A Study to Evaluate DCR-PHXC in Children and Adults With Primary Hyperoxaluria Type 1 and Primary Hyperoxaluria Type 2 (PHYOX2)

• ClinicalTrials.gov Identifier: NCT03847909
• Recruitment Status: Completed
• First Posted: February 20, 2019
• Last Update Posted: June 22, 2022
• 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 purpose of this study is to evaluate the efficacy and safety of DCR-PHXC in Children and Adults with Primary Hyperoxaluria Type 1 (PH1) and Primary Hyperoxaluria Type 2 (PH2)

Condition or disease	Intervention/treatment	Phase
Primary Hyperoxaluria Type 1 (PH1); Primary Hyperoxaluria Type 2 (PH2); Kidney Diseases; Urologic Diseases; Genetic Disease	Drug: DCR-PHXC; Drug: Sterile Normal Saline (0.9% NaCl)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of DCR-PHXC Solution for Injection (Subcutaneous Use) in Patients With Primary Hyperoxaluria
• Actual Study Start Date: October 28, 2019
• Actual Primary Completion Date: June 21, 2021
• Actual Study Completion Date: June 29, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: DCR-PHXC; Intervention, drug, DCR-PHXC	Drug: DCR-PHXC; Multiple fixed doses of DCR-PHXC by subcutaneous (SC) injection; Other Name: nedosiran
Placebo Comparator: Placebo - Sterile Normal Saline (0.9% NaCl); Placebo, sterile normal saline (0.9% NaCl) for subcutaneous (SC) injection	Drug: Sterile Normal Saline (0.9% NaCl); Sterile Normal Saline (0.9% NaCl) for subcutaneous (SC) injection, administered at same injection volume as DCR-PHXC, to serve as placebo

Outcome Measures

Primary Outcome Measures :

1. Area under the curve (AUC) of percent change from baseline in 24-hour urinary oxalate excretion between Day 90 and Day 180 [ Time Frame: 3 months (Last 3 months of the 6 month treatment period) ]
   Four measurements of percent change from baseline in 24-hour urinary oxalate are combined to determine a single AUC value

Secondary Outcome Measures :

1. 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 BSA in participants aged <18 years) on at least two consecutive study visits commencing at Day 90 and ending at Day 180 [ Time Frame: 3 months (Last 3 months of the 6 month treatment period) ]
2. Percent change in the summed surface area and number of kidney stones identified via kidney ultrasound from baseline to Day 180 [ Time Frame: 6 months ]
3. Percent change from baseline to Day 180 in plasma oxalate (for adults only) [ Time Frame: 6 months ]
   Four measurements of percent change from baseline in plasma oxalate are combined to determine a single AUC value
4. Rate of change in eGFR from baseline to Day 180 [ Time Frame: 6 months ]
5. AE and SAE throughout the study [ Time Frame: 6 months ]
6. Change from baseline in 12-lead ECG [ Time Frame: 6 months ]

   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.

7. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal physical examination findings [ Time Frame: 6 months ]

   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 may be performed at the Investigator's discretion at all other visits.

8. The incidence and severity of treatment-emergent adverse events (TEAE) and SAEs associated with abnormal vital signs [ Time Frame: 6 months ]

   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.

9. 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: 6 months ]
   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.
10. To characterize the PK of DCR-PHXC in PH patients [ Time Frame: 6 months ]
    Maximum observed plasma concentration (Cmax)
11. To characterize the PK of DCR-PHXC in PH patients [ Time Frame: 6 months ]
    Area under the plasma concentration versus time curve (AUC)

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• Capable and willing to provide written informed consent or assent
• Documented diagnosis of PH1 or PH2, confirmed by genotyping
• Must meet the 24 hour urine oxalate excretion requirements
• Less than 20% variation between the two 24-hour urinary creatinine excretion values 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

Key Exclusion Criteria:

• Renal or hepatic transplantation (prior or planned within the study period)
• Currently on dialysis or anticipated requirement for dialysis during the study period
• Plasma oxalate >30 µmol/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)
• Use of an RNA interference (RNAi) drug within the last 6 months
• Participation in any clinical study in which you received an investigational medicinal product (IMP) within 4 months before Screening
• 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
• Inability or unwillingness to comply with study procedures

Contacts and Locations

Locations

United States, Massachusetts

Clinical Trial Site

Boston, Massachusetts, United States, 02115

United States, Minnesota

Clinical Trial Site

Minneapolis, Minnesota, United States, 55905

United States, New York

Clinical Trial Site

New York, New York, United States, 10016

United States, Pennsylvania

Clinical Trial Site

Pittsburgh, Pennsylvania, United States, 15224

Australia

Clinical Trial Site

Parkville, Australia, 3052

Canada

Clinical Trial Site

Hamilton, Canada

France

Clinical Trial Site

Bron, France

Clinical Trial Site

Paris, France, 75019

Germany

Clinical Trial Site

Bonn, Germany, 53127

Clinical Trial Site

Heidelberg, Germany, 69120

Israel

Clinical Trial Site

Jerusalem, Israel, 9103102

Italy

Clinical Trial Site

Roma, Italy, 00165

Japan

Clinical Trial Site

Nagoya, Japan, 467-8601

Clinical Trial Site

Tochigi, Japan, 329-0431

Clinical Trial Site

Tokyo, Japan, 183-8561

Lebanon

Clinical Trial Site

Beirut, Lebanon, 2807

Clinical Trial Site

Beirut, Lebanon

Netherlands

Clinical Trial Site

Amsterdam, Netherlands, 1105 AZ

New Zealand

Clinical Trial Site

Auckland, New Zealand

Poland

Clinical Trial Site

Białystok, Poland

Romania

Clinical Trial Site

Bucharest, Romania

Spain

Clinical Trial Site

Barcelona, Spain, 08035

Clinical Trial Site

Santa Cruz, Spain, 38320

United Kingdom

Clinical Trial Site

Birmingham, United Kingdom

Clinical Trial Site

London, United Kingdom, WCIN 3JH

Clinical Trial Site

London, United Kingdom

Sponsors and Collaborators

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Investigators

• Study Director: Alexandra Haagensen, MD; Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

More Information

• Responsible Party: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• ClinicalTrials.gov Identifier: NCT03847909
• Other Study ID Numbers: DCR-PHXC-201
• First Posted: February 20, 2019
• Last Update Posted: June 22, 2022
• Last Verified: June 2022

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

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

PH1; PH2; Primary Hyperoxaluria; RNAi; RNAi therapeutic; GalNAc; LDHA gene; LDH; siRNA

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