A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease

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Brief Title

A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease

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

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.
    

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Safety and tolerability

Secondary Outcome

 Urine pharmacokinetics (PK) of DCR-A1AT

Condition

Alpha 1-Antitrypsin Deficiency

Intervention

DCR-A1AT

Study Arms / Comparison Groups

 DCR-A1AT
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

60

Start Date

October 24, 2019

Completion Date

June 2022

Primary Completion Date

December 2021

Eligibility 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
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Hardean Achneck, MD, 617-621-8097, [email protected]

Location Countries

Sweden

Location Countries

Sweden

Administrative Informations


NCT ID

NCT04174118

Organization ID

DCR-A1AT-101


Responsible Party

Sponsor

Study Sponsor

Dicerna Pharmaceuticals, Inc.


Study Sponsor

Hardean Achneck, MD, Study Director, Dicerna Pharmaceuticals


Verification Date

November 2019