Safety & Efficacy of DCR-PHXC in Patients With PH1/2 and ESRD

End Stage Renal Disease Clinical Trial

— PHYOX7  

Official title:

A Phase 2 Open-Label Study to Evaluate the Safety and Efficacy of DCR-PHXC in Patients With Primary Hyperoxaluria Type 1 or 2 and Severe Renal Impairment, With or Without Dialysis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04580420
• Other study ID #: DCR-PHXC-204
• Status: Recruiting
• Phase: Phase 2
• Start date: April 15, 2021
• Est. completion date: May 2025

Study information

• Verified date: August 2023
• Source: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Contact: Medical Information
• Phone: 617-621-8097
• Email: medicalinfo[@]dicerna.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this study is to evaluate DCR-PHXC in participants with PH1 or PH2 and severe renal impairment, with or without dialysis.

Description:

This is an open-label, repeat-dose, Phase 2 study of DCR-PHXC in participants with PH1 or PH2 and severe renal impairment, with or without dialysis.

Following the up-to-35- day screening period, participants will return to the clinic for monthly dosing visits through Day 180. Participants successfully completing the Day 180 visit will continue on to an extended follow-up period and receive open-label DCR-PHXC for an additional 3 years, or until DCR-PHXC is commercially available, whichever comes first. As participants in this extended treatment period will return to the clinic only every 3 months, participants and/or their caregivers may be trained in the at-home administration of DCR-PHXC or home health nurses may assist with administration of DCR -PHXC.

The total duration of the study is approximately 2 years from first participant, first visit, to last participant, last Day 180 visit, with up to an additional 3 years of extended follow-up.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 17
• Est. completion date: May 2025
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. Four age groups of participants will be enrolled, in sequence:

1. adults and adolescents (aged = 12 years)

2. children 6 to 11 years of age

3. children 2 to 5 years of age

4. infants and newborns from birth to < 2 years of age

2. . Documented diagnosis of PH1 or PH2, confirmed by genotyping

3. Estimated GFR at Screening <30mL/min normalized to 1.73m^2 BSA

4. Mean of 2 Plasma Oxalate >20µmol/L during screening

5. For participants receiving hemodialysis or peritoneal dialysis total duration of hemodialysis or peritoneal dialysis must be less than 18 months and hemodialysis or peritoneal dialysis regimen must have been stable for at least 2 weeks prior to Screening.

6. Body weight of:

1. adults and adolescents aged = 12 years: = 31.0 kg

2. children 6 to 11 years of age: = 12 kg

3. children 2 to 5 years of age: to be determined

4. infants and newborns from birth to < 2 years of age: to be determined

7. Male or Female

1. Male participants:

• A male participant with a female partner of childbearing potential must agree to use contraception during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period.

2. Female participants:

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP).

• OR

• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 12 weeks after the last dose of study intervention and agrees to refrain from harvesting/freezing eggs during this period.

3. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

8. Participant (and/or participant's parent or legal guardian if participant is a minor [defined as patient <18 years of age, or younger than the age of majority according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirement and restrictions listed in the informed consent form (ICF) and in the protocol.

1. Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority according to local regulations) must be able to provide written assent for participation.

2. For children younger than 12 years of age, assent will be based on local regulations

9. Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations)

Exclusion Criteria:

1. Prior hepatic transplantation; or scheduled transplantation within 6 months of Day 1. Prior renal transplantation is allowed.

2. Documented evidence of clinical manifestations of severe systemic oxalosis (including preexisting retinal, heart, or skin calcifications, or history of severe bone pain, pathological fractures, or bone deformations)

3. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to:

1. Severe intercurrent illness

2. Known causes of active liver disease/injury (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis)

3. Non-PH related conditions contributing to renal insufficiency

4. Physician concerns about intake of drugs of abuse or excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as = 21 units of alcohol per week in men and = 14 units of alcohol per week in women; where a "unit" of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1ounce shot of hard liquor)

4. Use of an RNAi drug, other DCR-PHXC, within the last 6 months

5. History of one or more of the following reactions to an oligonucleotide-based therapy:

1. Severe thrombocytopenia (platelet count = 100,000/µL)

2. Hepatotoxicity, defined as alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the upper limit of normal (ULN) and total bilirubin > 2 × ULN or international normalized ratio (INR) >1.5

3. Severe flu-like symptoms leading to discontinuation of therapy

4. Localized skin reaction from the injection (graded severe) leading to discontinuation of therapy

5. Coagulopathy/clinically significant prolongation of clotting time

6. Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months before Screening.

7. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender

8. Positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody test at Screening

9. Known hypersensitivity to DCR-PHXC or any of its ingredients

10. Inability or unwillingness to comply with the specified study procedures, including the lifestyle considerations

Related Conditions & MeSH terms

• End Stage Renal Disease
• Hyperoxaluria, Primary
• Kidney Failure, Chronic
• Primary Hyperoxaluria Type 1
• Primary Hyperoxaluria Type 2

Intervention

Drug:
• DCR-PHXC
Monthly dosing throughout study period

Locations

Country	Name	City	State
France	Clinical Trial Site	Bron
France	Clinical Trial Site	Paris
Germany	Clinical Trial Site	Bonn
Germany	Clinical Trial Site	Heidelberg
Italy	Clinical Trial Site	Roma
Lebanon	Clinical Trial Site	Beirut
Morocco	Clinical Trial Site	Casablanca
Romania	Clinical Trial Site	Oradea
Romania	Clinical Trial Site	Oradea
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Santa Cruz De Tenerife
United Arab Emirates	Clinical Trial Site	Dubai
United Kingdom	Clinical Trial Site	London
United Kingdom	Clinical Trial Site	London
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	New York	New York
United States	Clinical Trial Site	Rochester	Minnesota
United States	Clinical Trial Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Lebanon,  Morocco,  Romania,  Spain,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from Baseline in the Short Form (36) Health Survey (SF-36®) in adults	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	180 days
Other	Change from Baseline in the EQ-5D-5L™ in adults	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.	180 days
Other	Change from Baseline in the Pediatric Quality of Life Inventory (PedsQL™) in children	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.	180 days
Other	Changes from Baseline number of kidney stones	Evaluate the effect of DCR-PHXC on stone burden in participants with PH1 or PH2 and severe renal impairment through Kidney Ultrasound	180 days
Other	Changes from Baseline size of kidney stones	Evaluate the effect of DCR-PHXC on stone burden in participants with PH1 or PH2 and severe renal impairment through Kidney Ultrasound	180 days
Primary	Safety: Incidence of Events	To assess the efficacy of DCR-PHXC in lowering Pox in participants with PH1 or PH2 and severe renal impairment, with or without hemodialysis or peritoneal dialysis.	180 days
Primary	Safety: Incidence of Events	Characterize the safety of DCR-PHXC in participants with PH1 or PH2 and severe renal impairment, with or without dialysis.	180 days
Secondary	Change from Baseline in Plasma Oxalate Concentration	To evaluate the effect of DCR-PHXC on Plasma Oxalate concentration from Baseline to day 180	180 Days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing secondary parameters of the area under the curve.	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including secondary parameters of area under the curve (AUC)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing maximum observed concentration (Cmax).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including maximum observed concentration (Cmax)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing minimum concentration (Cmin).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including minimum observed concentration (Cmin)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing maximum concentration (Tmax).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including time to maximum concentration (Tmax)	180 days
Secondary	To characterize the PK of DCR PHXC in patients with PH by observing terminal elimination half-life (t1/2).	Population and individual pharmacokinetic (PK) parameters for DCR PHXC, including terminal elimination half-life (t1/2)	180 days
Secondary	Change in Frequency of Dialysis	Change from Baseline in the frequency of dialysis over 180 days	180 days
Secondary	Change in Duration of Dialysis	Change from Baseline in the duration of dialysis over 180 days	180 days