This study has been transitioned to CTIS with ID 2024-512260-54-00 check the CTIS register for the current data. PrimaryTo evaluate the effect of DCR PHXC on estimated glomerular filtration rate (eGFR) in participants with PH1Secondary:To identify…
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 Endpoint:
The annual rate of decline in eGFR in participants with PH1
Key Secondary Endpoint:
1. The incidence and severity of treatment-emergent adverse events (TEAE) and
serious adverse events (SAE)
2. Change from Baseline in 12-lead electrocardiogram (ECG), physical
examination findings, vital signs, and clinical laboratory tests (hematology,
chemistry, coagulation parameters, and urinalysis)
Secondary outcome
Secondary Endpoints:
1. 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 body surface area
(BSA) in participants aged < 18 years]) each assessment time point throughout
the study in PH1, PH2, and PH3 participant subgroups
2. The percentage of participants with spot urinary oxalate-to-creatinine ratio
<= the ULN or <= 1.5 x ULN at each assessment time point throughout the study in
PH1, PH2, and PH3 participant subgroups
3..Change from Baseline in the number of stone events over a 12-month period,
annually in Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
4. Change from Baseline in the stone burden and nephrocalcinosis grade at Year
1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
5. The number of participants with severe CKD (GFR = 15 29 mL/min) or ESRD (GFR
<15 mL/min); adjusted per 1.73 m2 BSA in participants aged < 18 years in PH1,
PH2, and PH3 participant subgroups
6. Change from Baseline 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 in PH1, PH2, and PH3 participant subgroups
7. Area under the curve (AUC) of 24-hour Uox from Day 90 to Day 180, based on
percent change from Baseline in PH1, PH2, and PH3 participant subgroups . This
endpoint will only be assessed in participants randomized to placebo in a
previous study of DCR-PHXC and pediatric siblings
8. Percent change from Baseline in 24-hour Uox at each assessment timepoints
throughout the study in PH1, PH2, and PH3 participant subgroups In those
participants randomized to placebo in a previous study of DCR PHXC and
pediatric siblings this endpoint will be assesses only after Month 6
9. Percent and absolute change from Baseline in spot urinary
oxalate-to-creatinine ratio at each assessment timepoint throughout the study
in PH1, PH2 and PH3 participant subgroups. In pediatric siblings, this endpoint
will be assessed only after Month 6
Exploratory:
1. The annual rate of decline in eGFR in participants with PH2 and PH3
2. Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC,
such as clearance (CL) volume of distribution (V) estimates area under the
curve (AUC), maximum observed concentration (Cmax), minimum observed
concentration (Cmin), time to maximum concentration (Tmax), and terminal
elimination half-life (t1/2)
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 Primary
Hyperoxaluria (PH), which is an ultra-rare autosomal recessive disease
characterized by excessive production of oxalate in the liver.
The proposed study is designed to provide patients previously enrolled in Phase
1 and 2 studies of DCR-PHXC long-term access to DCR-PHXC, and to evaluate the
long-term safety and efficacy of DCR-PHXC in patients with PH.
Study objective
This study has been transitioned to CTIS with ID 2024-512260-54-00 check the CTIS register for the current data.
Primary
To evaluate the effect of DCR PHXC on estimated glomerular filtration rate
(eGFR) in participants with PH1
Secondary:
To identify the proportion of participants with normalized or nearnormalized 24
hour urinary oxalate (Uox)
2. To identify the percentage of participants with spot urinary
oxalate-to-creatinine ratio <= the ULN or <= 1.5 x ULN
3. To assess the effect of DCR-PHXC on stone events in patients with PH
4. To assess the effect of DCR-PHXC on stone burden and nephrocalcinosis grade
in patients with PH
5. To evaluate the incidence of chronic kidney disease (CKD) and endstage renal
disease (ESRD) in participants with PH
6. To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in
patients with PH
7. To assess the efficacy of DCR PHXC in reducing Uox burden in patients with PH
8. To assess the long term efficacy of DCR-PHXC in reducing Uox burden in
patients with PH
Exploratory objectives:
1. To evaluate the effect of DCR-PHXC on eGFR in participants with PH2 and PH3
2. To characterize the PK of DCR PHXC in patients with PH
Study design
This is long-term, open-label, roll-over Phase 3 study of DCR-PHXC in patients
with primary hyperoxaluria previously enrolled in studies of DCR-PHXC.
Additionally, pediatric siblings of participants who either successfully
completed a Dicerna Pharmaceuticals, Inc. study of DCR-PHXC or completed 24
weeks of participation in Study DCR-PHXC-204 may be enrolled; such participants
will be referred to as *pediatric siblings*. Approximately 75 participants are
expected to enroll. All participants will receive open-label DCR-PHXC. The
duration of participation will be up to 6 years or until DCR-PHXC is
commercially or otherwise available to the participant.
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 subcutaneous (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. The dose in children aged 0 to 11 years
(inclusive) will be 3.5 mg/kg, not to exceed 170 mg.
Study burden and risks
At present, no therapies are approved by regulatory authorities for the
treatment of patients with PH. A number of supportive therapies are used in an
attempt to mitigate some of the effects of the disease, but affected patients
are at considerable risk of serious complications like renal stones,
nephrocalcinosis, renal failure, and systemic tissue damage due to oxalate
deposition. Combined liver and kidney transplantation is the only causative
therapy but is associated with short- and long-term complications as well.
DCR-PHXC treatment has the potential benefit to reduce or eliminate the excess
oxalate production in the liver and thus avoid the need for a combined liver
and kidney transplantation in patients not already on renal replacement
therapy. The potential risks with DCR-PHXC include low elevations of liver
function tests, muscle damage, and stimulation of pattern recognition receptors
(e.g., Toll-like receptors) leading to cytokine release, inflammation, and
injection site reactions. These risks can be monitored and should be reversible
after drug discontinuation. The preliminary results from the ongoing study,
DCR-PHXC-101, demonstrate the potential for DCR-PHXC to bring patients into a
near-normal or normal range of their 24-hour Uox values. Continuous
risk-benefit assessments will be conducted by the Sponsor, and the Medical
Monitor of the contract research organization (CRO) on an ongoing basis.
Hayden Ave. 75
Lexington MA 02421
US
Hayden Ave. 75
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
ROLL-OVER PARTICIPANTS AND THEIR PEDIATRIC SIBLINGS
1. Participants starting at birth are eligible for this study.
2.Documented diagnosis of PH, confirmed by genotyping (historically available
genotype information is acceptable for study eligibility)
3. Participant successfully completed a Dicerna Pharmaceuticals, Inc. study of
DCR-PHXC or is the sibling of a participant who either successfully completed a
Dicerna study of DCR-PHXC successfully completed a Dicerna Pharmaceuticals,
Inc. study of DCR-PHXC.
a. For participants rolling over from a multidose study of DCR-PHXC, enrollment
should occur within a window of 25 to 75 days from the last dose of study
intervention. In order to minimize any gap in administration of DCR-PHXC, every
effort should be made to enroll participants as soon as all assessments from
the previous study have been completed. It should be noted if the participant
was required to repeat the end-of-study (EOS) 24-hour Uox collection for
violation of completeness criteria.
4. Estimated GFR at screening >= 30 mL/min normalized to 1.73 m2 BSA,calculated
using the equations found in Section8.2.4.1 (Protocol). For infants aged less
than 12 months, serum creatinine below The 97.5th percentile of a healthy
population (Boer et al. 2010)
In the Netherlands, children aged 0 to 5 must have PH1 to be eligible for
enrollment. Pediatric patients with PH2 or PH3 are not eligible for enrollment,
as the efficacy of DCR-PHXC has not yet been established in patients with PH2
or PH3.
Exclusion criteria
ROLL-OVER PARTICIPANTS AND THEIR PEDIATRIC SIBLING
1. Prior renal or hepatic transplantation; or planned transplantation within
the study period
2. Currently receiving dialysis
3. Documented evidence of clinical manifestations of systemic oxalosis.
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 |
|---|---|
| EU-CTR | CTIS2024-512260-54-00 |
| EudraCT | EUCTR2018-003099-10-NL |
| ClinicalTrials.gov | NCT04042402 |
| CCMO | NL68771.000.19 |