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 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 assess the efficacy of DCR PHXC in reducing urinary oxalate burden in patients with PH (types 1 and 2) |
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E.2.2 | Secondary objectives of the trial |
1.To evaluate the effect of DCR-PHXC on urinary oxalate-to-creatinine ratio in patients with PH (types 1 and 2)
2.To identify the proportion of participants with normalized or near-normalized Uox
3.To identify the change in relative risk of participants for end-stage renal disease (ESRD)
4.To assess the efficacy of DCR PHXC in reducing Uox burden in patients with PH (types 1 and 2) over 6 months
5.To evaluate the effect of DCR-PHXC on plasma oxalate in patients with PH (types 1 and 2)
6.To assess the safety of DCR PHXC in patients with PH (types 1 and 2)
7.To characterize the PK of DCR PHXC in patients with PH (types 1 and 2)
Exploratory:
1. To evaluate the effect of DCR PHXC on:
a) stone burden in patients with PH (types 1 and 2)
b) estimated glomerular filtration rate (eGFR)
c) Quality of Life Assessments in patients with PH (types 1 and 2)
2. To evaluate the pharmacoeconomics/health care utilization of patients with PH (types 1 and 2)
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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.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 PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility)
3.24-hour Uox excretion ≥ 0.7 mmol (≥ 18 years of age) or ≥ 0.7 mmol per 1.73 m2 BSA (< 18 years of age) on at least 1 of the 2 assessments conducted in the screening period, with less than 30% variation between measurements. Individuals who do not achieve a less than 30% variation between the 2 Uox 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-30% variation, they will be excluded from participation.
4.Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA calculated using the Modification of Diet in Renal Disease formula in participants aged > 16 years), or the formula by Schwartz in participants aged 6 to 16 years (Levey et al., 1999; Schwartz et al., 2009; National Kidney Foundation, 2002)
Sex
5.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 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
6.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 or anticipating requirement for dialysis during the study period
3. Documented evidence of clinical manifestations of systemic oxalosis
4. 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
5. Routine or chronic use of more than 3 grams of acetaminophen/paracetamol daily
6. Use of an RNA interference (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 aminotransferase (ALT) or aspartate aminotransferase (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
8. Participants receiving pyridoxine 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
9. Participation in any clinical study in which they received an investigational medicinal product (IMP) within 4 months 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
Diagnostic assessments
10. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender
11. 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.
12. Positive urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines). Urine drug screening is not required in participants ≤ 12 years of age.
Other Exclusions
13. Known hypersensitivity to DCR PHXC
14. 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) |
Time-weighted standardized (TWS) area under the curve (AUC) from Day 90 to Day 180, based on percent change from Baseline in 24-hour Uox |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim analysis will be conducted upon completion of two-thirds of the participants for the purpose of re-evaluation of sample size or stopping the trial for efficacy. The O’Brien-Fleming boundaries will be used for this analysis, no futility boundaries will be utilized. The interim unblinded analysis will be performed by an independent statistician other than the person responsible for the primary analysis of this study and treatment codes will be revealed to that party only. |
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E.5.2 | Secondary end point(s) |
1. TWS AUC of 24-hour urinary oxalate-to-creatinine ratio from Day 90 to Day 180, based on percent change from Baseline
2. 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 BSA in participants aged < 18 years) on at least 2 consecutive visits, beginning with Day 90
3. Change from Baseline to Day 180 in the proportion of participants with 24-hour Uox levels in each of 4 quartile ranges (< 1.1 mmol, 1.1 to < 1.6 mmol, 1.6 to ≤ 2.4 mmol, and > 2.4 mmol/24 hours [values adjusted per 1.73 m2 body surface area (BSA) in participants aged < 18 years])
4. TWS AUC of 24-hour Uox from Day 1 to Day 180, based on percent change from Baseline
5. TWS AUC of plasma oxalate from Day 90 to Day 180, based on percent change from Baseline
6. Adverse events (AE) and SAEs; change from Baseline in 12 lead ECG, physical examination findings, vital signs, and clinical laboratory tests
7. Population and individual PK parameters for DCR PHXC
Exploratory endpoints:
1. Change from Baseline to Day 180 in the mass of kidney stones identified via kidney ultrasound and in the number of stone events over a 6-month period.
2. Change from Baseline to Day 180 in eGFR
3. Change from Baseline to Day 180 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
4. Change from Baseline to Day 180 in Quality-adjusted Life Years (QALY)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
An interim analysis will be conducted upon completion of two-thirds of the participants for the purpose of re-evaluation of sample size or stopping the trial for efficacy. The O’Brien-Fleming boundaries will be used for this analysis, no futility boundaries will be utilized. The interim unblinded analysis will be performed by an independent statistician other than the person responsible for the primary analysis of this study and treatment codes will be revealed to that party only. |
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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) | 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) | Yes |
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 | 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 | 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 | 23 |
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 |
Australia |
Canada |
France |
Germany |
Israel |
Italy |
Netherlands |
New Zealand |
Poland |
Romania |
Spain |
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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The end of the study is defined as completion of the last visit or procedure 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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |