A Study to Learn About the Safety and Effects of the Study Drug PRX-102 in Children and Adolescents with Fabry Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Chiesi Farmaceutici S.p.A.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

8 Oct 2024 → ongoing

Decision date (initial)

2024-09-20

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Chiesi Farmaceutici S.p.A.

External identifiers

EU CT number

2022-503128-29-00

ClinicalTrials.gov

NCT06328608

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

To evaluate the safety, pharmacodynamics, efficacy and pharmacokinetics of PRX-102 in three different age cohorts in paediatric patients with confirmed Fabry disease.

Conditions and MedDRA coding

Fabry's disease

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001828-PIP01-15

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male or female aged 2 to 7 years (Cohort A), 8 to 12 years (Cohort B), or 13 to <18 years (Cohort C)
2. A documented diagnosis of Fabry disease, as determined by the following: • Males: 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.
3. 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
4. Clinical condition that, in the opinion of the Investigator, requires treatment with enzyme replacement therapy (ERT).

Exclusion criteria 14

1. 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).
2. 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.
3. Currently taking another investigational drug for any condition.
4. Carry only known non-pathogenic Fabry mutations.
5. 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).
6. History of renal dialysis or kidney transplantation.
7. History of or current malignancy requiring treatment.
8. Severe cardiomyopathy or significant unstable cardiac disease within 6 months prior to screening.
9. 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.
10. 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
11. 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.
12. 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 amenorrhea, a single FSH measurement is insufficient.
13. 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.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 15

1. Safety Variables: •Treatment-emergent adverse events (TEAEs) • Infusion-related reactions (IRRs) • Injection site reactions (ISRs)
2. 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)
3. 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.
4. Efficacy Variables: Cardiac function: • Echocardiogram • Holter ECG • Cardiac biomarkers: • High-sensitivity cardiac troponin T (hs-cTnT) • N-terminal pro B-type natriuretic peptide (NT-proBNP)
5. Fabry disease biomarkers: • Plasma globotriaosylceramide (Gb3) concentration •Plasma globotriaosylsphingosine (lyso-Gb3) concentration • Urine lyso-Gb3 concentration
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Chiesi Farmaceutici S.p.A.

Sponsor organisation

Chiesi Farmaceutici S.p.A.

Address

Via Palermo 26 A

City

Parma

Postcode

43122

Country

Italy

Scientific contact point

Organisation

Chiesi Farmaceutici S.p.A.

Contact name

Clinical Development, Global Rare Diseases

Public contact point

Organisation

Chiesi Farmaceutici S.p.A.

Contact name

Clinical Development, Global Rare Diseases

Third parties 12

Locations

4 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 121 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications