Long Term Extension Study in Patients With Primary Hyperoxaluria (PHYOX3)

• ClinicalTrials.gov Identifier: NCT04042402
• Recruitment Status: Enrolling by invitation
• First Posted: August 2, 2019
• Last Update Posted: January 12, 2024
• Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Information provided by (Responsible Party): Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Study Description

Brief Summary:

The proposed study is designed to provide patients previously enrolled in Phase 1 and 2 studies of DCR-PHXC and their siblings (<18 years old) long-term access to DCR-PHXC, and to evaluate the long-term safety and efficacy of DCR-PHXC in patients with PH.

Condition or disease	Intervention/treatment	Phase
Primary Hyperoxaluria Type 1 (PH1); Primary Hyperoxaluria Type 2 (PH2); Kidney Diseases; Urologic Diseases; Genetic Disease; Primary Hyperoxaluria Type 3 (PH3)	Drug: DCR-PHXC	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Roll-Over Study to Evaluate the Long-Term Safety and Efficacy of DCR-PHXC Solution for Injection (Subcutaneous Use) in Patients With Primary Hyperoxaluria
• Actual Study Start Date: July 9, 2019
• Estimated Primary Completion Date: April 1, 2030
• Estimated Study Completion Date: April 1, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Open Label; Open label, monthly subcutaneous injection	Drug: DCR-PHXC; Multiple fixed doses of DCR-PHXC by subcutaneous (SC) injection; Other Name: Nedosiran

Outcome Measures

Primary Outcome Measures :

1. The annual rate of decline in eGFR in participants with PH1 [ Time Frame: Annual change from baseline ]
   To evaluate the effect of DCR PHXC on estimated glomerular filtration rate (eGFR) in participants with PH1

Secondary Outcome Measures :

1. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal 12 lead electrocardiogram (ECG) readings [ Time Frame: TEAEs and SAEs are evaluated monthly for 6 years ]

   To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with primary hyperoxaluria (PH) via change from baseline and abnormal ECG findings.

   Standard 12-lead ECGs will be performed in the supine position after the subject has rested comfortably for 10 minutes. The parameters assessed will be rhythm, ventricular rate, PR interval, QRS duration, QT interval, and corrected QT interval (QTcF, Fridericia correction). The Investigator or designee is responsible for reviewing the ECG(s) to assess whether the results are within normal limits and to determine the clinical significance of the results.

   Standardized ECG acquisition equipment will be provided to all clinical trial sites at the start of the trial, to ensure parity across all sites.

2. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal physical examination findings [ Time Frame: TEAEs and SAEs are evaluated monthly for 6 years ]

   To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with primary hyperoxaluria (PH) via change from baseline and incidence of abnormal physical exam findings.

   A full physical examination will include a complete review of body systems: eyes, ears, nose, and throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, and neurological. A full physical exam is done at Screening, Day 180 and if a participant ends the study early.

   A brief physical examination will minimally include chest/respiratory, heart/cardiovascular, dermatological/skin, and gastrointestinal/liver. A brief physical examination will be performed at the Investigator's discretion at all other visits.

3. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal vital signs [ Time Frame: TEAEs and SAEs are evaluated monthly for 6 years ]

   To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with primary hyperoxaluria (PH) via the change from baseline and incidence of abnormal vital signs.

   Vital signs include blood pressure, pulse/heart rate, oral body temperature, and respiratory rate.

   Parameters will be measured in the supine position, using an automated instrument or manually, after the participant has rested comfortably for 10 minutes. In the pediatric population, an age-appropriate cuff size should be used for blood pressure measurements.

   Temperature will be obtained in degrees Celsius (°C), pulse rate will be counted for a full minute and recorded in beats per minute, and respirations will be counted for a full minute and recorded in breaths per minute.

4. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs related to abnormal clinical laboratory tests (hematology, chemistry, coagulation parameters, and urinalysis) [ Time Frame: TEAEs and SAEs are evaluated monthly for 6 years ]
   To evaluate the safety and tolerability of DCR PHXC when administered monthly to patients with primary hyperoxaluria (PH) via the change from baseline and incidence of abnormal clinical laboratory tests.
5. To identify the proportion of participants with normalized or near-normalized 24 hour urinary oxalate (Uox) [ Time Frame: 24 hour urine collections (if applicable) are performed monthly for 6 months (or quarterly for PH1 multidose rollovers), quarterly for 2 1/2 years (or monthly for PH2/PH3 multidose rollovers until Month 12), and every 6 months for 3 years after that. ]
   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]) at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups
6. To identify the percentage of participants with spot urinary oxalate-to-creatinine ratio ≤ the ULN or ≤ 1.5 x ULN [ Time Frame: Spot urine collections are performed monthly for 6 months (or quarterly for PH1 multidose rollovers), quarterly for 2 1/2 years (or monthly for PH2/PH3 multidose rollovers until Month 12), and every 6 months for 3 years after that. ]
   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
7. To assess the effect of DCR-PHXC on stone events in patients with PH [ Time Frame: Evaluated yearly for 6 years ]
   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
8. To assess the effect of DCR-PHXC on stone burden grade in patients with PH [ Time Frame: Evaluated yearly for 6 years ]
   Change from Baseline in the stone burden grade at Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
9. To assess the effect of DCR-PHXC in nephrocalcinosis grade in patients with PH [ Time Frame: Evaluated yearly for 6 years ]
   Change from Baseline in nephrocalcinosis grade at Year 1, Year 2, etc. in PH1, PH2, and PH3 participant subgroups
10. To evaluate the incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in participants with PH [ Time Frame: eGFR is evaluated monthly for 6 months (or quarterly for multidose rollovers), quarterly for 2 1/2 years, and every 6 months for 3 years after that. ]
    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
11. Change from Baseline in the Short Form (36) Health Survey (SF-36®) in PH1, PH2, and PH3 participant subgroups [ Time Frame: Surveys are administered at screening, Day 180, yearly for 3.5 years, then at Month 72 (EOS). ]

    To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in patients with PH.

    The SF 36 is a set of generic, coherent, and easily administered quality-of-life measures that taps 8 health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. The 36 items are identical to the MOS SF 36 described in Ware and Sherbourne (1992). Participants respond to each item on a categorical scale. Categorical answers are transformed to a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. All items are scored so that a high score defines a more favorable health state.

12. Change from Baseline in the EQ-5D-5L™ in adults in PH1, PH2, and PH3 participant subgroups [ Time Frame: Surveys are administered at screening, Day 180, yearly for 3.5 years, then at Month 72 (EOS). ]

    To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in patients with PH.

    The EQ-5D-5L consists of the EQ 5D descriptive system and the EQ visual analogue scale (EQ VAS).

    The descriptive system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The digits for the 5 dimensions can be combined into a 5-digit number that describes the participant's health state.

    The EQ VAS records the participant's self-rated health on a 20-cm vertical VAS, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine.' Participants are asked to place an "X" on the line that represents their health on that day.

13. Change from Baseline in the Pediatric Quality of Life Inventory (PedsQL™) in children in PH1, PH2, and PH3 participant subgroups [ Time Frame: Surveys are administered at screening, Day 180, yearly for 3.5 years, then at Month 72 (EOS). ]

    To evaluate the effect of DCR-PHXC on Quality of Life (QoL) assessments in patients with PH.

    The 23-item PedsQL is comprised of 5 items in the Emotional, Social, and School Functioning dimensions (Psychosocial Health) and 8 items in the Physical Functioning (Physical Health) dimension. Items are reverse-scored on a 0 to 4 Likert scale and linearly transformed to a 0 to 100 scale, so that higher scores indicate better functioning and HRQOL. Scale Scores are the sum of the items in each dimension, divided by the number of items answered.

14. To assess the efficacy of DCR PHXC in reducing Uox burden in patients with PH: TWS AUC [ Time Frame: Monthly for 4 months (D90 through D180) ]
    Time-weighted standardized area under the curve (TWS 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 previously randomized to placebo in a previous study of DCR- PHXC and pediatric siblings.
15. To assess the long-term efficacy of DCR PHXC in reducing Uox burden in patients with PH [ Time Frame: 24 hour urine collections (if applicable) are performed monthly for 6 months (or quarterly for PH1 multidose rollovers), quarterly for 2 1/2 years (or monthly for PH2/PH3 multidose rollovers until Month 12), and every 6 months for 3 years after that. ]
    Percent change from Baseline in 24-hour Uox at each assessment time point 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 assessed only after Month 6
16. To assess the long-term efficacy of DCR-PHXC in reducing Uox burden in patients with PH [ Time Frame: Spot urine collections are performed monthly for 6 months (or quarterly for PH1 multidose rollovers), quarterly for 2 1/2 years (or monthly for PH2/PH3 multidose rollovers until Month 12), and every 6 months for 3 years after that. ]
    Percent and absolute change from Baseline in spot urinary oxalate-to-creatinine ratio at each assessment time point throughout the study in PH1, PH2, and PH3 participant subgroups. In pediatric siblings, this endpoint will be assessed only after Month 6

Other Outcome Measures:

1. To evaluate the effect of DCR PHXC on eGFR in participants with PH2 and PH3 [ Time Frame: Annual change from baseline ]
   The annual rate of decline in eGFR in participants with PH2 and PH3
2. To characterize the PK of DCR PHXC in patients with PH by observing minimum concentration (Cmin). [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including minimum observed concentration (Cmin)
3. To characterize the PK of DCR PHXC in patients with PH by observing maximum concentration (Tmax). [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including time to maximum concentration (Tmax)
4. To characterize the PK of DCR PHXC in patients with PH by observing terminal elimination half-life (t1/2). [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including terminal elimination half-life (t1/2)
5. To characterize the PK of DCR PHXC in patients with PH by observing clearance. [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including clearance (CL)
6. To characterize the PK of DCR PHXC in patients with PH by observing volume of distribution of estimates. [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including volume of distribution (V) estimates
7. To characterize the PK of DCR PHXC in patients with PH by observing the area under the curve (AUC) [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including secondary parameters of area under the curve (AUC)
8. To characterize the PK of DCR PHXC in patients with PH by observing maximum observed concentration (Cmax). [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150, and Day 180; multidose rollovers will just collect Day 1 and 180. Then there will be analyses every 6 months for 2.5 years, and annually for 3 years. ]
   Population and/or individual pharmacokinetic (PK) parameters for DCR PHXC, including maximum observed concentration (Cmax)

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

•Participant successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC.

OR Participant is the sibling of a participant who successfully completed a Dicerna Pharmaceuticals, Inc. study of DCR PHXC. Siblings must be younger than 18 years of age and must have genetically confirmed PH.

• 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.
• Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 body surface area (BSA), calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula in participants aged ≥ 18 years, or the multivariate equation by Schwartz in participants aged 12 months to 17 years. In Japan, the cystatin C-based Uemura formula will be used for participants aged 12 months to <2 years, the creatinine-based Uemura formula by will be used for participants aged 2 to 17 years, and the equation by Matsuo will be used in participants aged ≥ 18 years.

Key Exclusion Criteria:

• Renal or hepatic transplantation (prior or planned within the study period)
• Plasma oxalate > 30 µmol/L
• Currently on dialysis
• Documented evidence of clinical manifestations of systemic oxalosis

Contacts and Locations

Locations

United States, California

Clinical Research Site

San Francisco, California, United States, 94143

United States, Massachusetts

Clinical Trial Site

Boston, Massachusetts, United States, 02115

United States, Minnesota

Clinical Trial Site

Rochester, Minnesota, United States, 55905

United States, New York

Clinical Trial Site

New York, New York, United States, 10016

Australia, Queensland

Clinical Research Site

Herston, Queensland, Australia, 4029

Australia

Clinical Trial Site

Melbourne, Australia, 3052

Canada, Ontario

Clinical Research Site

Hamilton, Ontario, Canada, L8S 4K1

France

Clinical Trial Site

Bron, France, 69500

Clinical Trial Site

Paris, France, 75019

Germany

Clinical Trial Site

Bonn, Germany, 53127

Clinical Trial Site

Heidelberg, Germany, 69120

Italy

Clinical Research Site

Roma, Italy, 00165

Japan

Clinical Trial Site

Fukuoka, Japan, 830-0011

Clinical Trial Site

Nagoya, Japan, 467-8601

Clinical Trial Site

Tokyo, Japan, 183-8561

Lebanon

Clinical Trial Site

Beirut, Lebanon

Netherlands

Clinical Trial Site

Amsterdam, Netherlands, 1105AZ

Norway

Clinical Trial Site

Tromsø, Norway, 9019

Spain

Clinical Research Site

Barcelona, Spain, 08035

Clinical Trial Site

Barcelona, Spain, 08035

Turkey

Clinical Trial Site

Ankara, Turkey, 06560

United Kingdom

Clinical Trial Site

Hampstead, London, United Kingdom

Clinical Trial Site

Birmingham, United Kingdom

Sponsors and Collaborators

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Investigators

• Study Director: Verity Rawson, MB.CHB; Dicerna, A Novo Nordisk Company

More Information

• Responsible Party: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• ClinicalTrials.gov Identifier: NCT04042402
• Other Study ID Numbers: DCR-PHXC-301
• First Posted: August 2, 2019
• Last Update Posted: January 12, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Dicerna Pharmaceuticals, Inc., a Novo Nordisk company:

Primary Hyperoxaluria; PH1; PH2; RNAi; GalNAc; LDHA; LDH; siRNA; PH3

Additional relevant MeSH terms:

Kidney Diseases; Urologic Diseases; Hyperoxaluria, Primary; Genetic Diseases, Inborn; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hyperoxaluria; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases