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Trial record 1 of 1 for:    NCT04174118
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A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease

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ClinicalTrials.gov Identifier: NCT04174118
Recruitment Status : Recruiting
First Posted : November 22, 2019
Last Update Posted : November 22, 2019
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

Brief Summary:

This is a research study to test an experimental study drug (DCR-A1AT). This drug is being tested to see if it helps people with a rare condition known as Alpha-1 Antitrypsin Deficiency, or A1ATD. Prior to initiation of this study DCR-A1AT has not yet been tested in humans. This study will have 2 parts: Group A and Group B. Group A is for people who do not have A1ATD. Group B is for people who have been diagnosed with A1ATD. All study participants will be randomly assigned to either receive the study drug or a placebo. This will allow for the sponsor to compare the effects of the study drug with that of placebo. A placebo looks like the study drug but does not contain any of the study drug.

Group A: The main purpose of the first part of the study is to evaluate the safety profile of the study drug in people who do not have A1ATD. This part of the study will also help find the dose of the study drug that has an acceptable safety profile for testing.

Group B: This is the second part of the study. This part of the study is for people who have been diagnosed with A1ATD, so the people in the first part of the study cannot participate in the second part of the study. The main purpose of this part of the study is different because the drug will now be given to people who have A1ATD. This part of the study will also help find the dose of the study drug that is safest and works the best, but with people who have A1ATD. This way, this part of the study will show if the drug is potentially safe for and could potentially be effective against A1ATD.


Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Drug: DCR-A1AT Drug: Placebo Phase 1 Phase 2

Detailed Description:

A1ATD- associated liver disease is a progressive Alpha-1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma. The lack of function A1AT in individuals with PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity in neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism can be addressed with intravenous augmentation therapy, which aims to substitute the missing A1AT by infusing alpha1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of A1AT 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 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 in this particular patient population.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Double-Blind
Primary Purpose: Other
Official Title: A Phase 1/2 Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered DCR-A1AT in Healthy Adult Volunteers and Patients With Alpha1-Antitrypsin-Deficiency-Associated Liver Disease
Actual Study Start Date : October 24, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: DCR-A1AT

SAD Group A: Healthy volunteers will be administered a single dose of DCR-A1AT.

MAD Group B: Participants will be administered multiple doses of DCR-A1AT.

Drug: DCR-A1AT
DCR-A1AT will be administered subcutaneously (SC) at dose levels planned for group A. Group B dose levels to be determined upon review of data from group A.

Placebo Comparator: Placebo

Group A: Healthy volunteers will be administered a single dose of matching placebo.

Group B: Participants will be administered multiple doses of matching placebo.

Drug: Placebo
Sterile normal saline (0.9% NaCL) matching volume of DCR-A1AT doses will be administered subcutaneously (SC).




Primary Outcome Measures :
  1. Safety and tolerability [ Time Frame: Group A: approximately up to 2 months; Group B: approximately up to 6 months ]
    The incidence of adverse events (AE), serious adverse events (SAE), DLT, and AE leading to study drug discontinuation

  2. Evaluating safety and tolerability through physical exams [ Time Frame: Group A: approximately up to 2 months; Group B: approximately up to 6 months ]
    The incidence of clinically significant physical examination (PE) findings

  3. Changes in 12-lead electrocardiograms (ECG) [ Time Frame: Group A: approximately up to 2 months; Group B: approximately up to 6 months ]
    Absolute QTc > 500 msec and/or QTc change of > 60 msec from baseline will be evaluated


Secondary Outcome Measures :
  1. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
    Maximum observed concentration (Cmax)

  2. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Maximum observed concentration (Cmax)

  3. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Area under the curve (AUC)

  4. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
    Area under the curve (AUC)

  5. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
    Minimum observed concentration (Cmin)

  6. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Minimum observed concentration (Cmin)

  7. Plasma pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Time to maximum concentration (Tmax)

  8. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
    Time to maximum concentration (Tmax)

  9. Urine pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to Day 3; Group B: up to Day 3 ]
    Terminal elimination half-life (t1/2)

  10. Plama pharmacokinetics (PK) of DCR-A1AT [ Time Frame: Group A: up to 57 days; Group B: up to approximately 4 months ]
    Terminal elimination half-life (t1/2)

  11. Change in protein concentration [ Time Frame: Group A: up to day 57; Group B: up to 6 months ]
    Changes in A1AT protein concentrations

  12. Change in protein content [ Time Frame: Group A: not applicable; Group B: up to 6 months ]
    Change in hepatic Z-AAT protein content



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Group A:

  • Male or Female aged 18 to 55 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment.
  • Overtly Healthy, as determined by the investigator.
  • Serum A1AT protein concentration >100 mg/dL
  • Adequate forced expiratory volume in one second (FEV1) and adequate FEV1/forced vital capacity (FVC) ratio
  • Non-smokers with a <2 pack-year history and smoking cessation for at least 6 months with a negative urinary cotinine test a screening

Group B

  • Male or female aged 18 to 70 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment.
  • Documented diagnosis of PiZZ-type A1ATD
  • Documented A1ATD-associated liver disease
  • Serum A1AT protein concentration >10mg/dL
  • Has adequate pulmonary function test results per protocol
  • Smoking cessation for at least 3 months
  • Agrees to undergo liver biopsies

Exclusion Criteria:

Group A:

  • Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect participant safety
  • Clinically significant abnormal laboratory tests
  • Received an experimental drug within past 4 months
  • Prior to use of RNAi drug or oligonucleotide-based therapy
  • Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B (HBV)
  • Serum creatinine or estimated glomerular filtration rate (eGFR) outside normal reference ranges.

Group B:

  • History of chronic liver disease from any cause other than PiZZ-type A1ATD
  • History of gastrointestinal bleeding from esophageal or gastric varices
  • History of hepatic encephalopathy
  • History of acute exacerbations of underlying lung disease defined per protocol
  • Use of augmentation therapy within prior to 6 months
  • Prior use of RNAi drug
  • History of reactions to prior oligonucleotide-based therapy defined per protocol.
  • Received an experimental drug within the past 4 months.
  • Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B (HBV)
  • Lab values out of protocol-defined ranges and/or any lab value deemed as clinically significant and unacceptable.
  • Liver elastography per protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04174118


Contacts
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Contact: Dicerna Pharmaceuticals 617-621-8097 clinicaltrials@dicerna.com

Locations
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Sweden
Clinical Trial Consultants AB Recruiting
Uppsala, Sweden
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
Investigators
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Study Director: Hardean Achneck, MD Dicerna Pharmaceuticals

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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04174118    
Other Study ID Numbers: DCR-A1AT-101
First Posted: November 22, 2019    Key Record Dates
Last Update Posted: November 22, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Diseases
Alpha 1-Antitrypsin Deficiency
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes
Alpha 1-Antitrypsin
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action