AVALOTCAGENE ONTAPARVOVEC for Ornithine transcarbamylase deficiency | Late-onset ornithine transcarbamylase deficiency

Inclusion criteria

• {"criterion_text":"- 1. Male or female patient 12 years of age or older at the time of signed informed consent.\n- 10. From the time written informed consent is provided through Week 28, females of childbearing potential and fertile males must consent to use highly effective contraception as defined by the United States Food and Drug Administration (FDA) and Clinical Trial Facilitation Coordination Group (CTFG) Recommendations Related to Contraception and Pregnancy in Clinical Trials. If female, agree not to become pregnant. If male, agree to not father a child or donate sperm.\n- 2. Provide informed consent after the nature of the study has been explained, and prior to any research-related procedures. If a minor, be willing and able (if possible) to provide assent and have a legally authorized representative provide informed consent after the nature of the study has been explained and prior to any research-related procedures.\n- 3. Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation by enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis).\n- 4. Documented history of ≥ 1 symptomatic hyperammonemia episode with ammonia level ≥ 100 μmol/L for confirmation of clinical disease.\n- 5. Patient is currently receiving ammonia scavenger therapy and/or protein-restricted diet, is free from symptomatic hyperammonemia, and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline.\n- 6. Plasma 24-hour ammonia (AUC0-24) is ≤ 4800 μmol*h/L at screening. If the ammonia AUC0-24 is inconsistent with the patient’s clinical status, the assessment may be repeated to ensure accurate results.\n- 7. If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening\n- 8. If on a protein-restricted diet, must be on a stable protein-restricted diet as evidenced by a stable amount of total protein intake (ie, daily protein intake in grams per day does not vary more than 20%) for ≥ 4 weeks prior to screening.\n- 9. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood and urine collections, blood collections over a 24-hour period, questionnaires, cognitive assessments, and patient/caregiver reported outcome assessments. If a minor, must have a caregiver(s) willing and able to assist in all applicable study requirements."}

Exclusion criteria

• {"criterion_text":"- 1. Liver transplant, including hepatocyte cell therapy/transplant.\n- 10. Any of the following that, in the judgment of the Investigator, places the patient at increased risk for adverse effects: - Known hypersensitivity to DTX301, its excipients, or its placebo - Known hypersensitivity to prednisolone, its excipients, or its placebo\n- 11. Chronic use of inhibitors of urea synthesis (eg, valproic acid) or drugs that significantly affect renal clearance (eg, probenecid).\n- 12. Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or confound interpretation of results, including but not limited to: - Underlying conditions that may require systemic corticosteroids if the condition worsens (eg, autoimmune disorders) - Patients in a catabolic state (eg, due to current infection), or in whom a catabolic state may be reasonably foreseeable (eg, due to planned procedures) - Patient is considered vulnerable by local regulations (eg, imprisoned or institutionalized)\n- 13. Marked neurological deficit or compromise that, in the Investigator’s opinion, would interfere with the patient’s safety or ability to participate in the study.\n- 14. Pregnant or breastfeeding or planning to become pregnant within 64 weeks after receiving DTX301 (ie, through Visit 28 of this study).\n- 15. Participation (current or previous) in another gene transfer study.\n- 16. Use of any investigational product within 3 months prior to screening, or during the study.\n- 17. Patients who meet any of the following criteria are not eligible to undergo the URT: - Unable to fast safely for 12 hours - History of HAC triggered by minimal vomiting - Age < 18 years at screening Note: Any patient < 18 years of age at screening will not undergo ureagenesis rate testing for the duration of study.\n- 2. History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.\n- 3. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × ULN, total bilirubin > 1.5 × ULN (except if patient has a diagnosis of Gilbert’s syndrome), alkaline phosphatase > 2.5 × ULN. Note: Any of the LFTs may be retested.\n- 4. Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the CKD-EPI 2021 creatinine-based formula (Inker et al., 2021) for patients ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients < 18 years of age.\n- 5. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity. Note: Patients with a history of HCV infection must have documentation of 2 negative viral assays by PCR collected at least 6 months apart to be considered negative for HCV. Patients with a history of HCV infection who test positive for HCV RNA at screening can be rescreened once after they have been treated and have documentation of at least 2 negative samples collected at least 6 months apart.\n- 6. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Baseline (Day 0), or plasma viral load > 200 copies/mL, documented on 2 separate occasions, as measured by PCR.\n- 7. Active infection (viral or bacterial).\n- 8. Detectable pre-existing antibodies to the AAV8 capsid.\n- 9. History of a malignancy for which the patient has received treatment in the past 2 years, except for prostate cancer treated with watchful waiting or surgically removed nonmelanoma skin cancer."}

Primary endpoints

• {"endpoint_text":"- Plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 36","definition_or_measurement_approach":"Plasma ammonia measured by 24-hour ammonia AUC0-24 at Week 36 (24-hour ammonia sampling and AUC0-24 calculation)."}
• {"endpoint_text":"- Complete Responder rate at the final study visit after DTX301 exposure","definition_or_measurement_approach":"Proportion (rate) of subjects meeting criteria for Complete Responder at the final study visit following exposure to DTX301 (as defined in study SAP/protocol)."}

Secondary endpoints

• {"endpoint_text":"- Percentage of Complete Responders or Responders after DTX301 exposure","definition_or_measurement_approach":"Percent of subjects classified as Complete Responders or Responders after DTX301 exposure (as per responder definitions in protocol)."}
• {"endpoint_text":"- Annualized event rate of HACs pre-DTX301 exposure vs post-DTX301 exposure","definition_or_measurement_approach":"Comparison of annualized rates of hyperammonemic crises (HACs) before versus after DTX301 exposure."}
• {"endpoint_text":"- Annualized event Rate of ICEs pre-DTX301 exposure vs post-DTX301 exposure","definition_or_measurement_approach":"Comparison of annualized rates of intercurrent clinical events (ICEs) before versus after DTX301 exposure."}
• {"endpoint_text":"- Change from baseline to Week 36 in plasma ammonia (AUC0-24)","definition_or_measurement_approach":"Change in 24-hour plasma ammonia AUC0-24 from baseline to Week 36."}
• {"endpoint_text":"- Change in plasma ammonia (AUC0-24) after DTX301 exposure","definition_or_measurement_approach":"Assessment of change in 24-hour plasma ammonia AUC0-24 following DTX301 exposure (post-treatment comparisons)."}
• {"endpoint_text":"- Percentage of patients who have achieved complete management response (CMR) or management response (MR) after DTX301 exposure","definition_or_measurement_approach":"Percent of patients achieving CMR or MR after exposure to DTX301 based on predefined management response criteria."}
• {"endpoint_text":"- Change in baseline disease management (dietary protein and total scavenger medication use) with plasma ammonia (AUC0-24) (comparison between those with a reduction of elevated plasma ammonia [AUC0-24] at baseline vs those without)","definition_or_measurement_approach":"Change in disease management measures (dietary protein and total scavenger medication) correlated with plasma ammonia AUC0-24; comparison between subjects with baseline elevated ammonia reduction vs without."}
• {"endpoint_text":"- Incidence of TEAEs, TESAEs, treatment-related TEAEs, treatment-related TESAEs, and AESIs","definition_or_measurement_approach":"Safety endpoints: incidence and classification of treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), treatment-related events, and adverse events of special interest (AESIs)."}
• {"endpoint_text":"- Incidence of anti-OTC antibodies","definition_or_measurement_approach":"Incidence and titers of anti-OTC antibodies measured by validated immunoassays."}
• {"endpoint_text":"- Long-term durability of response based upon number of Complete Responders or Responders that have ≥ 2 consecutive visits as a Complete Responder or Responder and do not return to a lower Responder status for > 1 consecutive visit","definition_or_measurement_approach":"Durability measured as number of subjects with ≥2 consecutive visits meeting Complete Responder or Responder criteria without reversion for >1 consecutive visit."}
• {"endpoint_text":"- Change in plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 64 PEA-2 for patients who have an elevated ammonia AUC0-24 at baseline","definition_or_measurement_approach":"Change in 24-hour plasma ammonia AUC0-24 at Week 64 (PEA-2) among patients with elevated baseline AUC0-24."}

Methods

• Site-based recruitment through participating hospitals and clinics listed in each Member State (hospital/clinic investigators).
• Sponsor-contracted patient recruitment services: Pharmaceutical Product Development (PPD) listed with responsibility for Patient Recruitment.
• Country-specific recruitment arrangements documented (K1 recruitment arrangements documents per country).
• Use of remote patient support/consent platforms and e-tools (Clincierge documentation and vendor e-Diary system) and home health nurse services for decentralized visits (documented vendor services).

Italy

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

14-10-2024

Processing Time Days

21

Number Of Sites

3

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

7

Number Of Sites

2

Number Of Participants

3

Netherlands

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

01-10-2024

Processing Time Days

8

Number Of Sites

1

Number Of Participants

7

France

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

04-10-2024

Processing Time Days

11

Number Of Sites

2

Number Of Participants

4

Germany

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

07-10-2024

Processing Time Days

14

Number Of Sites

1

Number Of Participants

8

Portugal

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

03-10-2024

Processing Time Days

10

Number Of Sites

1

Number Of Participants

4

Primary sponsor

Full Name

Ultragenyx Pharmaceutical Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Pharmaceutical Product Development LLC (PPD Development LP)

Responsibilities

Patient Recruitment, laboratory and clinical trial support services (clinical chemistry/haematology, central lab services, site services).

Name

Almac Clinical Services LLC

Responsibilities

Clinical services support (logistics/operational support).

Third parties

• {"country":"United States","full_name":"Lumanity Patient Centered Outcomes LLC","duties_or_roles":"Patient Interview & Cognitive Debrief","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Clinical chemistry/haematology, Urinalysis, Coagulation panel, HBV, HIV, HCV, Amino Acid panel, Chemistry; Patient Recruitment and multiple clinical trial support functions","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Anti-OTC testing (anti-OTC antibody assays)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Cogstate Inc.","duties_or_roles":"Patient Assessment Self-Report (cognitive assessments)","organisation_type":"Pharmaceutical company"}
• {"country":"Croatia","full_name":"Primevigilance Zagreb d.o.o.","duties_or_roles":"Pharmacovigilance (safety monitoring)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Oracle America Inc.","duties_or_roles":"Electronic Data Capture (EDC)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Aparito Limited","duties_or_roles":"e-Diary (patient-reported data collection)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Metabolic Solutions Inc.","duties_or_roles":"Ureagenesis testing","organisation_type":"Health care"}
• {"country":"United States","full_name":"EPL Pathology Archives LLC","duties_or_roles":"Long term sample storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Professional Case Management Clinical Trials LLC","duties_or_roles":"Home Health Nurse services","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Netherlands","full_name":"Stichting EuroQol Research Foundation","duties_or_roles":"License holder for the EQ-5D-5L instruments (QoL)","organisation_type":"Patient organisation/association"}
• {"country":"United States","full_name":"Perkinelmer Genetics Inc.","duties_or_roles":"Genotyping","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Almac Clinical Services LLC","duties_or_roles":"Clinical services (unspecified role code 3)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Multiple sponsor duties including laboratory services, site services and Patient Recruitment","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Baylor Miraca Genetics Laboratories LLC","duties_or_roles":"PAGN in Urine testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"Amino acid, orotic acid and AAV8 Tab assay","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Switzerland","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"Manufacturing, storage, distribution","organisation_type":"Pharmaceutical company"}
• {"country":"Czechia","full_name":"Vseobecna Fakultni Nemocnice V Praze","duties_or_roles":"OTC Enyzme Activity","organisation_type":"Hospital/Clinic/Other health care facility"}