A Study of Belcesiran in Patients With AATLD

NCT04764448 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: DCR-A1AT-201
• Study Type: interventional
• Target: 16
• Locations: 13 countries
• Sites: 22

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.

Conditions

Alpha 1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (44)

• Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  Number of TEAEs and SAEs is presented. An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.

  Up to 2.6 years

• Number of Participants With TEAEs and SAEs

  Number of participants with TEAEs and SAEs is presented. An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.

  Up to 2.6 years

• Change From Baseline in Pulmonary Function Tests (PFTs): Forced Vital Capacity (FVC)

  Change in FVC from baseline (Day 1) to week 96 is presented. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.

  Baseline (Day 1), week 96

• Change From Baseline in PFT: Forced Expiratory Volume in One Second (FEV1)

  Change in FEV1 from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration.

  Baseline (Day 1), week 96

• Change From Baseline in PFT: FEV1/FVC Ratio

  Change in FEV1/FVC ratio from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.

  Baseline (Day 1), week 96

• Change From Baseline in PFT: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)

  Change in DLCO from baseline (Day 1) to week 96 is presented. DLCO is a measure of the quantity of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (specifically hemoglobin) in pulmonary capillaries. It is expressed as millimoles per minute per kilopascal (mmol/min/kPa).

  Baseline (Day 1), week 96

• Change From Baseline in 12 -Lead Electrochardiograms (ECGs): Mean Heart Rate

  Change from baseline (Day 1) to week 96 in mean heart rate is presented.

  Baseline (Day 1), week 96

• Change From Baseline in 12 -Lead ECGs: Mean Ventricular Rate

  Change from baseline (Day 1) to week 96 in mean ventricular rate is presented.

  Baseline (Day 1), week 96

• Change From Baseline in 12 -Lead ECGs: PR Interval, QRS Interval, QT Interval, QTcF Interval and RR Interval

  Change from baseline (Day 1) to week 96 in PR interval, QRS interval, QT interval, QTcF interval and RR interval is presented.

  Baseline (Day 1), week 96

• Number of Participants With Physical Examination Findings

  Number of participants with physical examination findings at week 96 is presented. The data is presented under categories:a) Normal, b) Abnormal, not clinically significant, c) Abnormal, clinically significant.

  At week 96

• Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure

  Change from baseline (Day 1) to week 96 in diastolic blood pressure and systolic blood pressure is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Vital Signs: Heart Rate

  Change from baseline (Day 1) to week 96 in heart rate is presented.

  Baseline (Day 1), week 96

• Vital Signs: Height at Baseline

  Height at baseline is presented.

  Baseline (Day 1)

• Change From Baseline in Vital Signs: Respiratory Rate

  Change from baseline (Day 1) to week 96 in respiratory rate is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Vital Signs: Temperature

  Change from baseline (Day 1) to week 96 in temperature is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Vital Signs: Weight

  Change from baseline (Day 1) to week 96 in weight is presented.

  Baseline (Day 1), week 96

• 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)

  Change from baseline (Day 1) to week 96 in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatine kinase, glutamate dehydrogenase, lactate dehydrogenase, biomarker creatine kinase (M30) and biomarker creatine kinase (M65) is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Albumin, Apolipoprotein A1, Protein, Biomarker Haptoglobin

  Change from baseline (Day 1) to week 96 in albumin, apolipoprotein A1, protein and biomarker haptoglobin is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Bilirubin, Creatinine and Direct Bilirubin

  Change from baseline (Day 1) to week 96 in bilirubin, creatinine and direct bilirubin is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglycerides and Urea Nitrogen

  Change from baseline (Day 1) to week 96 in chloride, cholesterol, glucose, potassium, sodium, triglycerides and urea nitrogen is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Gamma Glutamyl Transferase

  Change from baseline (Day 1) to week 96 in gamma glutamyl transferase is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets

  Change from baseline (Day 1) to week 96 in basophils, eosinophils, leucocytes, lymphocytes, monocytes, neutrophils and platelets is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Basophils/Leucocytes

  Change from baseline (Day 1) to week 96 in basophils/leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Eosinophils/Leucocytes

  Change from baseline (Day 1) to week 96 in eosinophils/leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Haematocrit

  Change from baseline (Day 1) to week 96 in haematocrit is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Lymphocytes/Leucocytes

  Change from baseline (Day 1) to week 96 in lymphocytes/leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Monocytes/Leucocytes

  Change from baseline (Day 1) to week 96 in monocytes/leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Neutrophils/Leucocytes

  Change from baseline (Day 1) to week 96 in neutrophils/leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Reticulocytes/Erythrocytes

  Change from baseline (Day 1) to week 96 in reticulocytes/erythrocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin Concentration and Haemoglobin

  Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin concentration and haemoglobin is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin

  Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Volume

  Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular volume is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Erythrocytes

  Change from baseline (Day 1) to week 96 in erythrocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Specific Gravity

  Change from baseline (Day 1) to week 96 in specific gravity is reported.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Urine Erythrocytes and Urine Leucocytes

  Change from baseline (Day 1) to week 96 in urine erythrocytes and urine leucocytes is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Potential of Hydrogen (pH)

  Change from baseline (Day 1) to week 96 in pH is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Activated Partial Thromboplastin Time and Prothrombin Time

  Change from baseline (Day 1) to week 96 in activated partial thromboplastin time and prothrombin time is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Prothrombin International Normalized Ratio

  Change from baseline (Day 1) to week 96 in prothrombin international normalized ratio is presented.

  Baseline (Day 1), week 96

• 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

  Change from baseline (Day 1) to week 96 in 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 is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: C-Reactive Protein

  Change from baseline (Day 1) to week 96 in C-reactive protein is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Complement Bb

  Change from baseline (Day 1) to week 96 in complement Bb is presented.

  Baseline (Day 1), week 96

• Change From Baseline in Clinical Laboratory Tests: Complement Total (CH50)

  Change from baseline (Day 1) to week 96 in CH50 is presented.

  Baseline (Day 1), week 96

• Cohort 1: Change From Baseline in Serum Alpha-1 Antitrypsin (AAT) Protein Concentrations

  Change from baseline (Day 1) to week 24 in serum AAT protein concentrations in Cohort 1 is presented.

  Baseline (Day 1), week 24

• Cohort 2: Change From Baseline in Serum AAT Protein Concentrations

  Change from baseline (Day 1) to week 48 in serum AAT protein concentrations in Cohort 2 is presented.

  Baseline (Day 1), week 48

Secondary Outcomes (1)

• Change From Baseline in Liver Fibrosis Ishak Score

  Baseline (Day 1), week 48

Study Arms (6)

Belcesiran Cohort 1

EXPERIMENTAL

Drug: Belcesiran

Placebo Cohort 1

PLACEBO COMPARATOR

Other: Placebo

Belcesiran Cohort 2

EXPERIMENTAL

Drug: Belcesiran

Placebo Cohort 2

PLACEBO COMPARATOR

Other: Placebo

Belcesiran Cohort 3

EXPERIMENTAL

Drug: Belcesiran

Placebo Cohort 3

PLACEBO COMPARATOR

Other: Placebo

Interventions

Belcesiran DRUG

Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.

Belcesiran Cohort 1

Placebo OTHER

Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.

Placebo Cohort 1

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dicerna Pharmaceuticals, Inc., a Novo Nordisk company: lead

Study Sites (23)

University of California - San Diego

La Jolla, California, 92093, United States

Location

University of Florida

Gainesville, Florida, 32611, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

St Vincent's Hospital Melbourne

Melbourne, Australia

Location

Medizinische Universitaet Innsbruck

Innsbruck, Austria

Location

Universitaire Ziekenhuizen Leuven

Leuven, Belgium

Location

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada

Location

CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie

Pessac, France

Location

Universitaetsklinikum Aachen, AoeR

Aachen, Germany

Location

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, Germany

Location

Beaumont Hospital

Dublin, Ireland

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Auckland Clinical Studies

Grafton, Auckland, 1010, New Zealand

Location

Waikato Hospital

Hamilton, New Zealand

Location

Hospital da Senhora da Oliveira - Guimaraes

Creixomil, Portugal

Location

Centro Hospitalar Universitario de Sao Joao

Porto, Portugal

Location

Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE

Vila Real, Portugal

Location

Hospital Universitario Marques de Valdecilla Santander

Santander, Cantabria, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

CTC Clinical Trial Consultants AB Uppsala

Uppsala, Sweden

Location

Addenbrooke's Hospital, Cambridge University

Cambridge, United Kingdom

Location

Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom

Location

Royal Free London NHS Foundation Trust, Royal Free Hospital

London, United Kingdom

Location

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Clinical Reporting Office (2834)
• Organization: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

clinicaltrials@novonordisk.com

(+1) 866-867-7178

Study Officials

• Thomas Bowman, MD

  Dicerna Pharmaceuticals / Novo Nordisk

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2021
• First Posted: February 21, 2021
• Study Start: February 12, 2021
• Primary Completion: December 8, 2023
• Study Completion: May 29, 2024
• Last Updated: December 31, 2024
• Results First Posted: December 31, 2024

Record last verified: 2024-12

Locations

ES (2); IE (1); SE (1); GB (3); BE (1); NZ (2); PT (3); AU (1); US (3); CA (1); NL (1); DE (2); FR (1)