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 efficacy of PTC923 in reducing blood Phe levels in subjects with PKU as measured by mean change in blood Phe levels from baseline to Weeks 5 and 6 (ie, the average of each respective treatment dose 2-week period of double-blind treatment) |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the proportion of subjects with baseline Phe levels ≥600 μmol/L who achieve Phe levels <600 μmol/L at the end of the double-blind treatment period •To evaluate the effect of PTC923 dose response on reducing blood Phe levels in subjects with PKU •To evaluate the PK of PTC923 in subjects with PKU •To assess the safety of PTC923 in subjects with PKU |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Approximately 30 subjects ≥12 years of age will participate in the PK sub study. At least 12 out of the 30 subjects ≥12 years of age participating in the PK sub study will be female. In addition, up to 6 subjects from each of these age groups will be included: 1) <2 years; 2) 2 to 5 years; and 3) 6 to 11 years. Blood samples will be collected from subjects participating in PK substudy to characterize the PK of sepiapte rin and BH4 following an intensive schedule on Part 1 Day 1 and Part 1 Day 2 for subjects >=2 . For subjects < 2years of age participating in the substudy, blood samples (2 on each occasion; total of 4 samples) will be collected on Part 1 Day 1 and Part 1 Day 14. In addition to blood drawn for PK sampling at specified timepoints, a small amount of blood will be drawn to a minicollect tube (~0.25 mL) at the same time and applied to the VAMS device for blood Phe and Tyr measurement. |
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E.3 | Principal inclusion criteria |
1.Informed consent and assent (if necessary, at the investigator’s discretion [ie, for children and/or subjects who are mentally impaired secondary to disease]) with parental/legal guardian consent 2.Male or female subjects of any age 3.Uncontrolled blood Phe level ≥360 μmol/L on current therapy anytime during Screening and uncontrolled blood Phe level ≥360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the subject's medical history (inclusive of the Screening value). 4.Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L 5.Women of childbearing potential, as defined in (CTFG 2020), must have a negative pregnancy test at Screening 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). 6.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. 7.Willing and able to comply with the protocol and study procedures 8.Willing to continue current diet unchanged while participating in the study
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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.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 3.History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy 4.Inability to tolerate oral medication 5.History of allergies or adverse reactions to synthetic BH4 or sepiapterin 6.Current participation in any other investigational drug study or use of any investigational agent within 30 days prior to Screening 7.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 8.A female who is pregnant or breastfeeding, or considering pregnancy 9.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 10.Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min) and/or under care of a nephrologist 11.Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 mL/min/1.73m2. In subjects ≥18 years of age, the Modification of Diet in Renal Disease Equation should be used to determine GFR. In subjects <18 years, the Bedside Schwartz Equation should be used to determine GFR. 12.Requirement for concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate) 13.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 14.Major surgery within the prior 90 days of screening 15.Concomitant treatment with BH4 supplementation (eg, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ) 16.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) |
The primary efficacy measure will be reduction in blood Phe levels in subjects with PKU as measured by mean change in Phe levels from baseline to Part 2 Weeks 5 and 6 (ie, the average of the 2-week period at the target dose of double-blind treatment). Baseline blood Phe level will be the mean of Day -1 and Day 1 (predose) blood Phe levels |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are the proportion of subjects with baseline Phe levels ≥600 μmol/L who achieve Phe levels <600 μmol/L at the end of the double-blind treatment period and the change from baseline in mean blood Phe levels at each PTC923 dose level (ie, each 2-week period in Part 2). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
each 2-week period in Part 2 |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 14 |
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 |
France |
Netherlands |
Spain |
Germany |
Italy |
Denmark |
Georgia |
Portugal |
Turkey |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |