E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Hyperoxaluria Type 3 |
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E.1.1.1 | Medical condition in easily understood language |
Primary hyperoxaluria is where the liver overproduces oxalate. Therefore calcium-oxalate crystals form in the urinary system and lead to the formation of kidney 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 safety and tolerability of a single dose of DCR-PHXC in patients with PH3 |
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E.2.2 | Secondary objectives of the trial |
1. To characterize the plasma PK of a single dose of DCR-PHXC in patients with PH3 2. To assess the efficacy of a single dose of DCR PHXC in reducing oxalate burden in patients with PH3 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age 1. At least 6 years of age at the time of signing the informed consent/assent Type of Participant and Disease Characteristics 2. Documented diagnosis of PH3, confirmed by genotyping (historically available genotype information is acceptable for study eligibility) 3. 24-hour Uox excretion ≥ 0.7 mmol (adjusted per 1.73 m2 BSA in participants < 18 years of age) in both collections performed in the screening period 4. Less than 20% variation between the two 24-hour urinary creatinine measurements 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. 5. Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA, calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula in participants aged ≥ 18 years (Levey & Stevens, 2010) or the multivariate formula by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012). 6. History of at least one stone event within the last 12 months. Stone events are defined as any of the following: a. Renal stone requiring medical intervention, e.g., outpatient procedures such as lithotripsy, or hospitalization or inpatient surgical intervention for confirmed stone-related pain and/or complications b. Stone passage with or without hematuria c. Renal colic requiring medication 7. 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 1 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 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. 8. 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. Others 9. Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations) |
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E.4 | Principal exclusion criteria |
Medical Conditions 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 > 30 µmol/L 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. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to: a. Severe intercurrent illness b. Known causes of active liver disease/injury or transaminase elevation (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis) c. Physician concerns about intake of drugs of abuse or excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 21 units of alcohol per week in men and ≥ 14 units of alcohol per week in women; where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor) d. history of serious mental illness that includes, but is not limited to, schizophrenia, bipolar disorder, or severe depression requiring hospitalization or pharmacological intervention e. 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 Prior/Concomitant Therapy 6. Use of an RNAi drug within the last 6 months 7. 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 transaminase (ALT) or aspartate transaminase (AST) > 3 times 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 Prior/Concurrent Clinical Study Experience 8. Participation in any clinical study in which they received an investigational medicinal product (IMP) within 4 months before Screening Diagnostic Assessments 9. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender 10. Positive screening for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies. If participant has been tested in the past 3 months, medical record documentation of this testing can be used for screening. 11. Positive anti-dsDNA test at Screening Other Exclusions 12. Known hypersensitivity to DCR-PHXC or any of its ingredients 13. Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations detailed in Section 5.3. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence and severity of treatment-emergent AEs, SAEs, and AESI • Changes from baseline in clinical laboratory test results, including hematology, serum chemistry, and urinalysis • Changes from baseline in vital signs measurements • Changes from baseline in 12-lead ECG findings • Incidence and nature of treatment-emergent clinically significant physical examination findings |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
All the primary end points will be evaluated from baseline to end of study. |
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E.5.2 | Secondary end point(s) |
1. Plasma PK parameters of DCR-PHXC and its metabolites, including Cmax, AUC(0-t), and AUC(0-inf), if estimable 2. The proportion of participants achieving a > 30% decrease from baseline in 24-hour Uox on 2 consecutive visits |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Plasma PK parameters will be evaluated until Day 29. 2. Decrease in 24-hour Uox will be evaluated from Baseline until End of Study. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
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 |
France |
Germany |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 9 |