PEGUNIGALSIDASE ALFA for Fabry disease

Inclusion criteria

• {"criterion_text":"- Male or female aged 2 to 7 years (Cohort A), 8 to 12 years (Cohort B), or 13 to <18 years (Cohort C)"}
• {"criterion_text":"- A documented diagnosis of Fabry disease, as determined by the following: •\tMales: Plasma and/or leukocyte alpha-galactosidase-A (α-GAL-A) activity (by activity assay) that is ≤ 5% of mean normal laboratory levels, or, if the enzymatic activity is above the 5% limit but still under the normal level, a confirmed disease-causing mutation of the α-GAL-A (GLA)gene. • Females: Historical genetic test results consistent with Fabry mutations, or, in the case of novel mutations, a first-degree male relative with Fabry disease. • All subjects: At least one of the following characteristic features of Fabry disease: neuropathic pain, cornea verticillata, and/or clustered angiokeratoma."}
• {"criterion_text":"- History of Fabry pain: • Episodic crises (Fabry crises) characterised by agonizing burning pain originating in the extremities and radiating inwards to the limbs and other parts of the body, OR • Chronic pain characterised by burning and tingling paraesthesia"}
• {"criterion_text":"- Clinical condition that, in the opinion of the Investigator, requires treatment with enzyme replacement therapy (ERT)."}

Exclusion criteria

• {"criterion_text":"- Estimated glomerular filtration rate (eGFR) at screening < 80 mL/min/1.73 m2, calculated using the Creatinine Cystatin C-based Chronic Kidney Disease in Children (CKiD) equation (2012)."}
• {"criterion_text":"- Additional Exclusion Criteria for Subjects Enrolled in Stage I:For subjects enrolled in Stage I (targeting up to 9 subjects total) these specific exclusion criteria, in addition to those above, apply: a) Female b) Non-classic form of Fabry disease c) Receipt of treatment for Fabry disease within 6 months prior to screening d) Positive for anti-PRX-102 antibodies at screening e) Aged 4 years or younger"}
• {"criterion_text":"- Additional Exclusion Criteria for Subjects in Stage II : For subjects enrolled in Stage II, these specific exclusion criteria, in addition to exclusion criteria #1 to #11 apply a) Unwilling to discontinue current ERT treatment for Fabry disease at least 14 days, or chaperone therapy at least 3 days, before baseline."}
• {"criterion_text":"- Additional Exclusion Criteria for Subjects in Stage II: Females: Pregnant or lactating, or of childbearing potential with a fertile male partner and/or unwilling to undergo pregnancy testing as outlined and to use a highly reliable method of contraception from the informed consent signature until 30 days after the last infusion. Note: Before the start of treatment, the Investigator will decide whether or not pregnancy testing and contraception counselling are necessary. Since over the course of the study, pre-pubertal girls may reach menarche and adolescents of either gender may become sexually active, the Investigator must periodically check on the status of these issues and implement pregnancy testing and/or contraception counselling if required. A female subject is considered of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhoea, a single FSH measurement is insufficient."}
• {"criterion_text":"- History of type I hypersensitivity reactions (anaphylactic or anaphylactoid life-threatening reaction) to other ERT treatment for Fabry disease or to any component of the study drug."}
• {"criterion_text":"- Initiation of treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), or a change of dose in ongoing treatment, in the 4 weeks prior to screening."}
• {"criterion_text":"- Subject with urine protein to creatinine ratio (UPCR) > 0.5 g/g (0.5 mg/mg or 500 mg/g) if not treated with an ACE inhibitor or ARB."}
• {"criterion_text":"- Currently taking another investigational drug for any condition."}
• {"criterion_text":"- Carry only known non-pathogenic Fabry mutations."}
• {"criterion_text":"- History of acute kidney injury in the 12 months prior to screening, including specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitic renal diseases); non-specific conditions (e.g., ischaemia, toxic injury); or extrarenal pathology (e.g., prerenal azotaemia, acute postrenal obstructive nephropathy)."}
• {"criterion_text":"- History of renal dialysis or kidney transplantation."}
• {"criterion_text":"- History of or current malignancy requiring treatment."}
• {"criterion_text":"- Severe cardiomyopathy or significant unstable cardiac disease within 6 months prior to screening."}
• {"criterion_text":"- Presence of any medical, emotional, behavioural, or psychological condition that in the judgement of the Investigator could interfere with the subject’s compliance with the requirements of the study."}

Primary endpoints

• {"endpoint_text":"- Safety Variables: •Treatment-emergent adverse events (TEAEs) • Infusion-related reactions (IRRs) • Injection site reactions (ISRs)","definition_or_measurement_approach":"Monitoring and collection of TEAEs, assessment of infusion-related reactions and injection-site reactions as safety endpoints (clinical reporting and investigator assessment)."}
• {"endpoint_text":"- Safety Variables: • Clinical laboratory tests • Physical examination • Vital signs • Electrocardiogram (ECG) • Assessment for the development of anti-drug antibodies (ADA) against PRX-102 • Use of pre-medications to manage infusion-related reactions • Growth and development (height, weight, and sexual development by Tanner staging)","definition_or_measurement_approach":"Clinical laboratory testing, physical exams, vital signs, ECGs, ADA assays against PRX-102, documentation of pre-medication use, and measurement of growth and Tanner staging for development."}
• {"endpoint_text":"- Efficacy Variables: Renal function: • eGFR, calculated using the Creatinine-Cystatin C–based Chronic Kidney Disease in Children (CKiD) (2012). •Albuminuria, as determined by the urine albumin-to-creatinine ratio (uACR) test, and proteinuria, as determined by the urine protein-to-creatinine ratio (UPCR) test.","definition_or_measurement_approach":"Renal function assessed by eGFR (CKiD 2012 creatinine-cystatin C equation), uACR and UPCR laboratory measurements."}
• {"endpoint_text":"- Efficacy Variables: Cardiac function: • Echocardiogram • Holter ECG • Cardiac biomarkers: •\tHigh-sensitivity cardiac troponin T (hs-cTnT) •\tN-terminal pro B-type natriuretic peptide (NT-proBNP)","definition_or_measurement_approach":"Cardiac function assessed by echocardiography, Holter ECG monitoring and measurement of cardiac biomarkers hs-cTnT and NT-proBNP."}
• {"endpoint_text":"- Fabry disease biomarkers: • Plasma globotriaosylceramide (Gb3) concentration •Plasma globotriaosylsphingosine (lyso-Gb3) concentration • Urine lyso-Gb3 concentration","definition_or_measurement_approach":"Measurement of plasma Gb3, plasma lyso-Gb3 and urine lyso-Gb3 concentrations as biochemical disease biomarkers."}
• {"endpoint_text":"- Other measures of Fabry disease: • Use of pain medications • Occurrence of Fabry clinical events (FCEs) • Mainz Severity Score Index (MSSI) • Paediatric Quality of Life Inventory -Gastrointestinal Symptoms (PedsQL-GI) questionnaire: parent version and age- appropriate subject version","definition_or_measurement_approach":"Collection of analgesic use, recording of Fabry clinical events, MSSI scoring and administration of PedsQL-GI (parent and age-appropriate subject versions)."}
• {"endpoint_text":"- Other measures of Fabry disease: • Fabry Specific Pediatric Health and Pain Questionnaire (FPHPQ): age appropriate subject version • Paediatric Quality of Life Inventory - Pain Questionnaire (PedsQL-PPQ): parent version and age- appropriate subject version","definition_or_measurement_approach":"Administration of FPHPQ and PedsQL-PPQ questionnaires (age-appropriate versions for subjects and parent versions)."}
• {"endpoint_text":"- Other measures of Fabry disease: • EuroQoL 5 Dimensions version for youth (EQ-5D-Y) questionnaire for assessment of quality of life: parent version and age- age-appropriate subject version","definition_or_measurement_approach":"Administration of EQ-5D-Y (parent and age-appropriate subject versions) to assess health-related quality of life."}
• {"endpoint_text":"- Measures to be used if a subject reaches the age of 18 years: • Gastrointestinal Symptom Rating Scale (GSRS) in place of the PedsQL-GI • Brief Pain Inventory - Short Form (BPI-SF) in place of the PedsQL-PPQ","definition_or_measurement_approach":"If subject turns 18, GSRS and BPI-SF replace the paediatric questionnaires to assess gastrointestinal symptoms and pain."}
• {"endpoint_text":"- Measures to be used if a subject reaches the age of 18 years: • Quality-of-life EuroQoL 5 Dimensions 5 Levels Questionnaires (EQ-5D-5L) questionnaire in place of the EQ-5D-Y • In addition, the FPHPQ will be dropped. The other measures (use of pain medications, occurrence of FCEs, and completion of the MSSI) will remain the same","definition_or_measurement_approach":"If subject turns 18, EQ-5D-5L replaces EQ-5D-Y; FPHPQ discontinued; other measures remain consistent."}
• {"endpoint_text":"- Pharmacokinetic Assessments: • The individual PK parameters and their relationship with PD and/or efficacy endpoints (e.g., with plasma lyso-Gb3 and/or any other relevant PD and/or efficacy endpoints) will be derived from the updated population PK model after the addition of the emerging data.","definition_or_measurement_approach":"Derivation of individual PK parameters and PK/PD relationships via updated population PK modelling using collected PK samples."}
• {"endpoint_text":"- Pharmacodynamic Assessments: Fabry disease is characterised by the progressive accumulation of Gb3 and its metabolite lyso-Gb3, so concentrations of Gb3 and lyso-Gb3 are biomarkers of the extent of the disease.","definition_or_measurement_approach":"Pharmacodynamic assessment via measurement of Gb3 and lyso-Gb3 concentrations as biomarkers of disease burden."}
• {"endpoint_text":"- Pharmacodynamic Assessments: For purposes of determining the dosages of PRX-102 to be used in Stage II for Cohorts A and B, blood samples and urine samples for measuring the concentration of Gb3 and lyso-Gb3 will be collected in Stage I E2W at Visits #1, #3, #7 and #14.","definition_or_measurement_approach":"PK/PD sampling every 2 weeks in Stage I (E2W) at specified visits to inform dose selection for Stage II using measured Gb3 and lyso-Gb3."}
• {"endpoint_text":"- Pharmacodynamic Assessments: For purposes of determining the dosages of PRX-102 to be used in Stage II for Cohorts A and B, blood samples and urine samples for measuring the concentration of Gb3 and lyso-Gb3 will be collected in Stage I E2W at Visits #1, #3, #7 and #14.","definition_or_measurement_approach":"Additional statement of PK/PD sampling schedule in Stage I (E2W) for dose determination (visits #1, #3, #7, #14)."}
• {"endpoint_text":"- Pharmacodynamic Assessments: For purpose of assessing efficacy, additional blood samples for the measurement of Gb3 and lyso-Gb3 and urine samples for the measurement of lyso-Gb3 will be collected at specified time points during the study in all cohorts.","definition_or_measurement_approach":"Collection of additional blood and urine samples at pre-specified time points across all cohorts for efficacy-related biomarker assessments (Gb3, lyso-Gb3)."}

Methods

• Brochures and recruitment materials targeted by age group (2-7 years, 8-12 years, 13-17 years) (documents: K2_Recruitment material_brochure-... for multiple age groups)
• Pre-enrolment prescreener materials (K2_Pre-screner / K2_Prescreener)
• Physician outreach letters (K2_Physician Letter) directed to clinicians treating metabolic / paediatric patients
• Featured trial materials and website listings (K2_Featured Trial; K2_Recruitment material_Website Citeline)
• Accellacare materials and memos (site-specific recruitment support / logistics)
• Use of eCOA/ePRO platforms for remote data capture (Medable eCOA) as part of study operations

France

Earliest CTIS Part Ii Submission Date

06-08-2024

Latest Decision Or Authorization Date

15-01-2026

Processing Time Days

527

Number Of Sites

2

Number Of Participants

2

Austria

Earliest CTIS Part Ii Submission Date

21-08-2024

Latest Decision Or Authorization Date

19-01-2026

Processing Time Days

516

Number Of Sites

1

Number Of Participants

1

Spain

Earliest CTIS Part Ii Submission Date

20-08-2024

Latest Decision Or Authorization Date

19-01-2026

Processing Time Days

517

Number Of Sites

1

Number Of Participants

1

Norway

Earliest CTIS Part Ii Submission Date

16-08-2024

Latest Decision Or Authorization Date

30-01-2026

Processing Time Days

532

Number Of Sites

1

Number Of Participants

3

Primary sponsor

Full Name

Chiesi Farmaceutici S.p.A.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Italy

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Clinical Operations, Study start up

Third parties

• {"country":"United States","full_name":"Transperfect Translations International Inc.","duties_or_roles":"Translations","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Mapi Research Trust","duties_or_roles":"COA licensing","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"SGS France","duties_or_roles":"Central Lab for ADA, nAb and PK analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Clinical Operations, Study start up","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Central ECG & Holter ECG and Central Echo","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Canada","full_name":"Waters-CHUS Expertise Centre in Clinical Mass Spectrometry","duties_or_roles":"Central Lab for Lyso-Gb3 & Gb3","organisation_type":"Health care"}
• {"country":"United Kingdom","full_name":"World Courier (U.K.) Limited","duties_or_roles":"Transport of IP from site to patients’ homes and shipment back to site","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Clinical Payments","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Group Limited","duties_or_roles":"IMP Supply","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medable Inc.","duties_or_roles":"eCOA (ePROs)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Quipment","duties_or_roles":"IP Infusion Pumps provision to sites","organisation_type":"Non-Pharmaceutical company"}