A Phase 3 study of an Investigational Drug, Lumasiran (ALN-GO1) in patients with advanced primary hyperoxaluria Type 1

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

20 Jan 2020 → 24 Jun 2025

Decision date (initial)

2023-07-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alnylam Pharmaceuticals, Inc., United States

External identifiers

EU CT number

2023-503382-29-00

EudraCT number

2019-001346-17

ClinicalTrials.gov

NCT04152200

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Pharmacokinetic, Efficacy

Cohort A
• Evaluate the effect of lumasiran on plasma oxalate in patients who are not on dialysis therapy
Cohort B
• Evaluate the effect of lumasiran on plasma oxalate levels in patients who are on dialysis therapy

Secondary objectives 10

1. Evaluate the effect of lumasiran on change in plasma oxalate area under the curve (AUC) between dialysis sessions
2. Evaluate the long-term effects of lumasiran on change in plasma oxalate
3. Evaluate the effect of lumasiran on change in urinary oxalate excretion
4. Evaluate quality of life in patients with PH1
5. Characterize the PK of lumasiran
6. Evaluate the effect of lumasiran on nephrocalcinosis
7. Evaluate the effect of lumasiran on dialysis requirements
8. Evaluate the effect of lumasiran on the occurrence of renal stones
9. Evaluate the effect of lumasiran on renal function
10. Evaluate the effect of lumasiran on change in measures of systemic oxalosis

Conditions and MedDRA coding

Primary Hyperoxaluria Type 1 (PH1)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002079-PIP01-16

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Cohort A and B: Have reached at least 37 weeks estimated gestational age (full-term infant) at consent (or assent)
2. Documentation or confirmation of PH1 as determined by genetic analysis prior to initial dosing.
3. Patients with eGFR ≤45 mL/min/1.73 m2 as calculated by the MDRD formula if ≥18 years or Schwartz Bedside Formula if ≥12 months to <18 years, or patients <12 months of age with serum creatinine that is considered elevated for age at consent.
4. The mean of the three most recent screening plasma oxalate samples collected prior to Day 1 is ≥20 μmol/L. In Cohort B, these 3 collections may include the first pre-dialysis sample from each plasma oxalate profile.
5. If taking therapeutic vitamin B6 (pyridoxine), must have been on stable regimen for at least 90 days before consent, and is able and willing to remain on this stable regimen until at least the Month 6 visit. Dose adjustments for interval weight gain are acceptable.
6. Patient is willing and able to comply with the study requirements and to provide written informed consent. In the case of patients under the age of legal consent, the legal guardian(s) must provide informed consent and the patient should provide assent per local and national requirements.
7. Cohort B Only 1: On a stable hemodialysis regimen for at least 4 weeks prior to Screening plasma oxalate assessment; able and willing to maintain this regimen through Month 6 visit, with changes to dialysis regimen permitted only when medically indicated.

Exclusion criteria 15

1. Has any of the following laboratory parameter assessments at Screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× ULN for age b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert's syndrome are eligible if the total bilirubin is <2× ULN c. International normalized ratio (INR) >1.5 for patients not on anticoagulants. Patients on oral anticoagulants (eg, warfarin) with an INR <3.5 will be allowed. d. Hemoglobin <8.0 mg/dL
2. Has known active human immunodeficiency virus (HIV) infection; or evidence of current or chronic hepatitis C virus (HCV) or hepatitis B (HBV) infection.
3. Received an investigational agent within the last 30 days or 5 halflives, whichever is longer, prior to the first dose of study drug, or are in follow-up of another clinical study during Screening. Consultation with the Medical Monitor is required if treated with unapproved products prior to consent regardless of the time interval prior to the first dose of study drug.
4. Known history of allergic reaction to an oligonucleotide or GalNAc.
5. Diagnosis of conditions other than PH1 contributing to renal insufficiency such as glomerulonephritis, nephrotic syndrome, or lupus nephritis.
6. Any condition or comorbidity, which in the opinion of the Investigator, would make the patient unsuitable for dosing or would interfere with study compliance, data interpretation, patient safety, and/or patient participation in the study. This includes significant active and poorly controlled (unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders unrelated to PH1 identified by key laboratory abnormalities or medical history.
7. Unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL].
8. History of alcohol abuse, within the last 12 months before screening, in the opinion of the investigator.
9. Patients with a previous liver transplant or for whom a liver transplant is anticipated in the next 6 months.
10. Patients with a previous kidney transplant who are currently receiving immunosuppression to prevent transplant rejection.
11. Patients maintained on a peritoneal dialysis regimen.
12. Patients who in the opinion of the Investigator plan to start dialysis replacement therapy in the next 6 months.
13. Any comorbidity or condition that, in the opinion of the Investigator, is anticipated to prevent participation in at least 12 months of the study
14. Is not willing to comply with the contraceptive requirements during the study period, as described in study protocol.
15. Female patient is pregnant, planning a pregnancy, or breast feeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Cohort A: Percent change in plasma oxalate from Baseline to Month 6
2. Cohort B: Percent change in plasma oxalate from Baseline to Month 6

Secondary endpoints 7

1. Primary Analysis Period (Baseline to 6 months): Percent change in plasma oxalate AUC between dialysis sessions (Cohort B)
2. Absolute change in plasma oxalate
3. Change in the following parameters: *Urinary oxalate measured by percent and absolute change in 24-hour urinary oxalate excretion corrected for body surface area (BSA) and spot urinary oxalate:creatinine ratio, when available *QoL assessed by the PedsQL Total Score for patients ≥2 to <18 years of age at consent, and as assessed by KDQOL Burden of Kidney Disease and Effect of Kidney Disease on Daily Life subscales, and SF-12 Physical Component Summary and Mental Component Summary, in patients ≥18
4. Plasma PK parameters of lumasiran
5. Percent change in plasma oxalate AUC between dialysis sessions (Cohort B)
6. Percent and absolute change in plasma oxalate
7. Change in the following parameters: *Nephrocalcinosis as assessed by renal ultrasound; *Frequency and mode of dialysis (Cohort B); *Frequency of renal stone events; *Urinary oxalate measured by 24-hour urinary oxalate excretion corrected for BSA, and spot urinary oxalate:creatinine ratio; *Renal function as assessed by estimated glomerular filtration rate (eGFR) (Cohort A); *Measures of systemic oxalosis in the following systems: -Cardiac -Skeletal -Ocular; *QoL(Quality of life) assessed

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trial Information Line

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trial Information Line

Third parties 6

Locations

4 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications