NCT05001269已完成2 期
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
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company14 个研究点 分布在 11 个国家目标入组 27 人开始时间: 2022年2月22日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 27
- 试验地点
- 14
- 主要终点
- Efficacy: Percent change in urinary oxalate to creatinine ratio
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Birth to 11 years of age inclusive, at the time of signing the informed consent.
- •Documented diagnosis of PH1 or PH2 or PH3 confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
- •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
- •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).
- •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.
- •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.
- •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.
- •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.
- •Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations)
排除标准
- •Prior renal or hepatic transplantation; or planned transplantation within the study period
- •Currently receiving dialysis or anticipating requirement for dialysis during the study period
- •Plasma oxalate (Pox) > 30 μmol/L at Screening
- •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)
- •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:
- •Severe intercurrent illness
- •Known causes of active liver disease/injury or transaminase elevation (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis [NAFLD/NASH])
- •History of serious mental illness that includes, but is not limited to, schizophrenia, bipolar disorder, or severe depression requiring hospitalization or pharmacological intervention
- •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
- •Use of an RNAi drug within the last 6 months
- •History of 1 or more of the following reactions to an oligonucleotide-based therapy:
- •Severe thrombocytopenia (platelet count ≤ 100,000/µL)
- •Hepatotoxicity, defined as ALT or AST > 3 times the upper ULN and total bilirubin > 2 × ULN or INR > 1.5
- •Severe flu-like symptoms leading to discontinuation of therapy
- •Localized skin reaction from the injection (graded severe) leading to discontinuation of therapy
- •Coagulopathy/clinically significant prolongation of clotting time
- •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
- •Liver function test (LFT) abnormalities: ALT and/or AST > 1.5 × ULN for age and gender
- •Known hypersensitivity to nedosiran, or any of its ingredients
- •Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations detailed in Section 5.3.
研究组 & 干预措施
Open-Label DCR-PHXC
Experimental
Open-Label monthly subcutaneous injection of DCR-PHXC based on age and weight.
干预措施: nedosiran (Drug)
结局指标
主要结局
Efficacy: Percent change in urinary oxalate to creatinine ratio
时间窗: 180 days
Evaluate the effect of nedosiran on percent change in urinary oxalate-to-creatinine ratio
Efficacy: Absolute change in urinary oxalate to creatinine ratio
时间窗: 180 days
Evaluate the effect of nedosiran on absolute change in urinary oxalate-to-creatinine ratio
Percent Change From Baseline to Month 6 in Spot Urinary Oxalate-to-creatinine Ratio in PH1, PH2, or PH3 Participant Subgroups
时间窗: 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
时间窗: 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.
次要结局
- Safety: Changes from baseline in ECG: Ventricular Rate(180 days)
- Safety: Changes from baseline in ECG: QRS duration(180 days)
- Safety: Changes from baseline in Vitals: temperature(180 days)
- Safety: Changes from baseline in Vitals: pulse rate(180 days)
- Safety: Changes from baseline: Labs - Hematology(180 days)
- Safety: Changes from baseline in ECG: PR interval(180 days)
- Safety: Changes from baseline in ECG: QT interval(180 days)
- Safety: Changes from baseline: Labs - Clinical Chemistry(180 days)
- Safety: Changes from baseline: Labs - Coagulation(180 days)
- Safety: Changes from baseline: Labs - Antibody(180 days)
- Safety: Incidence of Events(180 days)
- Safety: Changes from baseline: Physical Exam(180 days)
- Safety: Changes from baseline in Vitals: respiratory rate(180 days)
- Safety: Changes from baseline: Labs - Plasma Oxalate(180 days)
- To characterize the PK of DCR PHXC in patients with PH by observing secondary parameters of the area under the curve.(180 days)
- To characterize the PK of DCR PHXC in patients with PH by observing terminal elimination half-life (t1/2).(180 days)
- To characterize the PK of DCR PHXC in patients with PH by observing minimum concentration (Cmin).(180 days)
- Safety: Changes from baseline: Labs - Urine Oxalate(180 days)
- To characterize the PK of DCR PHXC in patients with PH by observing maximum concentration (Tmax).(180 days)
- Safety: Changes from baseline in ECG: Rhythm(180 days)
- Safety: Changes from baseline in Vitals: blood pressure(180 days)
- To characterize the PK of DCR PHXC in patients with PH by observing maximum observed concentration (Cmax).(180 days)
- Safety: Changes from baseline: Labs - Urinalysis(180 days)
- Efficacy: eGFR changes(180 days)
- Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From baseline (Week 0) up to Month 6)
- Number of Treatment Emergent Adverse Events and Serious Adverse Events-Nature(From baseline (Week 0) up to Month 6)
- Change From Baseline in 12-lead Electrocardiogram (ECG)- ECG Mean Heart Rate(Baseline (Week 0), Month 6)
- Change From Baseline in 12-lead ECG- RR Interval(Baseline (Week 0), Month 6)
- Change From Baseline in 12-lead ECG-PR Interval, Aggregate(Baseline (Week 0), Month 6)
- Change From Baseline in 12-lead ECG-QRS Duration, Aggregate(Baseline (Week 0), Month 6)
- Change From Baseline in 12-lead ECG-QT Interval, Aggregate(Baseline (Week 0), Month 6)
- Change From Baseline in 12-lead ECG-QTcF Interval, Aggregate(Baseline (Week 0), Month 6)
- Change From Baseline in Participants With Significant Findings- Physical Examination(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment- Height(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Weight(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Body Mass Index (BMI)(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Oral Body Temperature(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Respiratory Rate(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Heart Rate(Baseline (Week 0), Month 6)
- Change From Baseline in Vital Sign Assessment-Systolic Blood Pressure and Diastolic Blood Pressure(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Erythrocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Hemoglobin(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Hematocrit(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Volume(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Erythrocytes Mean Corpuscular Hemoglobin Concentration(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Reticulocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Haematology Assessment: Platelets(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Mean Platelet Volume(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Lymphocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Monocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Eosinophils(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Basophils(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Neutrophils(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Lymphocytes/Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Monocytes/Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Eosinophils/Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Basophils/Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Hematology Assessment: Neutrophils/Leukocytes(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Alanine Aminotransferase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Aspartate Aminotransferase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Lactate Dehydrogenase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Glutamate Dehydrogenase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Gamma Glutamyl Transferase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Alkaline Phosphatase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Bilirubin and Direct Bilirubin(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Protein(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Albumin(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Creatine Kinase(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Sodium(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Chloride(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Potassium(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Creatinine(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Blood Urea Nitrogen(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Cystatin C(Baseline (Week 0), Month 6)
- Change From Baseline in Clinical Chemistry Parameter: Plasma Oxalate(Baseline (Week 0), Month 6)
- Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax), if Estimable(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(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(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(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(Baseline (Week 0), Month 6)
研究者
研究点 (14)
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