Study for patients with Primary Hyperoxaluria to evaluate the Long-Term Safety and Efficacy of DCR-PHXC Solution for Injection

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dicerna Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

20 Aug 2019 → ongoing

Decision date (initial)

2024-08-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Dicerna Pharmaceuticals Inc., a wholly owned subsidiary of Novo Nordisk

External identifiers

EU CT number

2024-512260-54-00

EudraCT number

2018-003099-10

WHO UTN

U1111-1224-7484

ClinicalTrials.gov

NCT04042402

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the effect of DCR-PHXC on estimated glomerular filtration rate (eGFR) in participants with PH1

Secondary objectives 10

1. Key Secondary: To evaluate the safety and tolerability of DCR-PHXC when administered monthly to patients with PH
2. To identify the proportion of participants with normalized or near-normalized 24-hour Uox
3. To identify the percentage of participants with spot urinary oxalate-to-creatinine ratio ≤ the ULN and ≤ 1.5 x ULN
4. To assess the effect of DCR-PHXC on stone events in patients with PH
5. To assess the effect of DCR-PHXC on stone burden and nephrocalcinosis grade in patients with PH
6. To evaluate the incidence of CKD and ESRD in participants with PH
7. To evaluate the effect of DCR-PHXC on QoL assessments in patients with PH
8. To assess the efficacy of DCR-PHXC in reducing Uox burden in patients with PH
9. To assess the long-term efficacy of DCR-PHXC in reducing Uox burden in patients with PH
10. Exploratory: To evaluate the effect of DCR-PHXC on eGFR in participants with PH2 and PH3

Conditions and MedDRA coding

Primary Hyperoxaluria

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002493-PIP01-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Participants starting at birth are eligible for this study
2. Documented diagnosis of PH, confirmed by genotyping (historically available genotype information is acceptable for study eligibility)
3. Participant successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC, or is the sibling of a participant who either successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC or completed 24 weeks of participation in Study DCR-PHXC-204. a. For participants rolling over from a multidose study of DCR-PHXC, enrollment should occur within a window of 25 to 75 days from the last dose of study intervention. In order to minimize any gap in administration of DCR-PHXC, every effort should be made to enroll participants as soon as all assessments from the previous study have been completed. It should be noted if the participant was required to repeat the end-of-study (EOS) 24-hour Uox collection for violation of completeness criteria. b. Siblings must i. be younger than 18 years of age ii. meet all other eligibility criteria (including genotyping) iii. have two 24-hour Uox values ≥ 0.7 mmol (adjusted per 1.73 m2 BSA) at Screening OR for siblings aged 0 to 5 years old, average spot Uox-to-creatinine ratio at Screening above 2 times the 95th percentile for age based on Matos et al, 1999: 1. 0.44 mol/mol in participants < 6 months 2. 0.34 mol/mol in participants from 6 months to <12 months 3. 0.26 mol/mol in participants 12 months to < 2 years 4. 0.20 mol/mol in participants from 2 to < 3 years and 5. 0.16 mol/mol in participants from 3 to 5 years iv. Participants who perform 24-hour collections must have less than 20% variation between the two 24-hour urinary creatinine excretion values obtained in the screening period. Individuals who do not achieve < 20% variation between the 2 screening values may undergo a second round of urine collection. An extra 7 calendar days may be added to the screening window for participants to complete a second round of urine collection. Should potential participants again fail to achieve the within- 20% variation, they will be excluded from participation
4. Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA, calculated using the equations found in Section 8.2.4.1. For infants aged less than 12 months, serum creatinine below the 97.5th percentile of a healthy population (Boer et al., 2010). Note: For participants rolling over from a 6-month multidose study of DCR-PHXC, the eGFR/serum creatinine value from either the Day 150 or Day 180 (EOS) visit may be used for screening.
5. Body weight ≥ 12.75 kg for pediatric siblings
6. Male participants: A male participant with a female partner of childbearing potential must agree to use contraception, as detailed in Section 10.4.2, 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 10.4.1), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Section 10.4.1 OR A WOCBP who agrees to follow the contraceptive guidance in Section 10.4.2 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.
7. Participant (and/or participant's parent or legal guardian if participant is a minor [defined as patient < 18 years of age, or younger than the age of majority, according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. a. Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority, according to local regulations) must be able to provide written assent for participation. b. For children younger than 12 years of age, assent will be based on local regulations.
8. In the Netherlands, children aged 0 to 5 must have PH1 to be eligible for enrollment. Pediatric patients with PH2 or PH3 are not eligible for enrollment, as the efficacy of DCR PHXC has not yet been established in patients with PH2 or PH3

Exclusion criteria 11

1. Prior renal or hepatic transplantation; or planned transplantation within the study period
2. Inability or unwillingness to comply with the specified study procedures, including collection of 24-hour urine samples, and the lifestyle considerations detailed in Section 5.3
3. Currently receiving dialysis
4. Documented evidence of clinical manifestations of systemic oxalosis (including pre-existing retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations)
5. Use of an RNAi drug (other than DCR-PHXC) within the last 6 months
6. History of one or more of the following reactions to an oligonucleotide-based therapy: a. severe thrombocytopenia (platelet count ≤ 100,000/μL) b. hepatotoxicity, defined as (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 × the upper limit of normal [ULN]) and (total bilirubin > 2 × ULN or International Normalized Ratio [INR] >1.5) c. severe flu-like symptoms leading to discontinuation of therapy d. localized skin reaction from the injection (graded severe) leading to discontinuation of therapy e. coagulopathy/clinically significant prolongation of clotting time
7. Participants receiving pyridoxine (vitamin B6) must have been at a stable dose for at least 4 weeks prior to Day 1 and must be willing to remain on the same stable dose throughout the study
8. Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months or 5 times the half-life of the drug (whichever is longer) before Screening. a. For IMPs (other than DCR-PHXC) with the potential to reduce urine and/or plasma oxalate concentrations, these concentrations must have returned to historical baseline levels prior to Screening
9. Plasma oxalate > 30 μmol/L Note: For participants ≥ 18 years of age rolling over from a 6-month multidose study of DCR-PHXC, the plasma oxalate value from either the Day 150 or Day 180 (EOS) visit may be used for screening. If the previous study is blinded at the time of entry in DCR-PHXC-301, plasma oxalate values will be reviewed by the unblinded Medical Monitor. For participants < 18 years of age rolling over from a 6-month multidose study of DCR-PHXC, the plasma oxalate value from Screening in the previous study will be used
10. Known hypersensitivity to DCR-PHXC or any of its ingredients
11. In Germany, when deciding whether this study is suitable for a particular patient, the Investigator should consider the availability and appropriateness of lumasiran or other approved treatment options for PH prior to screening patients into this study. Patients who are suitable for and have access to an approved PH1 treatment should be excluded from the study. If the eGFR value for a participant declines to < 30 mL/min/1.73m2, the Investigator should contact the Medical Monitor for advice regarding study intervention

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The annual rate of decline in eGFR in participants with PH1

Secondary endpoints 12

1. Key Secondary: 1. The incidence and severity of TEAE and SAE
2. Key Secondary: 2. Change from Baseline in 12-lead ECG, physical examination findings, vital signs, and clinical laboratory tests (hematology, chemistry, coagulation parameters, and urinalysis)
3. The proportion of participants with a 24-hour Uox level (< 0.46 mmol/24 hours or ≥ 0.46 - < 0.60 mmol/24 hours [adjusted per 1.73 m2 BSA in participants aged < 18 years]) at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups
4. The percentage of participants with spot urinary oxalate-to-creatinine ratio ≤ the ULN or ≤ 1.5 x ULN at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups
5. Change from Baseline in the number of stone events over a 12-month period, annually in Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
6. Change from Baseline in the stone burden and nephrocalcinosis grade at Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
7. The number of participants with severe CKD (GFR = 15-29 mL/min) or ESRD (GFR < 15 mL/min); adjusted per 1.73 m2 BSA in participants aged < 18 years in PH1, PH2, and PH3 participant subgroups
8. Change from Baseline in the SF-36 and EQ-5D-5L in adults; and in the PedsQL in children in PH1, PH2, and PH3 participant subgroups
9. AUC of 24-hour Uox from Day 90 to Day 180, based on percent change from Baseline in PH1, PH2, and PH3 participant subgroups. This endpoint will only be assessed in participants randomized to placebo in a previous study of DCR-PHXC and pediatric siblings
10. Percent change from Baseline in 24-hour Uox at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups. In those participants randomized to placebo in a previous study of DCR-PHXC and pediatric siblings, this endpoint will be assessed only after Month 6
11. Percent and absolute change from Baseline in spot urinary oxalate-to-creatinine ratio at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups. In pediatric siblings, this endpoint will be assessed only after Month 6
12. Exploratory: The annual rate of decline in eGFR in participants with PH2 and PH3

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dicerna Pharmaceuticals Inc.

Sponsor organisation

Dicerna Pharmaceuticals Inc.

Address

75 Hayden Avenue

City

Lexington

Postcode

02421-7994

Country

United States

Scientific contact point

Organisation

Dicerna Pharmaceuticals Inc.

Contact name

EU Submission Hub

Public contact point

Organisation

Dicerna Pharmaceuticals Inc.

Contact name

EU Submission Hub

Third parties 12

Locations

6 EU/EEA countries · 10 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 136 files

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

Application history

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