A Study to Evaluate Lumasiran in Children and Adults With Primary Hyperoxaluria Type 1 (ILLUMINATE-A)

ILLUMINATE-A: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study With an Extended Dosing Period to Evaluate the Efficacy and Safety of Lumasiran in Children and Adults With Primary Hyperoxaluria Type 1

The purpose of this study is to evaluate the efficacy and safety of lumasiran in children and adults with primary hyperoxaluria type 1 (PH1).

Study Overview

• Status: Completed
• Conditions: Primary Hyperoxaluria Type 1 (PH1)
• Intervention / Treatment: Drug: Placebo; Drug: Lumasiran

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Clinical Trial Site
  • Paris, France
    • Clinical Trial Site
• Germany
  • Bonn, Germany
    • Clinical Trial Site
• Israel
  • Haifa, Israel
    • Clinical Trial Site
  • Jerusalem, Israel
    • Clinical Trial Site
  • Nahariya, Israel
    • Clinical Trial Site
• Netherlands
  • Amsterdam, Netherlands
    • Clinical Trial Site
• Switzerland
  • Bern, Switzerland
    • Clinical Trial Site
• United Arab Emirates
  • Dubai, United Arab Emirates
    • Clinical Trial Site
• United Kingdom
  • Birmingham, United Kingdom
    • Clinical Trial Site
  • London, United Kingdom, NW3 2QG
    • Clinical Trial Site
  • London, United Kingdom, WC1N 3JH
    • Clinical Trial Site
• United States
  • California
    • San Diego, California, United States, 92120
      • Clinical Trial Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Clinical Trial Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Clinical Trial Site
  • New York
    • New York, New York, United States, 10029
      • Clinical Trial Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Willing to provide written informed consent or assent and to comply with study requirements
• Confirmation of PH1 disease
• Meet the 24 hour urine oxalate excretion requirements
• If taking Vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days

Exclusion Criteria:

• Clinically significant health concerns (with the exception of PH1) or clinical evidence of extrarenal systemic oxalosis
• Clinically significant abnormal laboratory results
• Known active or evidence of HIV or hepatitis B or C infection
• An estimated GFR of < 30 mL/min/1.73m^2 at screening
• Received an investigational agent within 30 days or 5 half-lives before the first dose of study drug or are in follow-up of another clinical study
• History of kidney or liver transplant
• Known history of multiple drug allergies or allergic reaction to an oligonucleotide or GalNAc
• History of intolerance to subcutaneous injection
• Women who are pregnant, planning a pregnancy, or breast-feeding or those of child bearing potential and not willing to use contraception
• History of alcohol abuse within the last 12 months, or unable or unwilling to limit alcohol consumption throughout the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo/Lumasiran; Lumasiran-matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC) at Day 1 and Months 1, 2 and 3 during the 6-Month Double-blind (DB) Period, followed by lumasiran SC, 3.0 mg/kg, at Months 6, 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month Open-label Extension (OLE) period.	Drug: Placebo; Placebo by SC injection; Drug: Lumasiran; Lumasiran by SC injection; Other Names: ALN-GO1
Experimental: Lumasiran/Lumasiran; Lumasiran was administered SC, 3.0 mg/kg, at Day 1 and Months 1, 2 and 3 during the 6-Month DB Period, followed by lumasiran SC, 3.0 mg/kg at Month 6, and lumasiran-matching placebo SC at Months 7 and 8 during the 3-Month Blinded Treatment Extension Period, followed by lumasiran SC, 3.0 mg/kg, at Month 9 and then every three months during the 51-Month OLE period.	Drug: Placebo; Placebo by SC injection; Drug: Lumasiran; Lumasiran by SC injection; Other Names: ALN-GO1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in 24-hour Urinary Oxalate Excretion Corrected for Body Surface Area (BSA) From Baseline to Month 6	Percent change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average percent change from baseline across Months 3 through 6. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.	Baseline to Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in 24-hour Urinary Oxalate Corrected for BSA From Baseline to Month 6	Absolute change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average absolute change from baseline across Months 3 through 6. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.	Baseline to Month 6
Percent Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline to Month 6	Percent change in 24-hour urinary oxalate:creatine ratio was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.	Baseline to Month 6
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below 1.5 x ULN at Month 6	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m^2 for 24-hour urinary oxalate excretion corrected for BSA.	Month 6
Percentage of Participants With 24-hour Urinary Oxalate Level Corrected for BSA at or Below ULN at Month 6	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m^2 for 24-hour urinary oxalate excretion corrected for BSA.	Month 6
Percentage Change in Plasma Oxalate From Baseline to Month 6	Percent change in plasma oxalate (umol/L) was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.	Baseline to Month 6
Absolute Change in Plasma Oxalate From Baseline to Month 6	Absolute change in plasma oxalate (umol/L) was estimated by an average percent change from baseline across Months 3 through 6. A negative change from Baseline indicates a favorable outcome.	Baseline to Month 6
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Week 2 and Months 1, 2, 3, 4, 5 and 6	eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients >1 year to <18 years of age at screening. Change from baseline to Month 6 is reported.	Baseline, Week 2, Months 1, 2, 3, 4, 5 and 6
Absolute Change in 24-hour Urinary Oxalate Excretion Corrected for BSA From Baseline in the Extension Period	Absolute change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average absolute change from baseline in the extension periods. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.	From Baseline to Month 54 and Month 60
Percentage Change in 24-hour Urinary Oxalate Excretion Corrected by BSA From Baseline in the Extension Period	Percent change in 24-hour urinary oxalate excretion corrected for BSA was estimated by an average percent change from baseline in the extension periods. Only valid urine samples without any non-protocol-related issues were included in the analysis. A negative change from Baseline indicates a favorable outcome.	From Baseline to Month 54 and Month 60
Percentage of Time That 24-hour Urinary Oxalate is at or Below 1.5 × ULN During Lumasiran Treatment	The upper limit of normal (ULN) = 0.514 mmol/24hr/1.73m^2 for 24-hour urinary oxalate excretion corrected for BSA.	Up to Month 60
Absolute Change in 24-hour Urinary Oxalate:Creatinine Ratio From Baseline in the Extension Period	Absolute change in 24-hour urinary oxalate:creatinine ratio was estimated by an average absolute change from baseline to the end of the OLE period at Month 54 and Month 60. A negative change from Baseline indicates a favorable outcome.	From Baseline to Month 54 and Month 60
Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline in the Extension Period	eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients ≥18 years of age and the Schwartz Bedside Formula for patients >1 year to <18 years of age at screening.	From Baseline to Month 54 and Month 60
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a clinical investigational participant administered a medicinal product & which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization/prolongation of existing hospitalization, results in persistent/significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event that may not be immediately life-threatening/result in death/hospitalization but may jeopardize the participant & may require intervention to prevent one of the other outcomes listed above. All Lumasiran Treated Set: All participants who received any amount of lumasiran including participants who took lumasiran during 6-month double-blinded period & participants who initially took placebo during the 6-month double-blinded period and then switched to lumasiran during the extension period.	DB Period (Placebo): From first dose of study drug (Day 1) up to Month 6; Placebo/Lumasiran: From first dose of lumasiran (Month 6) up to end of study (Month 60); Lumasiran/Lumasiran: From first dose of lumasiran (Day 1) up to end of study (Month 60).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Renal Stone Events	A renal stone event is defined as a patient-reported event that includes ≥1 of the following: visit to healthcare provider because of a renal stone; medication for renal colic; stone passage; macroscopic hematuria due to a renal stone. Lower rates indicate a favorable outcome.	12-Month Period prior to Informed Consent, 6-Month DB Period
Change From Baseline in Nephrocalcinosis as Assessed by Renal Ultrasound	Renal ultrasound data were used to grade medullary nephrocalcinosis findings (range: 0 to 3), where a higher grade indicates greater severity. Improving=if both sides improve, or one side improves and the other side has no change; No change=if both sides have no change; Worsening=if both sides worsen, or one side worsens and the other side has no change; Indeterminate=if one side improves and the other side worsens.	Baseline, Month 6

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, Deschenes G, Shasha-Lavsky H, Saland JM, Van't Hoff WG, Fuster DG, Magen D, Moochhala SH, Schalk G, Simkova E, Groothoff JW, Sas DJ, Meliambro KA, Lu J, Sweetser MT, Garg PP, Vaishnaw AK, Gansner JM, McGregor TL, Lieske JC; ILLUMINATE-A Collaborators. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021 Apr 1;384(13):1216-1226. doi: 10.1056/NEJMoa2021712.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2018
• Primary Completion (Actual): November 5, 2019
• Study Completion (Actual): January 12, 2024

Study Registration Dates

• First Submitted: September 19, 2018
• First Submitted That Met QC Criteria: September 19, 2018
• First Posted (Actual): September 21, 2018

Study Record Updates

• Last Update Posted (Actual): August 12, 2024
• Last Update Submitted That Met QC Criteria: August 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: RNAi therapeutic; siRNA; PH1; Oxalate; AGT; Primary hyperoxaluria
• Additional Relevant MeSH Terms: Metabolic Diseases; Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Hyperoxaluria; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hyperoxaluria, Primary; Renal Agents; Lumasiran
• Other Study ID Numbers: ALN-GO1-003; 2018-001981-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No