| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Phenylketonuria (PKU) is a serious inherited metabolic disorder in which phenylalanine (Phe) accumulates to abnormally high levels in the blood and brain. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| 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 in adult subjects with PKU, the efficacy of pegvaliase when administered through an Induction/Titration /Maintenance dose regimen.
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| E.2.2 | Secondary objectives of the trial |
To evaluate whether treatment with pegvaliase can enable reduction or discontinuation of medical food protein intake and increase of intact (natural, complete) protein intake using a prospectively defined algorithm, whilst still maintaining blood Phe control (≤ 600 µmol/L).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged ≥ 18 years of age at the time of Screening.
2. A current diagnosis of PKU with both of the following:
a. Average Phe concentration of > 600 μmol/L at Screening Visits 1 and 2.
b. Average blood Phe concentration of > 600 μmol/L over the past 6 months (per available data).
3. Non-responsive to sapropterin (Kuvan) as determined from a 7-day BH4 response test or previous treatment with sapropterin not effective, based on an inadequate control of blood Phe (basis of judgement documented).
4. Has identified a competent person or persons ≥ 18 years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration for at least the first 6 months of self-administration. A home healthcare nurse may perform the study drug observations.
5. For females of childbearing potential, must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. (Females are considered not to have childbearing potential if they have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to Screening, or have had a total hysterectomy).
6. If sexually active, female subjects must be willing to use one highly effective method and one acceptable method of contraception while participating in the study and 4 weeks after completion of the study:
a. Highly effective methods of contraception may include: (1) primary forms: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal) or
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable); (2) secondary forms: include intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion.
b. Acceptable (but not highly effective) methods of contraception may include: progestogen-only oral hormonal contraception*, where inhibition of ovulation is not the primary mode of action; male or female condom with or without spermicide; cap, diaphragm or sponge with spermicide.
c. Females who have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to Screening, have a vasectomised partner (with medical assessment of surgical success), have had a total hysterectomy, or are sexually abstinent do not need to use any other forms of contraception during the study.
*Note that the use of two methods of hormonal contraception is not advised.
7. Is willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures.
8. Is willing and able to comply with all study procedures.
9. Is in generally good health, as evidenced by physical examination. |
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| E.4 | Principal exclusion criteria |
1. In the judgment of the investigator, is likely to be able to achieve control of blood Phe below 600 μmol/L with MNT (basis of judgment documented).
2. Use of any medication that is intended to treat PKU including the use of sapropterin (Kuvan), within 14 days prior to administration of study drug (Day 1; first dose of pegvaliase).
3. Not willing or unlikely to be able to perform independent self-administration (or to allow carer administration) or not have the ability to recognise the signs and symptoms of acute systemic hypersensitivity reactions (ASHRs).
4. Not willing or unlikely to be able to use adrenaline/epinephrine injection device (auto injector or prefilled syringe) and have them readily available at all times throughout pegvaliase treatment.
5. Not willing or unlikely to be able to maintain their diet in accordance with dietary information presented in the protocol.
6. Based on the clinical judgement of the investigator, does not have the neurocognitive and linguistic capacities to comprehend and answer the patient-reported outcome questionnaires.
7. Not willing or unlikely to be able to complete the study diary.
8. Use or planned use of any injectable drugs containing PEG (other than pegvaliase), including medroxyprogesterone injection, within 3 months prior to Screening (or within five elimination half-lives, whichever is longer) and during study participation.
9. Concurrent disease or condition that would interfere with study participation or safety.
10. Alanine aminotransferase (ALT) concentration ≥ 2 times the upper limit of normal (ULN).
11. Subjects with known renal pathology, persistent albuminuria (elevated urine albumin creatinine ratio above the ULN measured on first morning void, confirmed on a repeat measurement), or creatinine > 1.5 times the ULN.
12. Pregnant or breastfeeding at Screening or planning to become pregnant (subject or partner of subject) or breastfeed at any time during the study.
13. Use of any investigational product or investigational medical device within 30 days prior to Screening or requirement for any investigational agent prior to completion of all scheduled study assessments.
14. Previous exposure to pegvaliase.
15. Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or terminating early from study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percentage of subjects with blood Phe concentration ≤ 600 µmol/L by Week 60.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A subject is considered to have achieved Phe concentration ≤ 600 µmol/L by Week 60 if they have at least 2 consecutive blood Phe assessments ≤ 600 µmol/L at or prior to Week 60. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint is assessed in subjects who were either on medical food or had < 1 x RDI for total protein at baseline, as the percentage of subjects who met both of the following criteria:
• At Week 60, have either a reduction in protein intake from medical food from baseline and/or an increase in intact protein intake from baseline*
• At Week 60, have a blood Phe concentration ≤ 600 μmol/L
* A limited number of specific scenarios that that are not considered to represent a clinical improvement in nutritional status will be defined in the Statistical Analysis Plan (SAP), and these subjects will be excluded from the analysis |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Austria |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Turkey |
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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