Clinical trial NCT04764448: A Study of Belcesiran in Patients With AATLD
Official title: A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alpha 1-Antitrypsin Deficiency
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2021-02-21
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ AATD-associated liver disease (AATLD).

The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.

Detailed description: AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.

Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.

Eligibility criteria: Inclusion Criteria:

* 18 to 75 years, inclusive, at the time of consent.
* Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
* AATD-associated liver disease documented by liver biopsy at Screening.
* Consent to undergo paired liver biopsies.
* Lung, renal and liver function within acceptable limits
* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

* History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
* Child-Pugh Score B or C.
* History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
* History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
* Use of an RNAi drug at any time.

Primary outcomes:
measure: Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 2.6 years
measure: Number of Participants With TEAEs and SAEs
timeFrame: Up to 2.6 years
measure: Change From Baseline in Pulmonary Function Tests (PFTs): Forced Vital Capacity (FVC)
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in PFT: Forced Expiratory Volume in One Second (FEV1)
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in PFT: FEV1/FVC Ratio
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in PFT: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in 12 -Lead Electrochardiograms (ECGs): Mean Heart Rate
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in 12 -Lead ECGs: Mean Ventricular Rate
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in 12 -Lead ECGs: PR Interval, QRS Interval, QT Interval, QTcF Interval and RR Interval
timeFrame: Baseline (Day 1), week 96
measure: Number of Participants With Physical Examination Findings
timeFrame: At week 96
measure: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Vital Signs: Heart Rate
timeFrame: Baseline (Day 1), week 96
measure: Vital Signs: Height at Baseline
timeFrame: Baseline (Day 1)
measure: Change From Baseline in Vital Signs: Respiratory Rate
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Vital Signs: Temperature
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Vital Signs: Weight
timeFrame: Baseline (Day 1), week 96
measure: Change in Clinical Laboratory Tests: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Creatine Kinase, Glutamate Dehydrogenase, Lactate Dehydrogenase, Biomarker Creatine Kinase (M30) and Biomarker Creatine Kinase (M65)
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Albumin, Apolipoprotein A1, Protein, Biomarker Haptoglobin
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Bilirubin, Creatinine and Direct Bilirubin
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglycerides and Urea Nitrogen
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Gamma Glutamyl Transferase
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Basophils/Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Eosinophils/Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Haematocrit
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Lymphocytes/Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Monocytes/Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Neutrophils/Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Reticulocytes/Erythrocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin Concentration and Haemoglobin
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Volume
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Erythrocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Specific Gravity
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Urine Erythrocytes and Urine Leucocytes
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Activated Partial Thromboplastin Time and Prothrombin Time
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Prothrombin International Normalized Ratio
timeFrame: Baseline (Day 1), week 96
measure: Change in Clinical Laboratory Tests: Alpha Fetoprotein, Biomarker Hyaluronic Acid, Biomarker Matrix Metalloproteinase 9, Biomarker Procollagen 3 N-Terminal Propeptide, Biomarker Tissue Inhibitor of Metalloproteinase 1, Complement C3a and Complement C5a
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: C-Reactive Protein
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Complement Bb
timeFrame: Baseline (Day 1), week 96
measure: Change From Baseline in Clinical Laboratory Tests: Complement Total (CH50)
timeFrame: Baseline (Day 1), week 96
measure: Cohort 1: Change From Baseline in Serum Alpha-1 Antitrypsin (AAT) Protein Concentrations
timeFrame: Baseline (Day 1), week 24
measure: Cohort 2: Change From Baseline in Serum AAT Protein Concentrations
timeFrame: Baseline (Day 1), week 48
Secondary outcomes:
measure: Change From Baseline in Liver Fibrosis Ishak Score
timeFrame: Baseline (Day 1), week 48
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California - San Diego
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
city: Innsbruck
country: Austria
facility: Medizinische Universitaet Innsbruck
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal (CHUM)
state: Quebec
city: Pessac
country: France
facility: CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie
city: Aachen
country: Germany
facility: Universitaetsklinikum Aachen, AoeR
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein Campus Kiel
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies
state: Auckland
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Creixomil
country: Portugal
facility: Hospital da Senhora da Oliveira - Guimaraes
city: Porto
country: Portugal
facility: Centro Hospitalar Universitario de Sao Joao
city: Vila Real
country: Portugal
facility: Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla Santander
state: Cantabria
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Uppsala
country: Sweden
facility: CTC Clinical Trial Consultants AB Uppsala
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital, Cambridge University
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust, Royal Free Hospital
Study officials:
affiliation: Dicerna Pharmaceuticals / Novo Nordisk
name: Thomas Bowman, MD
role: STUDY_DIRECTOR
References: