Primary Hyperoxaluria MedDRA version: 20.1 Level: PT Classification code 10020703 Term: Hyperoxaluria System Organ Class: 10038359 - Renal and urinary disorders
Conditions
Interventions
Product Name: DCR-PHXC
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DCR-L1360
Current Sponsor code: DCR-L1360
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type
Sponsors
Dicerna Pharmaceuticals Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: PH patients must meet all of the following criteria to be eligible for participation in this study. 1. Patient and/or patient's parent or guardian if the patient is a minor (defined as patient < 18 years of age, or younger than the age of majority, according to local regulations), a. Understands the full nature and purpose of the study, including possible risks and side effects. b. Is willing and able to comply with all study procedures including collection of 24-hr urine samples. c. Provides informed consent. 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. For children younger than 12 years of age, assent will be based on local regulations. 2. Male or female, at least 6 years of age at the time of obtaining informed consent. 3. Patients aged 6 to 11, inclusive, must have a minimum body weight of 25 kg. Patients aged 12 to 17, inclusive, must have a minimum body weight of 35 kg. 4. Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility). 5. 24-hr urine oxalate excretion =0.7 mmol for patients 18 years and older, or =0.7 mmol per 1.73 m2 body surface area (BSA) for patients 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. 6. eGFR =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 patients 6 to < 18 years old (Levey et al., 1999; Schwartz et al., 2009; National Kidney Foundation, 2002). 7. Males, female patients of childbearing potential and female partners of male patients 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 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 1 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 IUD inserted at least 1 month prior to the screening visit. e. Vasectomized partner (at least 6 months post-procedure) prior to the screening visit. f. Postmenopausal women: defined as 12 months with no menses prior to screening and a serum FSH in the menopausal range at screening. 8. For WOCP: a negative pregnancy test at sc
Exclusion criteria
Exclusion criteria: PH patients meeting any of the following criteria will be excluded from this study: 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. 5. Presence of any medical condition or co-morbidities that would interfere with study compliance or data interpretation or potentially impact patient 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. f. any clinically significant (in the opinion of the Investigator), age-appropriate abnormality in screening data (including serum chemistry, hematology, coagulation parameters, blood pressure, pulse rate, and ECG findings) 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 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: ALT and/or AST >1.5 times ULN for age and gender. 9. 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 subject has been tested in the past 3 months, medical record documentation of this testing can 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 11. Known hypersensitivity to DCR-PHXC or any of its ingredients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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.;Main Objective: 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. ;Secondary Objective: 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 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 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 pharmacodynamic (PD) effects of single doses of DCR PHXC in patients with PH aged 12 to 17 and adults. Looking at the changes in plasma glyoxalate.;Timepoint(s) of evaluation of this end point: Safety will be measured at multiple intervals 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 42 (1008 hours) and 57 (1344 hours). PK urine: 2ml aliquots to be taken from pooled urine 0-6hrs, 6-12hrs and 12-24 hours. 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Not Applicable;Timepoint(s) of evaluation of this end point: Not Applicable | — |
Countries
France, Germany, Netherlands, United Kingdom, United States
Contacts
Public ContactRalf Rosskamp
Dicerna Pharmaceuticals Inc
Outcome results
None listed