A Placebo-Controlled, Single-Blind, Single-Center Phase 1 Study in Normal Healthy Volunteers and Open-Label Multi Center Study in Patients with Primary Hyperoxaluria to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of DCR PHXC Solution for Injection (subcutaneous use)
- Conditions
- Over production of Oxalateprimary hyperoxaluria1003836010038430
- Registration Number
- NL-OMON46435
- Lead Sponsor
- Dicerna Pharmaceutical Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 5
PH patients must meet all of the following criteria to be eligible for participation in this study.
1. Patient
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.
2. Male or female, at least 18 years of age at the time of obtaining informed consent. ;3. Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
4. 24-hr urine oxalate excretion >=0.7 mmol on at least one of the two assessments conducted in the screening period, with less than 30% variation between both oxalate measurements.
5. eGFR >=30 mL/min normalized to 1.73 m2 BSA calculated using the Modification of Diet in Renal Disease (MDRD) formula (Levey et al., 1999; National Kidney Foundation, 2002).
6. 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 females: defined as 12 months with no menses prior to screening and a serum FSH >26 IU/L at screening. ;7. For WOCP: a negative pregnancy test at screening and Day 0 ;8. 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 patient with PH2 is receiving pyridoxine, this should be discontinued at least 4 weeks prior to study entry
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.
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 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.
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. 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Safety analysis will be based on the Safety Analysis Set, which will include<br /><br>all volunteers and patients who received a<br /><br>full or partial dose of DCR-PHXC. This will be the primary analysis population<br /><br>for safety evaluation.</p><br>
- Secondary Outcome Measures
Name Time Method <p>* PK analysis will be based on the PK Analysis Set, which will include all<br /><br>volunteers and patients who received a full<br /><br>dose of DCR-PHXC and have sufficient data for at least 1 post-dose PK<br /><br>assessment.<br /><br><br /><br>* PD analysis will be based on the PD Analysis Set, which will include all PH<br /><br>patients who received a full dose of<br /><br>DCR-PHXC and have at least 1 post-dose PD assessment.</p><br>