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

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company27 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Primary Hyperoxaluria Primary Hyperoxaluria Type 1 Primary Hyperoxaluria Type 2 Primary Hyperoxaluria Type 3

Interventions

nedosiranDRUG

Monthly subcutaneous dosing throughout study period

Eligibility

Sex: ALLMax age: 11 Years

Medical Language ↔ Plain English

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.

Locations (13)

Clinical Research Site

Rochester, Minnesota, United States

Clinical Research Site

Hamilton, Ontario, Canada

Clinical Trial Site

Bonn, Germany

Outcomes

Primary Outcomes

Percent Change From Baseline to Month 6 in Spot Urinary Oxalate-to-creatinine Ratio in PH1, PH2, or PH3 Participant Subgroups

This outcome measure reported percent change from baseline to Month 6 in spot urinary oxalate-to-creatinine ratio in pediatric participants (birth to 11 years of age) with genetically confirmed primary hyperoxaluria type 1 (PH1), primary hyperoxaluria type 2 (PH2), or primary hyperoxaluria type 3 (PH3) subgroups.

Time frame: Baseline (Week 0), Month 6

Absolute Change From Baseline to Month 6 in Spot Urinary Oxalate-to-creatinine Ratio in PH1, PH2, or PH3 Participant Subgroups

This outcome measure reported absolute change from baseline to Month 6 in spot urinary oxalate-to-creatinine ratio in pediatric participants (birth to 11 years of age) with genetically confirmed PH1, PH2, or PH3 subgroups.

Time frame: Baseline (Week 0), Month 6

Secondary Outcomes

Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

This outcome measure reported number of incidents of TEAEs and SAEs. An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, and medical events. An AE will be defined as treatment emergent if they have an onset or worsen in severity after a participant receives the study intervention.

Time frame: From baseline (Week 0) up to Month 6

Number of Treatment Emergent Adverse Events and Serious Adverse Events-Nature

This outcome measure reported nature of TEAEs and SAEs. An AE is any untoward medical occurrence in clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent disability/incapacity, is a congenital anomaly/birth defect, and medical events. An AE is treatment emergent if they have an onset or worsen in severity after a participant receives the study intervention. TEAEs are considered as leading to discontinuation if the action taken is marked as "drug withdrawn" on the case report form. TEAEs of special interest include injection site reactions, muscle pain and weakness, and kidney stone events.

Data from ClinicalTrials.gov

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Clinical Research Site

Heidelberg, Germany

Clinical Trial Site

Roma, Italy

Clinical Research Site

Fukuoka, Japan

Clinical Research Site

Nagoya, Japan

Clinical Research Site

Beirut, Lebanon

Clinical Research Site

Bialystok, Poland

Clinical Research Site

Barcelona, Spain

...and 3 more locations

Time frame: From baseline (Week 0) up to Month 6

Change From Baseline in 12-lead Electrocardiogram (ECG)- ECG Mean Heart Rate

This outcome measure reported change from baseline to Month 6 in ECG mean heart rate.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in 12-lead ECG- RR Interval

This outcome measure reported change from baseline to Month 6 in RR Interval.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in 12-lead ECG-PR Interval, Aggregate

This outcome measure reported change from baseline to Month 6 in aggregate PR Interval.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in 12-lead ECG-QRS Duration, Aggregate

This outcome measure reported change from baseline to Month 6 in aggregate QRS Interval.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in 12-lead ECG-QT Interval, Aggregate

This outcome measure reported change from baseline to Month 6 in aggregate QT Interval.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in 12-lead ECG-QTcF Interval, Aggregate

This outcome measure reported change from baseline to Month 6 in aggregate QTcF Interval.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Participants With Significant Findings- Physical Examination

This outcome measure reported change from baseline to Month 6 in number of participants with significant findings (physical examination). Change from baseline was calculated using formula: value at current time point - baseline value.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment- Height

This outcome measure reported change from baseline to Month 6 in participants heights.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Weight

This outcome measure reported change from baseline to Month 6 in participants weights.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Body Mass Index (BMI)

This outcome measure reported change from baseline to Month 6 in participants BMI.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Oral Body Temperature

This outcome measure reported change from baseline to Month 6 in participants oral body temperature.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Respiratory Rate

This outcome measure reported change from baseline to Month 6 in participants respiratory rate.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Heart Rate

This outcome measure reported change from baseline to Month 6 in participants heart rate.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Vital Sign Assessment-Systolic Blood Pressure and Diastolic Blood Pressure

This outcome measure reported change from baseline to Month 6 in participants systolic and diastolic blood pressure.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Erythrocytes

This outcome measure reported change from baseline to Month 6 in participants erythrocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Hemoglobin

This outcome measure reported change from baseline to Month 6 in participants hemoglobin.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Hematocrit

This outcome measure reported change from baseline to Month 6 in participants hematocrit.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Volume

This outcome measure reported change from baseline to Month 6 in participants erythrocytes mean corpuscular volume.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin

This outcome measure reported change from baseline to Month 6 in participants erythrocytes mean corpuscular hemoglobin.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin Concentration

This outcome measure reported change from baseline to Month 6 in participant's erythrocytes mean corpuscular hemoglobin concentration.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Reticulocytes

This outcome measure reported change from baseline to Month 6 in participants reticulocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Haematology Assessment: Platelets

This outcome measure reported change from baseline to Month 6 in participants platelets.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Mean Platelet Volume

This outcome measure reported change from baseline to Month 6 in participants mean platelet volume.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Leukocytes

This outcome measure reported change from baseline to Month 6 in participants leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Lymphocytes

This outcome measure reported change from baseline to Month 6 in participants lymphocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Monocytes

This outcome measure reported change from baseline to Month 6 in participants monocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Eosinophils

This outcome measure reported change from baseline to Month 6 in participants eosinophils.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Basophils

This outcome measure reported change from baseline to Month 6 in participants basophils.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Neutrophils

This outcome measure reported change from baseline to Month 6 in participants neutrophils.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Lymphocytes/Leukocytes

This outcome measure reported change from baseline to Month 6 in the ratio of lymphocytes/leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Monocytes/Leukocytes

This outcome measure reported change from baseline to Month 6 in the ratio of monocytes/leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Eosinophils/Leukocytes

This outcome measure reported change from baseline to Month 6 in the ratio of eosinophils/leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Basophils/Leukocytes

This outcome measure reported change from baseline to Month 6 in the ratio of basophils/leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Hematology Assessment: Neutrophils/Leukocytes

This outcome measure reported change from baseline to Month 6 in the ratio of neutrophils/leukocytes.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Alanine Aminotransferase

This outcome measure reported change from baseline to Month 6 in alanine aminotransferase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Aspartate Aminotransferase

This outcome measure reported change from baseline to Month 6 in aspartate aminotransferase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase

This outcome measure reported change from baseline to Month 6 in lactate dehydrogenase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Glutamate Dehydrogenase

This outcome measure reported change from baseline to Month 6 in glutamate dehydrogenase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Gamma Glutamyl Transferase

This outcome measure reported change from baseline to Month 6 in gamma glutamyl transferase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Alkaline Phosphatase

This outcome measure reported change from baseline to Month 6 in alkaline phosphatase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Bilirubin and Direct Bilirubin

This outcome measure reported change from baseline to Month 6 in bilirubin and direct bilirubin.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Protein

This outcome measure reported change from baseline to Month 6 in protein.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Albumin

This outcome measure reported change from baseline to Month 6 in albumin.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Creatine Kinase

This outcome measure reported change from baseline to Month 6 in creatine kinase.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Sodium

This outcome measure reported change from baseline to Month 6 in sodium.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Chloride

This outcome measure reported change from baseline to Month 6 in chloride.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Potassium

This outcome measure reported change from baseline to Month 6 in potassium.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Creatinine

This outcome measure reported change from baseline to Month 6 in creatinine.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Blood Urea Nitrogen

This outcome measure reported change from baseline to Month 6 in blood urea nitrogen.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Cystatin C

This outcome measure reported change from baseline to Month 6 in blood urea Cystatin C.

Time frame: Baseline (Week 0), Month 6

Change From Baseline in Clinical Chemistry Parameter: Plasma Oxalate

This outcome measure reported change from baseline to Month 6 in blood urea plasma oxalate.

Time frame: Baseline (Week 0), Month 6

Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax), if Estimable

This outcome measure, if estimable, was expected to report Cmax which is defined as maximum observed concentration. However, in this study, a non-compartmental PK analysis was not planned or executed due to the limited PK samples (2 PK concentration - time data points between 0 to 4 hours and 4 to 24 hours following dose administration on Day 1) collected in pediatric participants per protocol, hence this PK parameter was not estimated. To estimate Cmax, at least one data point prior to Tmax and one data point post-Tmax at the designated time points are needed; however, only two flexible post-dose PK concentration data points were available in this study. Although Cmax was not estimated in this study, the PK data collected in this study will be used in a population PK analysis in the future.

Time frame: Baseline (Week 0), Month 6

Plasma PK Parameters: Area Under the Concentration-time Curve Calculated to the Last Observable Concentration at Time t (AUCt), if Estimable

This outcome measure, if estimable, was expected to report AUCt which is deﬁned as area under the concentration-time curve calculated from time zero to the last observable concentration at time t. However, in this study, a non-compartmental PK analysis was not planned or executed due to the limited PK samples (2 PK concentration - time data points between 0 to 4 hours and 4 to 24 hours following dose administration on Day 1) collected in pediatric participants per protocol, hence this PK parameter was not estimated. To estimate AUCt, at least one data point prior to Tmax and three data points post-Tmax at the designated time points are needed; however, only two ﬂexible post-dose PK concentration data points were available in this study. Although AUCt was not estimated in this study, the PK data collected in this study shall be used in a population PK analysis in the future.

Time frame: Day 1: Postdose 0- to 4-hour and 4- to 24-hour, Days 2, 30, and 90: post dose, Day 150: predose and Day 150: postdose: 0- to 4-hour and 4- to 24-hour

Plasma PK Parameters: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC∞), if Estimable

This outcome measure, if estimable, was expected to report AUC∞ which is defined as area under the concentration-time curve calculated to the last observable concentration at time t. However, in this study, a non-compartmental PK analysis was not planned or executed due to the limited PK samples (2 PK concentration - time data points between 0 to 4 hours and 4 to 24 hours following dose administration on Day 1) collected in pediatric participants per protocol, hence this PK parameter was not estimated. To estimate AUC∞, at least one data point prior to Tmax and three data points post-Tmax at the designated time points are needed; however, only two flexible post-dose PK concentration data points were available in this study. Although AUC∞ was not estimated in this study, the PK data collected in this study will be used in a population PK analysis in the future.

Time frame: Day 1: Postdose 0- to 4-hour and 4- to 24-hour, Days 2, 30, and 90: post dose, Day 150: predose and Day 150: post-dose: 0- to 4-hour and 4- to 24-hour

Percentage of Participants With Spot Urinary Oxalate-to-Creatinine Ratio <=Upper Limit of Normal (ULN) or <=1.5*ULN at Any Time Point Through Month 6 in PH1, PH2, or PH3 Participant Subgroups

This outcome measure reported percentage of participants from baseline to Month 6 Oxalate-to-creatinine Ratio less than and equal to (\<=) ULN or \<=1.5\*ULN at any time point through Month 6 in pediatric participants (birth to 11 years of age) with genetically confirmed PH1, PH2, or PH3 subgroups.

Time frame: From baseline (week 0) through Month 6

Change From Baseline in eGFR at Month 6 (Only in Participants >=12 Months of Age at Screening) in PH1, PH2, or PH3 Participant Subgroups

This outcome measure reported Change from Baseline in GFR estimated Cystatin C at Month 6 (only in participants \>=12 Months of age at Screening) in PH1, PH2, or PH3 participant subgroups. The eGFR was calculated using multivariate Schwartz equation using formula: eGFR=39.8\*\[ht/Scr\]\^0.456 \[1.8/cysC\]\^0.418 \[30/BUN\]\^0.0791.076\^male\[ht/1.4\]\^0.179 where ht (height) = meters, Scr (serum creatinine) = milligrams per deciliter (mg/dL), cysC (cystatin C) = mg/L, and BUN (blood urea nitrogen) = mg/dL.

Time frame: Baseline (Week 0), Month 6