E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Primary hyperoxaluria is where the liver overproduces oxalate. As a result calcium-oxalate crystals form in the urinary system and lead to stones and impaired kidney function. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020703 |
E.1.2 | Term | Hyperoxaluria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of DCR PHXC on estimated glomerular filtration rate (eGFR) in participants with PH1
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E.2.2 | Secondary objectives of the trial |
Key Secondary: To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with PH
Secondary: 1. To identify the proportion of participants with normalized or near-normalized 24 hour Uox 2. To identify the % of participants with spot urinary oxalate-to-creatinine ratio ≤ the ULN or ≤ 1.5 x ULN 3. To assess the effect of DCR-PHXC on stone events in patients with PH 4. To assess the effect of DCR-PHXC on stone burden and nephrocalcinosis grade in patients with PH 5. To evaluate the incidence of CKD and ESRD in participants with PH 6. To evaluate the effect of DCR-PHXC on QoL assessments in patients with PH 7. To assess the efficacy of DCR PHXC in reducing Uox burden in patients with PH 8. To assess the long-term efficacy of DCR PHXC in reducing Uox burden in patients with PH
Exploratory objectives: 1. To evaluate the effect of DCR PHXC on eGFR in participants with PH2 and PH3 2. To characterize the PK of DCR-PHXC in patients with PH |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, an individual must meet all of the following criteria: Age 1. Participants starting at birth are eligible for this study. Type of Participant and Disease Characteristics 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. Weight 5. Body weight ≥ 12.75 kg for pediatric siblings Sex 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 10.4.2, 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. Informed Consent/Assent 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. |
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E.4 | Principal exclusion criteria |
An individual who meets any of the following criteria will be excluded from participation in this study: Medical Conditions 1. Prior renal or hepatic transplantation; or planned transplantation within the study period 2. Currently receiving dialysis 3. 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) Prior/Concomitant Therapy 4. Use of an RNAi drug (other than DCR-PHXC) within the last 6 months 5. 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 6. 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. Prior/Concurrent Clinical Study Experience 7. 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. Diagnostic Assessments 8. 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. Other Exclusions 9. Known hypersensitivity to DCR PHXC or any of its ingredients 10. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The annual rate of decline in eGFR in participants with PH1.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ongoing evaluation of all medical assessments and patient’s quality of life questionnaires. Continuous risk-benefit assessments will be conducted by the Sponsor and the Medical Monitor of the CRO. |
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E.5.2 | Secondary end point(s) |
Key Secondary: •The incidence and severity of treatment-emergent adverse events (TEAE) and serious adverse events (SAE) •Change from Baseline in 12-lead electrocardiogram (ECG), physical examination findings, vital signs, and clinical laboratory tests (hematology, chemistry, coagulation parameters, and urinalysis) Secondary: 1. 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 body surface area (BSA) in participants aged < 18 years]) at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups 2. 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 3. 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 4. Change from Baseline in the stone burden and nephrocalcinosis grade at Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups 5. 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 6. Change from Baseline in the Short Form (36) Health Survey (SF-36®) and EQ-5D-5L™ in adults; and in the Pediatric Quality of Life Inventory (PedsQL™) in children in PH1, PH2, and PH3 participant subgroups 7. Area under the curve (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 8. 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 9. 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 Exploratory: 1. The annual rate of decline in eGFR in participants with PH2 and PH3 2. Population and/or individual pharmacokinetic (PK) parameters for DCR-PHXC, such as clearance (CL), volume of distribution (V) estimates, area under the curve (AUC), maximum observed concentration (Cmax), minimum observed concentration (Cmin), time to maximum concentration (Tmax), and terminal elimination half-life (t1/2) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ongoing evaluation of all medical assessments and patient’s quality of life questionnaires. Continuous risk-benefit assessments will be conducted by the Sponsor and the Medical Monitor of the CRO. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United Arab Emirates |
Australia |
Canada |
Japan |
Lebanon |
Morocco |
United Kingdom |
United States |
France |
Germany |
Italy |
Netherlands |
Norway |
Poland |
Spain |
Türkiye |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A participant is considered to have completed the study if he or she has completed all phases of the study, including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3 of the protocol. The end of the study is defined as completion of the last visit or procedure for the last participant shown in the SoA in the trial globally.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |