Nedosiran in Pediatric Patients From Birth to 11 Years of Age With PH and Relatively Intact Renal Function

Primary Hyperoxaluria Clinical Trial

— PHYOX8  

Official title:

A Phase 2 Open-Label Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nedosiran in Pediatric Patients From Birth to 11Years of Age With Primary Hyperoxaluria and Relatively Intact Renal Function

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05001269
• Other study ID #: DCR-PHXC-203
• Status: Recruiting
• Phase: Phase 2
• Start date: February 22, 2022
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Contact: Medical Information
• Phone: 617-621-8097
• Email: medicalinfo[@]dicerna.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this study is to evaluate nedosiran in participants 11 years of age and younger who have Primary Hyperoxaluria with relatively intact renal function.

Description:

This is an open-label, repeat-dose, Phase 2 study of nedosiran in participants 11 years of age or younger who have PH1, PH2 or PH 3 and relatively intact renal function.

Following the up-to-35- day screening period, participants will return to the clinic for monthly dosing visits through Day 180.

The total duration of this study is approximately 15 months from first participant, first visit, until last participant, last visit.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 11 Years

Eligibility

Inclusion Criteria:

1. Birth to 11 years of age inclusive, at the time of signing the informed consent.

2. Documented diagnosis of PH1 or PH2 or PH3 confirmed by genotyping (historically available genotype information is acceptable for study eligibility).

3. Average spot Uox to creatinine ratio at Screening above 2 times the 95th percentile for age (Matos et al, 1999):

• > 0.44 mol/mol in participants < 6 months

• > 0.34 mol/mol in participants from 6 months to < 12 months

• > 0.26 mol/mol in participants 12 months to < 2 years

• > 0.20 mol/mol in participants from 2 to < 3 years and

• > 0.16 mol/mol in participants from 3 to < 5 years > 0.14 mol/mol in participants from 5 to <7 years > 0.12 mol/mol in participants from 7 to 11 years

4. Estimated GFR at Screening = 30 mL/min normalized to 1.73 m2 BSA. See Section 8.2.6.1 for equations. For infants aged less than 12 months, serum creatinine below the 97th percentile of a healthy population (Boer et al., 2010).

5. Participants must have been on a stable treatment regimen for PH for 3 months prior to Day 1 and parent(s)/legal guardian should be willing to ensure participant remains on the same stable treatment regimen during the study. Dose adjustments for interval weight gain are acceptable.

6. Male or Female

Male participants:

A male participant with a female partner of childbearing potential must agree to use contraception, as detailed in Section 10.5.2, during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period.

Female participants:

A female participant is eligible to participate if she is not pregnant (see Section 10.5.1), not breastfeeding, and at least 1 of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Section 10.5.1 OR A WOCBP who agrees to follow the contraceptive guidance in Section 10.5.2 during the treatment period and for at least 12 weeks after the last dose of study intervention.

Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Note: If the childbearing potential changes after start of the study (e.g., a premenarchal female participant experiences menarche) or the risk of pregnancy changes (e.g., a female participant who is not heterosexually active becomes active), the participant must discuss this with the Investigator, who should determine if a female participant must begin a highly effective method of contraception or a male participant must use a condom. If reproductive status is questionable, additional evaluation should be considered.

7. Participant's parent or legal guardian is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

a. For children younger than 12 years of age, assent will be based on local regulation. If assent is required, participant must be able to provide written assent for participation.

8. A legal guardian or primary caregiver must be available to help the study-site personnel ensure follow up; accompany the participant to the study site on each assessment day according to the SoA (e.g., able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures); consistently and consecutively be available to provide information on the participant using the rating scales during the scheduled study visits; accurately and reliably dispense study intervention as directed.

9. Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations)

Exclusion Criteria:

1. Prior renal or hepatic transplantation; or planned transplantation within the study period

2. Currently receiving dialysis or anticipating requirement for dialysis during the study period

3. Plasma oxalate (Pox) > 30 µmol/L at Screening

4. Documented evidence of clinical manifestations of severe systemic oxalosis (including preexisting retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations)

5. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact participant's safety including, but not restricted to:

1. Severe intercurrent illness

2. Known causes of active liver disease/injury or transaminase elevation (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis [NAFLD/NASH])

3. History of serious mental illness that includes, but is not limited to, schizophrenia, bipolar disorder, or severe depression requiring hospitalization or pharmacological intervention

4. Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological diseases, including dermatological including rash, severe eczema or dermatitis, or connective tissue diseases or disorders

6. Use of an RNAi drug within the last 6 months

7. History of 1 or more of the following reactions to an oligonucleotide-based therapy:

1. Severe thrombocytopenia (platelet count = 100,000/µL)

2. Hepatotoxicity, defined as ALT or AST > 3 times the upper ULN and total bilirubin > 2 × ULN or INR > 1.5

3. Severe flu-like symptoms leading to discontinuation of therapy

4. Localized skin reaction from the injection (graded severe) leading to discontinuation of therapy

5. Coagulopathy/clinically significant prolongation of clotting time

8. Participation in any clinical study in which they received an IMP within 4 months or 5 times the half-life of the drug (whichever is longer) before Screening

a. For IMPs with the potential to reduce urine and/or plasma oxalate concentrations, these concentrations must have returned to historical baseline levels prior to Screening

9. Liver function test (LFT) abnormalities: ALT and/or AST > 1.5 × ULN for age and gender

10. Known hypersensitivity to nedosiran, or any of its ingredients

11. Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations detailed in Section 5.3.

Related Conditions & MeSH terms

• Hyperoxaluria, Primary
• Primary Hyperoxaluria
• Primary Hyperoxaluria Type 1
• Primary Hyperoxaluria Type 2
• Primary Hyperoxaluria Type 3

Intervention

Drug:
• nedosiran
Monthly subcutaneous dosing throughout study period

Locations

Country	Name	City	State
Canada	Clinical Research Site	Hamilton	Ontario
Germany	Clinical Trial Site	Bonn
Germany	Clinical Research Site	Heidelberg
Italy	Clinical Trial Site	Roma
Japan	Clinical Research Site	Fukuoka
Japan	Clinical Research Site	Nagoya
Lebanon	Clinical Research Site	Beirut
Poland	Clinical Research Site	Bialystok
Spain	Clinical Research Site	Barcelona
Turkey	Clinical Research Site	Yenimahalle	Ankara
United Arab Emirates	Clinical Trial Site	Dubai
United Kingdom	Clinical Trial Site	London
United States	Clinical Research Site	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Italy,  Japan,  Lebanon,  Poland,  Spain,  Turkey,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from Baseline in Plasma Oxalate Concentration	Assess the effect of DCR-PHXC on Plasma Oxalate concentration from baseline	180 days
Other	Change from Baseline number of kidney stones	Assess the effect of DCR-PHXC on stone burden from baseline on annualized stone events	180 days
Other	Change from baseline PedsQL™	Change from Baseline in the Pediatric Quality of Life Inventory (PedsQL™)	180 days
Other	Change from baseline WPAI	Change from Baseline in the Work Productivity and Activity Impairment Questionnaire: Primary Hyperoxaluria V2.0, Clinical Practice Version (WPAI:PH, V2.0, CPV) - Caregiver	180 days
Primary	Efficacy: Percent change in urinary oxalate to creatinine ratio	Evaluate the effect of nedosiran on percent change in urinary oxalate-to-creatinine ratio	180 days
Primary	Efficacy: Absolute change in urinary oxalate to creatinine ratio	Evaluate the effect of nedosiran on absolute change in urinary oxalate-to-creatinine ratio	180 days
Secondary	Safety: Incidence of Events	Characterize the safety of nedosiran in children 11 years of age and younger based on treatment emergent adverse events, and serious adverse events.	180 days
Secondary	Safety: Changes from baseline in ECG: Rhythm	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in ECG.	180 days
Secondary	Safety: Changes from baseline in ECG: Ventricular Rate	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in ECG.	180 days
Secondary	Safety: Changes from baseline in ECG: PR interval	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in ECG.	180 days
Secondary	Safety: Changes from baseline in ECG: QRS duration	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in ECG.	180 days
Secondary	Safety: Changes from baseline in ECG: QT interval	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in ECG.	180 days
Secondary	Safety: Changes from baseline: Physical Exam	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in physical exam and physician review of systems based on CTCAE v5.0	180 days
Secondary	Safety: Changes from baseline in Vitals: temperature	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in vital signs.	180 days
Secondary	Safety: Changes from baseline in Vitals: pulse rate	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in vital signs.	180 days
Secondary	Safety: Changes from baseline in Vitals: respiratory rate	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in vital signs.	180 days
Secondary	Safety: Changes from baseline in Vitals: blood pressure	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in vital signs.	180 days
Secondary	Safety: Changes from baseline: Labs - Hematology	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Clinical Chemistry	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Coagulation	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Antibody	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Plasma Oxalate	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Urinalysis	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	Safety: Changes from baseline: Labs - Urine Oxalate	Characterize the safety of nedosiran in children 11 years of age and younger changes from baseline in clinical laboratory tests.	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing secondary parameters of the area under the curve.	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including secondary parameters of area under the curve (AUC)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing maximum observed concentration (Cmax).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including maximum observed concentration (Cmax)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing minimum concentration (Cmin).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including minimum observed concentration (Cmin)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing maximum concentration (Tmax).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including time to maximum concentration (Tmax)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing terminal elimination half-life (t1/2).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including terminal elimination half-life (t1/2)	180 days
Secondary	Efficacy: eGFR changes	Evaluate the effect of nedosiran on eGFR from baseline	180 days