E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
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 |
|
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 |
|
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 |
The primary objective for part A of the study is to evaluate the safety and tolerability of single doses of DCR PHXC in healthy volunteers.
The primary objective for part B of the study is to evaluate the safety and tolerability of single doses of DCR PHXC in Primary Hyperoxaluria patients. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective of part A of the study is: • To characterize the pharmacokinetics parameters (PK) of single doses of DCR PHXC. This means, for example, looking to see how fast the drug is absorbed and seeing how much of the drug reaches the blood stream. • To evaluate what effect the drug has on the body (pharmacodynamic) after single doses of DCR PHXC are given to healthy volunteers and patients with PH. To measure this we will look at biochemical markers including, but not limited to, changes in plasma oxalate and glycolate , and urine oxalate and glycolate concentrations
The exploratory objectives are: • To evaluate the onset and magnitude of change in urine oxalate concentration (Screening, Day 1, 15, 29) in NHV after a single SC dose of DCR PHXC after ingestion of 10-20 g of gelatin. (Group A only).
The secondary objective of part B of the study is: • To characterize the pharmacokinetics parameters (PK) of single doses of DCR-PHXC. This means, for example, looking to |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For Part A & Part B of the study:
1. Subject understands the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all study procedures and restrictions. 2. Females and males and their female partner(s) of childbearing potential must be willing to use a highly effective and approved contraceptive method (s) from the date of informed consent until 12 weeks after the last dose of Investigational Medicinal Product (IMP). A highly effective method of contraception is defined as fulfilling at least one of the following: a. Strict abstinence: When this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.] b. Surgically sterile (having undergone one of the following surgical procedures: hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 6 weeks post-sterilization. c. Combined hormonal oral contraceptive (estrogen and progesterone), implanted, or injectable contraceptive on a stable dose for at least one month prior to the screening visit plus a barrier method. Combined hormonal contraception is considered a highly effective method of contraception only if it is associated with inhibition of ovulation. If associated with inhibition of ovulation, progesterone-only hormonal contraception is also considered a highly effective method of contraception. d. Intrauterine devices plus condoms. Hormonal intra-uterine device (IUD) inserted at least 1 month prior to the screening visit. e. Double-barrier methods [e.g., Condom and Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository]. Of note, a female condom and a male condom, or two male condoms, should not be used together as friction between the two can result in either product failing. f. Vasectomized partner (at least 6 months post-procedure) prior to the screening visit. 3. Postmenopausal females: defined as 12 months with no menses prior to screening and a serum follicle stimulating hormone (FSH) > 26 IU/L at Screening visit. 4. For females: a negative pregnancy test at screening and Day 0 visit.
PART A specific 1. Male or female subjects between 18 and 55 years of age, inclusively. 2. Subject must have a body mass index (BMI) between 19.0-32 kg/m2, inclusive. 3. Non-smokers, at least 1 month tobacco free, and willing to remain tobacco free through EOS. Subjects must also be free from nicotine-containing products (e.g. nicotine patch.) 4. Subjects must be otherwise healthy. Healthy status will be defined based on the opinion of the principal investigator (PI) by the absence of evidence of any clinically significant, active, or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, serology, and urinalysis. 5. Subjects must have hematology and clinical chemistry tests and urine analyses within the normal range, unless abnormalities are classified as Not Clinically Significant (NCS) by the investigator or qualified designee. Liver panel tests must be normal. Retests may be conducted one time for liver panel results.
Part B specific 1. Male or female, at least 6 years of age at the time of obtaining informed consent. 2. Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility). 3. 24-hour urine oxalate excretion ≥ 0.7 mmol for subjects 18 years and older, or ≥ 0.7 mmol per 1.73 m2 body surface area (BSA) for subjects less than 18 years of age, on at least one of the two assessments conducted in the Screening period, with less than 30% variation between both oxalate measurements. 4. Estimated glomerular filtration rate ≥ 30 mL/min normalized to 1.73 m2 BSA calculated using the Modification of Diet in Renal Disease (MDRD) formula in adults (age ≥ 18 years), or the formula by Schwartz in subjects 6 to < 18 years old [Levey et al., 1999; Schwartz et al., 2009; National Kidney Foundation, 2002]. See Appendix B of protocol. 5. Postmenopausal females: defined as 12 months with no menses prior to screening and a serum follicle stimulating hormone (FSH) > 26 IU/L at screening. 6. Patients with PH1 receiving pyridoxine at stable doses at least 4 weeks prior to study entry must be willing to remain on the same stable dose during the study. In the unlikely event that a subject with PH2 is receiving pyridoxine, this should be discontinued at least 4 weeks prior to study entry 7. Patient must have a minimum body weight of 25kg
|
|
E.4 | Principal exclusion criteria |
Part A and Part B: 1. History of alcohol consumption exceeding more than 21 units in males, 14 units in females, per week as determined by the Investigator. 2. Males with female partners who are planning to attempt to become pregnant during this study or within 90 days after last dosing of IMP.
Part A specific: 1. Presence of any medical condition or co-morbidities that would interfere with study compliance or data interpretation or potentially impact subject safety including, but not restricted to: a. severe intercurrent illness b. routine vaccination within 30 days prior to dosing and through EOS visit c. known causes of active liver disease/ injury or transaminase elevation (e.g., alcoholic liver disease, Nonalcoholic fatty liver disease/ steatohepatitis [NAFLD/NASH]) d. physician concerns about excess alcohol consumption e. routine or chronic use of more than 3 grams of paracetamol daily. 2. History of kidney stones. 3. Women who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 90 days after last dosing of IMP. 4. Use of any investigational agent within 90 days before the first dose of study medication. If a subject has participated in prior siRNA or antibody studies, a washout period of at least 6 months before the first administered dose in this study is required. 5. Use of tobacco products within 30 days prior to dosing and through EOS visit. 6. Strenuous activity, sunbathing, and contact sports within 48 hours (2 days) prior to dose administration and through to the EOS visit or Day 29. 7. History of donation of more than 450 mL of blood within 90 days prior to dosing in the clinical research center or planned donation less than 30 days after receiving IMP. 8. Plasma or platelet donation within 7 days of dosing and throughout the entire study. 9. Positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies. If subject has been tested in the past 3 months, historical data may be used. 10. History of one or more of the following reactions to an oligonucleotide-based therapy a. Severe thrombocytopenia b. Hepatotoxicity c. Severe flu-like symptoms leading to discontinuation of therapy d. Localized skin reaction from the injection (Grade 3 or higher) leading to discontinuation of therapy. e. Coagulopathy/ clinically important prolongation of clotting time
Part B specific 1. Prior renal and/or hepatic transplantation. 2. Currently receiving dialysis. 3. Documented evidence of clinical manifestations of systemic oxalosis. 4. Participation in any clinical study where they received an investigational medical product within 4 months before enrollment. For IMPs with the potential to reduce Uox and or plasma oxalate, these concentrations must have returned to historical baseline levels. a. If patient participated in an earlier cohort in this study (DCR-PHXC-101), a minimum of 8 weeks must have elapsed prior to re-enrollment and urinary oxalate excretion must have returned to ≥ 80% of baseline. 5. Presence of any medical condition or co-morbidities that would interfere with study compliance or data interpretation or potentially impact subject safety including, but not restricted to: a. severe intercurrent illness b. routine vaccination within 30 days prior to dosing and through EOS visit c. known causes of active liver disease/ injury or transaminase elevation (e.g., alcoholic liver disease, Nonalcoholic fatty liver disease/ steatohepatitis (NAFLD/NASH) d. physician concerns about excess alcohol consumption e. routine or chronic use of more than 3 grams of acetaminophen daily. 6. History of alcohol consumption exceeding more than 21 units in males, 14 units in females, per week as determined by the Investigator. See Section 5 of the protocol for details. 7. Women who are pregnant, lactating, or planning to attempt to become pregnant during this study or within 90 days after last dosing of IMP. 8. Liver function test (LFT) abnormalities: alanine transaminases (ALT) and/or aspartate transaminases (AST) > 1.5 times upper limit of normal (ULN) for age and gender. 9. History of one or more of the following reactions to an oligonucleotide-based therapy a. Severe thrombocytopenia b. Hepatotoxicity c. Severe flu-like symptoms leading to discontinuation of therapy D. Localized skin reaction from the injection (Grade 3 or higher) leading to discontinuation of therapy. E. Coagulopathy/ clinically important prolongation of clotting time
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety analysis will be based on the Safety Analysis Sets, which will include all volunteers and patients who received a full or partial dose of DCR PHXC. This will be the primary analysis population for safety evaluation.
PK analysis will be based on the PK analysis sets (PK Set), which will include all volunteers and patients who received a full dose of DCR PHXC and have sufficient data for at least 1 post-dose PK assessment.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety will be measured at multiple intervals in Part A and Part B
Part A PK blood measured at the following: Pre-dose, Day 1, and at 5, 15 and 30 minutes and 1, 2, 4, 6, 8, and 12 hours after the injection, and at Days 2 (24 hours), 3 (48 hours), 8 (168 hours), 15 (336 hours), 22 (504 hours) and 29 (672 hours) and 42 (1008 hours) and 57 (1344 hours) for part B only.
Part A & B PK urine: 2ml aliquots to be taken from pooled urine 0-6hrs, 6-12hrs and 12-24 hours.
Part B PK blood for aged 6-11 patient group at the following: Pre-dose, Day 1, and at 30 minutes and 2, and 8 hrs after the injection, and at Days 2 (24 hrs), 15 (336 hrs), and 57 (1344 hrs). |
|
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 | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
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) | 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 | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 2 |