Primary Hyperoxaluria, Primary Hyperoxaluria Type 1, Primary Hyperoxaluria Type 2, Primary Hyperoxaluria Type 3
Conditions
Keywords
PH1, PH2, PH3, pediatric
Brief 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.
Detailed 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.
Interventions
DRUGnedosiran
Monthly subcutaneous dosing throughout study period
Sponsors
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Children 2-11 years of age will begin enrolling prior to the under 2 year old age group's open.
Eligibility
Sex/Gender
ALL
Age
No minimum to 11 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Month 6 in Spot Urinary Oxalate-to-creatinine Ratio in PH1, PH2, or PH3 Participant Subgroups | Baseline (Week 0), Month 6 | 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. |
| Absolute Change From Baseline to Month 6 in Spot Urinary Oxalate-to-creatinine Ratio in PH1, PH2, or PH3 Participant Subgroups | Baseline (Week 0), Month 6 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From baseline (Week 0) up to Month 6 | 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. |
| Number of Treatment Emergent Adverse Events and Serious Adverse Events-Nature | From baseline (Week 0) up to Month 6 | 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. |
| Change From Baseline in 12-lead Electrocardiogram (ECG)- ECG Mean Heart Rate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in ECG mean heart rate. |
| Change From Baseline in 12-lead ECG- RR Interval | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in RR Interval. |
| Change From Baseline in 12-lead ECG-PR Interval, Aggregate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in aggregate PR Interval. |
| Change From Baseline in 12-lead ECG-QRS Duration, Aggregate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in aggregate QRS Interval. |
| Change From Baseline in 12-lead ECG-QT Interval, Aggregate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in aggregate QT Interval. |
| Change From Baseline in 12-lead ECG-QTcF Interval, Aggregate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in aggregate QTcF Interval. |
| Change From Baseline in Participants With Significant Findings- Physical Examination | Baseline (Week 0), Month 6 | 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. |
| Change From Baseline in Vital Sign Assessment- Height | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants heights. |
| Change From Baseline in Vital Sign Assessment-Weight | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants weights. |
| Change From Baseline in Vital Sign Assessment-Body Mass Index (BMI) | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants BMI. |
| Change From Baseline in Vital Sign Assessment-Oral Body Temperature | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants oral body temperature. |
| Change From Baseline in Vital Sign Assessment-Respiratory Rate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants respiratory rate. |
| Change From Baseline in Vital Sign Assessment-Heart Rate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants heart rate. |
| Change From Baseline in Vital Sign Assessment-Systolic Blood Pressure and Diastolic Blood Pressure | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants systolic and diastolic blood pressure. |
| Change From Baseline in Hematology Assessment: Erythrocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants erythrocytes. |
| Change From Baseline in Hematology Assessment: Hemoglobin | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants hemoglobin. |
| Change From Baseline in Hematology Assessment: Hematocrit | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants hematocrit. |
| Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Volume | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants erythrocytes mean corpuscular volume. |
| Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants erythrocytes mean corpuscular hemoglobin. |
| Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin Concentration | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participant's erythrocytes mean corpuscular hemoglobin concentration. |
| Change From Baseline in Hematology Assessment: Reticulocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants reticulocytes. |
| Change From Baseline in Haematology Assessment: Platelets | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants platelets. |
| Change From Baseline in Hematology Assessment: Mean Platelet Volume | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants mean platelet volume. |
| Change From Baseline in Hematology Assessment: Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants leukocytes. |
| Change From Baseline in Hematology Assessment: Lymphocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants lymphocytes. |
| Change From Baseline in Hematology Assessment: Monocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants monocytes. |
| Change From Baseline in Hematology Assessment: Eosinophils | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants eosinophils. |
| Change From Baseline in Hematology Assessment: Basophils | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants basophils. |
| Change From Baseline in Hematology Assessment: Neutrophils | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in participants neutrophils. |
| Change From Baseline in Hematology Assessment: Lymphocytes/Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in the ratio of lymphocytes/leukocytes. |
| Change From Baseline in Hematology Assessment: Monocytes/Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in the ratio of monocytes/leukocytes. |
| Change From Baseline in Hematology Assessment: Eosinophils/Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in the ratio of eosinophils/leukocytes. |
| Change From Baseline in Hematology Assessment: Basophils/Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in the ratio of basophils/leukocytes. |
| Change From Baseline in Hematology Assessment: Neutrophils/Leukocytes | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in the ratio of neutrophils/leukocytes. |
| Change From Baseline in Clinical Chemistry Parameter: Alanine Aminotransferase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in alanine aminotransferase. |
| Change From Baseline in Clinical Chemistry Parameter: Aspartate Aminotransferase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in aspartate aminotransferase. |
| Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in lactate dehydrogenase. |
| Change From Baseline in Clinical Chemistry Parameter: Glutamate Dehydrogenase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in glutamate dehydrogenase. |
| Change From Baseline in Clinical Chemistry Parameter: Gamma Glutamyl Transferase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in gamma glutamyl transferase. |
| Change From Baseline in Clinical Chemistry Parameter: Alkaline Phosphatase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in alkaline phosphatase. |
| Change From Baseline in Clinical Chemistry Parameter: Bilirubin and Direct Bilirubin | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in bilirubin and direct bilirubin. |
| Change From Baseline in Clinical Chemistry Parameter: Protein | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in protein. |
| Change From Baseline in Clinical Chemistry Parameter: Albumin | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in albumin. |
| Change From Baseline in Clinical Chemistry Parameter: Creatine Kinase | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in creatine kinase. |
| Change From Baseline in Clinical Chemistry Parameter: Sodium | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in sodium. |
| Change From Baseline in Clinical Chemistry Parameter: Chloride | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in chloride. |
| Change From Baseline in Clinical Chemistry Parameter: Potassium | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in potassium. |
| Change From Baseline in Clinical Chemistry Parameter: Creatinine | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in creatinine. |
| Change From Baseline in Clinical Chemistry Parameter: Blood Urea Nitrogen | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in blood urea nitrogen. |
| Change From Baseline in Clinical Chemistry Parameter: Cystatin C | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in blood urea Cystatin C. |
| Change From Baseline in Clinical Chemistry Parameter: Plasma Oxalate | Baseline (Week 0), Month 6 | This outcome measure reported change from baseline to Month 6 in blood urea plasma oxalate. |
| Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax), if Estimable | Baseline (Week 0), Month 6 | 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. |
| Plasma PK Parameters: Area Under the Concentration-time Curve Calculated to the Last Observable Concentration at Time t (AUCt), if Estimable | 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 | 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. |
| Plasma PK Parameters: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC∞), if Estimable | 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 | 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. |
| 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 | From baseline (week 0) through Month 6 | 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. |
| Change From Baseline in eGFR at Month 6 (Only in Participants >=12 Months of Age at Screening) in PH1, PH2, or PH3 Participant Subgroups | Baseline (Week 0), Month 6 | 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. |
Countries
Canada, Germany, Italy, Japan, Lebanon, Poland, Spain, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Contacts
STUDY_DIRECTORSarb Shergill, PhD
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Participant flow
Recruitment details
The study was conducted at 13 sites in 9 countries.
Pre-assignment details
This is Phase 2, open-label, single-arm uncontrolled study in pediatric participants with genetically confirmed primary hyperoxaluria (PH), with relatively intact renal function based upon estimated glomerular filtration rate (eGFR) and serum creatinine.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 3.54 years STANDARD_DEVIATION 1.198 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants |
| Race/Ethnicity, Customized Multiple | 11 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants |
| Race/Ethnicity, Customized White | 9 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 13 | 0 / 9 | 0 / 27 |
| other Total, other adverse events | 5 / 5 | 11 / 13 | 7 / 9 | 23 / 27 |
| serious Total, serious adverse events | 1 / 5 | 3 / 13 | 1 / 9 | 5 / 27 |
Outcome results
None listed