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

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ClinicalTrials.gov Identifier: NCT04042402
Recruitment Status : Enrolling by invitation
First Posted : August 2, 2019
Last Update Posted : July 16, 2021
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

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 Drug: DCR-PHXC Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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 : December 2023
Estimated Study Completion Date : December 2023


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




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


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 3 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 3 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 3 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 3 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 are performed monthly for 6 months and then quarterly for 2 1/2 years. Participants rolling from a repeat dose study will perform 24 hour urine collections quarterly for 3 years. ]
    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 quarterly intervals throughout the study

  6. To assess the effect of DCR-PHXC on stone events in patients with PH [ Time Frame: Evaluated yearly for 3 years. ]
    Change from Baseline in the number of stone events over a 12-month period, annually in Year 1, Year 2, etc.

  7. To assess the effect of DCR-PHXC on stone burden in patients with PH [ Time Frame: Evaluated yearly for 3 years. ]
    Change from Baseline in the stone burden observed over a 12-month period, annually in Year 1, Year 2, etc.

  8. 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 and then quarterly for 2 1/2 years. Patients coming from a repeat dose study will be evaluated quarterly for 3 years. ]
    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


Other Outcome Measures:
  1. Change from Baseline in the Short Form (36) Health Survey (SF-36®) in adults [ Time Frame: Surveys are administered at screening, 6 months and then yearly 2.5 years ]

    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.


  2. Change from Baseline in the EQ-5D-5L™ in adults. [ Time Frame: Surveys are administered at screening, 6 months and then yearly 2.5 years ]

    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.


  3. Change from Baseline in the Pediatric Quality of Life Inventory (PedsQL™) in children [ Time Frame: Surveys are administered at screening, 6 months and then yearly 2.5 years ]

    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.


  4. 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. This endpoint will only be assessed in participants previously randomized to placebo in a multidose study of DCR-PHXC.

  5. To assess the long-term efficacy of DCR PHXC in reducing Uox burden in patients with PH [ Time Frame: Every 3 months (Month 6 through Month 36) ]
    Based on percent change from Baseline, at 3 month intervals throughout the study. This endpoint will only be assessed only after month 6 in participants previously randomized to placebo in a multidose study of DCR-PHXC as well as pediatric siblings of participants who successfully completed a Dicerna study of DCR-PHXC.

  6. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including minimum observed concentration (Cmin)

  7. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including time to maximum concentration (Tmax)

  8. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including terminal elimination half-life (t1/2)

  9. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including clearance (CL)

  10. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including volume of distribution (V) estimates

  11. To characterize the PK of DCR PHXC in patients with PH by observing secondary parameters of the area under the curve. [ Time Frame: Participants rolling from a single dose study will be analyzed at Day 1, Day 2, Day 30, Day 31, Day 150 and if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including secondary parameters of area under the curve (AUC)

  12. 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 if the participant stops early. ]
    Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including maximum observed concentration (Cmax)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

•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 (Levey & Stevens, 2010), or the multivariate equation by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012). In Japan, the formula by Uemura et al. will be used for participants aged 6 to 17 years, and the equation by Matsuo et al. will be used in participants aged ≥ 18 years (Uemura et al., 2014; Matsuo et al., 2009).

Key Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04042402


Locations
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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
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
Nagoya, Japan, 467-8601
Clinical Trial Site
Tokyo, Japan, 183-8561
Lebanon
Clinical Trial Site
Beirut, Lebanon
Netherlands
Clinical Trial Site
Amsterdam, Netherlands, 1105AZ
Spain
Clinical Research Site
Barcelona, Spain, 08035
Clinical Trial Site
Barcelona, Spain, 08035
United Kingdom
Clinical Trial Site
Hampstead, London, United Kingdom
Clinical Trial Site
Birmingham, United Kingdom
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04042402    
Other Study ID Numbers: DCR-PHXC-301
First Posted: August 2, 2019    Key Record Dates
Last Update Posted: July 16, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.:
Primary Hyperoxaluria
PH1
PH2
RNAi
GalNAc
LDHA
LDH
siRNA
Additional relevant MeSH terms:
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Kidney Diseases
Hyperoxaluria, Primary
Urologic Diseases
Genetic Diseases, Inborn
Hyperoxaluria
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases