment to Study Completion.)
Arm/Group Title	Phenoptin
Arm/Group Description	In Part 1, subjects continued their usual treatment regimen. In Part 2, subjects on non-registered formulations of BH4 at enrollment began Phenoptin treatment at approximately the same daily dose; subjects not receiving BH4 at enrollment began treatment at 5mg/kg/day Phenoptin. Half a dose was administered orally twice daily, to achieve a full dose/day. In Part 3, subjects receives 10 mg/kg/day Phenoptin, administered orally twice for three weeks, followed by 20 mg/kg/day once daily for remaining 4 weeks. In extension phase, subjects were offered the option to continue treatment with Phenoptin, either resumed with previously taken BH4 (tetrahydrobiopterin) formulations. All 12 subjects participated in Part 1, Part 2 and Extension Phase. Subjects completed Part 2 are offered the option of participating in Part 3, Subjects who agreed to participate proceeded to Part 3. Among 12 subjects, 2 participated in Part 3.
All Cause Mortality
	Phenoptin
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Phenoptin
	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)
Infections and infestations
Upper Respiratory Tract Infection	1/12 (8.3%)	1
Nervous system disorders
Dyskinesia	1/12 (8.3%)	1
Renal and urinary disorders
Nephrolithiasis	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	1/12 (8.3%)	1
Surgical and medical procedures
Medical Device Change	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Phenoptin
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Neutropenia	1/12 (8.3%)
Ear and labyrinth disorders
Vertigo	1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain upper	2/12 (16.7%)
Constipation	1/12 (8.3%)
Diarrhoea	7/12 (58.3%)
Dyspepsia	1/12 (8.3%)
Nausea	1/12 (8.3%)
Vomiting	4/12 (33.3%)
General disorders
Fatigue	2/12 (16.7%)
Irritability	1/12 (8.3%)
Pyrexia	1/12 (8.3%)
Immune system disorders
Seasonal allergy	1/12 (8.3%)
Infections and infestations
Bronchitis	1/12 (8.3%)
Candidiasis	1/12 (8.3%)
Cellulitis	1/12 (8.3%)
Ear infection	1/12 (8.3%)
Gastroenteritis	1/12 (8.3%)
Gastroenteritis bacterial	1/12 (8.3%)
Gastroenteritis viral	2/12 (16.7%)
Nasopharyngitis	5/12 (41.7%)
Otitis media	2/12 (16.7%)
Pharyngitis streptococcal	2/12 (16.7%)
Respiratory tract infection	1/12 (8.3%)
Sinusitis	2/12 (16.7%)
Skin candida	1/12 (8.3%)
Tonsillitis	1/12 (8.3%)
Urinary tract infection	1/12 (8.3%)
Viral skin infection	1/12 (8.3%)
Viral upper respiratory tract infection	1/12 (8.3%)
Upper respiratory tract infection	2/12 (16.7%)
Injury, poisoning and procedural complications
Contusion	1/12 (8.3%)
Excoriation	1/12 (8.3%)
Eye injury	1/12 (8.3%)
Face injury	1/12 (8.3%)
Fall	1/12 (8.3%)
Investigations
Alanine aminotransferase increased	1/12 (8.3%)
Aspartate aminotransferase increased	1/12 (8.3%)
Blood bilirubin increased	1/12 (8.3%)
Blood calcium increased	2/12 (16.7%)
Blood creatinine increased	1/12 (8.3%)
Gamma-glutamyltransferase increased	1/12 (8.3%)
Lymphocyte count increased	1/12 (8.3%)
Metabolic function test abnormal	1/12 (8.3%)
Neutrophil count decreased	1/12 (8.3%)
Protein urine present	1/12 (8.3%)
Urine ketone body present	1/12 (8.3%)
Urine leukocyte esterase positive	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Neck pain	1/12 (8.3%)
Nervous system disorders
Dizziness	1/12 (8.3%)
Dysaesthesia	1/12 (8.3%)
Dystonia	1/12 (8.3%)
Nervous system disorder	1/12 (8.3%)
Neurological symptom	2/12 (16.7%)
Paraesthesia	1/12 (8.3%)
Dyskinesia	2/12 (16.7%)
Psychiatric disorders
Abnormal behaviour	1/12 (8.3%)
Self injurious behaviour	1/12 (8.3%)
Renal and urinary disorders
Nephrolithiasis	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/12 (8.3%)
Cough	2/12 (16.7%)
Pharyngolaryngeal pain	2/12 (16.7%)
Postnasal drip	1/12 (8.3%)
Rhinorrhoea	2/12 (16.7%)
Tonsillar hypertrophy	1/12 (8.3%)
Respiratory distress	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Ecchymosis	1/12 (8.3%)
Hyperhidrosis	1/12 (8.3%)
Ingrowing nail	1/12 (8.3%)
Rash	1/12 (8.3%)
Rash generalised	1/12 (8.3%)
Skin inflammation	1/12 (8.3%)
Surgical and medical procedures
Medical device change	1/12 (8.3%)

Limitations/Caveats

Due to the small sample size in this study, a single patient AE exceeded the 5% maximum AE reporting threshold. Many of these manifestations are due to primary BH4 deficiency disease and the associated inadequate neurotransmitters.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.