Primary:To assess the efficacy of DCR-PHXC in reducing urinary oxalate burden in patients with PH (types 1 and 2)Key Secondary:To assess the efficacy of DCR-PHXC in reducing urinary oxalate burden over time in patients with PHSecondary:1. To…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Inborn errors of metabolism
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary End point:
The proportion of participants with a reduction from baseline in 24-hour Uox of
at least 70%, based on a AUC and/or reaching normalization or
near-normalization of 24-hour Uox on at least 2 consecutive visits, starting
from Day 90. Normalization of Uox is defined as < 0.46 mmol/24 hours;
near-normalization is defined as * 0.46 to < 0.60 mmol/24 hours (values
adjusted per 1.73 m2 BSA in participants aged < 18 years).
Secondary outcome
Key Secondary Endpoint:
AUC from Day 90 to Day 180, based on percent change from Baseline in 24-hour Uox
Secondary Endpoints:
1. Percent change in the summed surface area and number of kidney stones
identified via kidney ultrasound from Baseline to Day 180
2. Percent change in plasma oxalate from Baseline to Day 180 (for adults only)
3. Rate of change in eGFR from Baseline to Day 180
4. AE and SAE; change from Baseline in 12-lead ECG, physical examination
findings, vital signs, and clinical laboratory tests
5. Population and individual PK parameters for DCR-PHXC
Exploratory Endpoints
1. Number of stone events over a 6-month period
2. TWS AUC of 24-hour Uox from Day 1 to Day 180, based on percent change from
Baseline
3. Percent change in 24-hour Uox from Baseline to Day 180
4. TWS AUC of 24-hour urinary oxalate-to-creatinine ratio from Day 90 to Day
180, based on percent change from Baseline
5. Change from Baseline to Day 180 in the SF-36 and EQ-5D--5L in adults; and in
the PedsQL* in children
6. Uox in spot urine and 24-hour urine
Background summary
DCR-PHXC consists of the drug substance (DCR-L1360), a synthetic
double-stranded (hybridized duplex) ribonucleic acid (RNA) oligonucleotide
conjugated to N-acetyl-D-galactosamine (GalNAc) amino-sugar residues, as a
sterile solution in water for injection (WFI). DCR-PHXC is designed to
selectively reduce LDHA messenger ribonucleic acid (mRNA) and lactate
dehydrogenase (LDH) activity in the liver, and subsequently decrease liver
oxalate production. DCR-PHXC is being developed as a treatment for PH, an
ultra-rare autosomal recessive disease characterized by excessive production of
oxalate in the liver.
The proposed study is designed to evaluate the efficacy, safety, tolerability,
and pharmacokinetics (PK) of DCR-PHXC versus placebo in patients with PH1 and
PH2.
Study objective
Primary:
To assess the efficacy of DCR-PHXC in reducing urinary oxalate burden in
patients with PH (types 1 and 2)
Key Secondary:
To assess the efficacy of DCR-PHXC in reducing urinary oxalate burden over time
in patients with PH
Secondary:
1. To evaluate the effect of DCR-PHXC on stone burden in patients with PH
2. To evaluate the effect of DCR-PHXC on plasma oxalate in patients with PH
3. To evaluate the effect of DCR-PHXC on eGFR
4. To assess the safety of DCR-PHXC in patients with PH
5. To characterize the PK of DCR-PHXC in patients with PH
Tertiary/Exploratory:
1. To evaluate the effect of DCR-PHXC on stone events in patients with PH
2. To assess the efficacy of DCR-PHXC in reducing Uox burden in patients with
PH over 6 months
3. To assess the efficacy of DCR-PHXC in reducing Uox in patients with PH at
month 6
4. To evaluate the effect of DCR-PHXC on urinary oxalate-to-creatinine ratio in
patients with PH
5. To evaluate the effect of DCR-PHXC on QoL Assessments in patients with PH
6. To evaluate the relationship between Uox spot urine and 24-hour urine
measurement in patients with PH
Study design
This is a 6-month, randomized, placebo-controlled, double-blind study of
DCR-PHXC in patients with primary hyperoxaluria (PH1 and PH2). Potential
participants are screened over an up-to-6-week period prior to randomization to
DCR-PHXC or placebo.Approximately 40 participants will be screened to achieve
36 evaluable participants.
Intervention groups and duration of participation: Eligible participants will
be randomized in a 2 to 1 (DCR-PHXC to placebo) ratio. Following the up-to-35
-day screening period (with, participants will return to the clinic for interim
visits through Day 180. Note: an extra 7-day period days will be allowed for
participants who are required to repeat screening 24-hour urine collections),
participants will return to the clinic for interim visits through Day 180. or
for repeat of initially unanalyzable screening laboratory assessment samples.
The total time on study for each participant is approximately 7 months.
Study Duration is approximately 18 months from first participant, first visit
to last participant, last visit. After completion of the study, eligible
participants will be offered the opportunity to enroll into a long-term
open-label extension study (DCR-PHXC-301).
A DSMC will be convened to provide periodic review of the efficacy and safety
data. The DSMC will consist of 3 voting members who are independent of the
study team and Sponsor.
Intervention
DCR-PHXC is a synthetic ribonucleic acid interference (RNAi) drug that consists
of double-stranded oligonucleotides conjugated to a GalNAc ligand. DCR-PHXC is
a pale yellow, sterile solution of the siRNA (DCR-L1360) at a concentration of
170 mg/mL in water for injection (WFI).
DCR-PHXC is administered monthly as a SC injection into the abdomen or thigh.
The dose of DCR-PHXC in adults and in adolescents (12-17 years old) weighing at
least 50 kg will be 170 mg. For adolescents weighing less than 50 kg, the dose
will be 136 mg. In children aged 6 to 11 years of age, the dose of DCR-PHXC
will be determined from ongoing review of pharmacokinetic (PK) and
pharmacodynamic (PD) data via a Modelling and Simulation (M&S) approach.
The placebo comparator is a sterile, preservative-free normal saline 0.9%
solution for subcutaneous (SC) injection, which is of similar osmolality to the
DCR-PHXC formulation. Placebo will be administered as a SC injection in the
thigh or abdomen in a volume equivalent to the dose of DCR-PHXC.
Study burden and risks
In studies with other drugs of the same class as the study drug, there have
been events such as a release of immune substances called a cytokine release, a
response of the body to injuries, resulting in inflammation, mild reddening,
soreness, itching, or swelling at the place where the study treatment was
injected (called injection site reactions), and elevated liver enzymes may be
indicative of abnormalities of the liver.
Other symptoms that patients may develop are fatigue, nausea, vomiting,
abdominal pain or tenderness around the liver, fever, or rash. Patients may
also have general muscle pain or weakness from the study drug.
Observations from older drugs of the same class as the study drug have been
changes in blood clotting, a reduction in blood platelets (called
thrombocytopenia), and mild or moderate abnormalities of the liver. The study
drug used in this research may have risks that are not well-known or
understood. Therefore, there may be other risks that are not yet known.
Please refer to Protocol Section 2.3.3.Known Potential Benefits and 2.3.5.
Overall Risk-Benefit Analysis for the possible benefits of the participation.
Hayden Ave. 33
Lexington MA 02421
US
Hayden Ave. 33
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
Key inclusion criteria:
- 24-hour Uox excretion * *0.7 mmol (adjusted per 1.73 m2 body surface area
[BSA] in participants < 18 years of age) in both collections performed in the
screening period. Of the first 24 participants enrolled, at least 12 (50%) must
have at least one 24 hour Uox excretion * 1.6 mmol (adjusted per 1.73 m2 BSA in
participants aged < 18 years).
- Less than 20% variation between the two 24-hour urinary creatinine excretion
values [mmol/24 hr/kg] derived from the two 24-hour urine collections in the
screening period.
- Estimated GFR at screening * 30 mL/min normalized to 1.73 m2 BSA,
calculated using the CKD-EPI formula in participants aged * 18 years or the
2012 multivariate equation by Schwartz in participants aged 6 to 17 years.
Exclusion criteria
Key exclusion criteria:
- Prior renal or hepatic transplantation; or planned transplantation within
the study period
- Currently receiving dialysis or anticipating requirement for dialysis during
the study period
- Plasma oxalate > 30 *mol/L
- 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).
- Liver function test (LFT) abnormalities: Alanine aminotransferase (ALT)
and/or aspartate aminotransferase (AST) >1.5 times upper limit of normal (ULN)
for age and gender.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003098-91-NL |
| CCMO | NL68734.000.19 |