E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metabolic Disorders - Phenylketonuria |
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E.1.1.1 | Medical condition in easily understood language |
Phenylketonuria (PKU) is an autosomal-recessive inborn error of metabolism characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH), which metabolizes phenylalanine (Phe) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034873 |
E.1.2 | Term | Phenylketonuria (PKU) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the long-term safety of PTC923 in subjects with PKU • To evaluate changes from baseline in dietary Phe/protein consumption |
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E.2.2 | Secondary objectives of the trial |
• To evaluate PTC923 effect on quality of life (QOL) using the Phenylketonuria-quality of life (PKU-QOL) questionnaire in the subset of subjects who are able to complete the PKU-QOL (ie, subjects whose primary language is English [British or American], Turkish, Dutch, German, Spanish, Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11 years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages ≥18 years Adult PKU-QOL) • To evaluate PTC923 effect of QOL using the European Quality of Life 5 Dimensions (EQ-5D) (EQ-5D for Youth [EQ-5D-Y] Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D- 5 Levels (EQ-5D5L ([≥16 years]) •To evaluate the pharmacokinetics (PK) of sepiapterin and tetrahydrobiopterin (BH4) following PTC923 dosing |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed consent and assent (if necessary, at the investigator’s discretion [ie, for children and/or subjects that are mentally impaired secondary to disease]) with parental/legal guardian consent 2. Male or female subjects of any age 3. Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L 3. Women of childbearing potential, as defined in (CTFG 2020), must have a negative pregnancy test at study entry and agree to abstinence or the use of at least one highly effective form of contraception (with a failure rate of <1% per year when used consistently and correctly): • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: − Oral − Intravaginal − Transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: − Oral − Injectable − Implantable • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomized partner with confirmed azoospermia Highly effective contraception or abstinence must be continued for the duration of the study, and for up to 90 days after the last dose of the study drug. All females will be considered of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group without other known or suspected cause) or have been permanently sterilized surgically (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy). 4. Males who are sexually active with women of childbearing potential who have not had a vasectomy must agree to use a barrier method of birth control during the study and for up to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active. Males who have undergone a vasectomy are not required to use a contraceptive method if at least 16 weeks post procedure. 5. Willing and able to comply with the protocol and study procedure 6. Willing to continue current diet unchanged while participating in the study (unless specifically instructed to change diet during the study by the investigator) |
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E.4 | Principal exclusion criteria |
1. The individual, in the opinion of the investigator, is unwilling or unable to adhere to the requirements of the study 2. Inability to tolerate oral medication 3. A female who is pregnant or breastfeeding, or considering pregnancy 4. Serious neuropsychiatric illness (eg, major depression) not currently under medical control, that in the opinion of the investigator or sponsor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject 5. Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min) as estimated most recently during qualifying participation in a feeder study) and/or under care of a nephrologist 6. Any other condition that in the opinion of the investigator or sponsor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject 7. Requirement for concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate) 8. Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ) Additional criteria for subjects who did not participate in a feeder study: 9. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, and peptic ulcer disease, etc) that could affect the absorption of study drug 10. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy 11. History of allergies or adverse reactions to synthetic BH4 or sepiapterin 12. Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening 13. Any clinically significant laboratory abnormality as determined by the investigator. In general, each laboratory value from Screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range, unless deemed not clinically significant by the investigator 14. Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73 m2. In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation should be used to determine GFR. In subjects <18 years of age, the Bedside Schwartz Equation should be used to determine GFR. 15. Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin 4-alpha-carbinolamine dehydratase genes 16. Major surgery within the prior 90 days of screening 17. Unwillingness to washout from BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety is a primary endpoint: Safety of long-term treatment with PTC923 will be measured by number of treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical laboratory tests, vital signs, and physical examinations.
Primary efficacy endpoint is the change from baseline in dietary Phe/protein consumption measured during Dietary Phe Tolerance Assessment period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety of long-term treatment with PTC923 will be measured by number of treatment-emergent adverse events (TEAEs), including assessment of severity of TEAEs, clinical laboratory tests, vital signs, and physical examinations.
Dietary Phe tolerance evaluated at Baseline and every 2 weeks over the course of 26 weeks assessment period |
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E.5.2 | Secondary end point(s) |
• Changes from baseline in QOL using PKU-QOL questionnaire in the subset of subjects who are able to complete the PKU-QOL (ie, subjects whose primary language is English [British or American], Turkish, Dutch, German, Spanish, Italian, Portuguese, or French) (ages 6 to 8 years Parent PKU-QOL; ages 9 to 11 years Child PKU-QOL; ages 12 to 17 years Adolescent PKU-QOL; ages ≥18 years Adult PKU-QOL) • Changes from baseline in QOL using the EQ-5D (EQ-5D-Y Proxy Version 1 [3 to 7 years]; EQ-5D-Y [8 to 15 years]; EQ-5D-5L ([≥16 years]) •PK assessment of sepiapterin and BH4 concentrations in plasma following dosing of sepiapterin |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary measures will be evaluated at 6-month intervals starting at M8D1. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Mexico |
United States |
Georgia |
Turkey |
Denmark |
France |
Germany |
Italy |
Netherlands |
Portugal |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |