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Recruiting NCT07227207

A Study of TSRA-196 in Adults With PiZZ Alpha-1 Antitrypsin Deficiency (AATD)

Phase I / Phase II Interventional Alpha-1 Antitrypsin Deficiency (AATD)

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: TSRA-196.
Who it may be relevant to
Registry conditions: Alpha-1 Antitrypsin Deficiency (AATD). Basic parameters: 18 years — 70 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
United States, Australia
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

Unsure about the terms? Read our patient guide →

Official title

A Phase 1/2, Open-Label, Multi-Center, Dose Escalation, Dose Expansion, and Single Repeat Dose Study of TSRA-196 in Adults With the PiZZ Genotype Who Have Lung and/or Liver Disease Associated With Severe Alpha-1 Antitrypsin Deficiency

Overview

This is a Phase 1/2, open-label, multi-center, dose escalation (Part 1), dose expansion (Part 2), and single repeat dose (Part 3) study to evaluate the safety, tolerability, efficacy, and PK/PD parameters of TSRA-196 in adults with the PiZZ genotype who have lung and/or liver disease associated with severe alpha-1 antitrypsin deficiency (AATD)

Interventions

  • Drug TSRA-196
    TSRA-196 is an in-vivo genome editing product formulated in lipid nanoparticles (LNPs) for the treatment of patients with alpha-1 antitrypsin deficiency (AATD), via intravenous (IV) infusion

Primary outcome measures

  • Part 1 (Dose Escalation): Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) [Time frame: 1 Year]
  • Part 2 (Dose Expansion): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after TSRA-196 treatment [Time frame: 1 Year]
  • Part 2 (Dose Expansion): Change in functional AAT concentrations (determined using an elastase inhibition assay) from baseline to end of study [Time frame: 1 Year]
  • Part 3 (Single Repeated Dose): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after a second dose of TSRA-196 [Time frame: 1 Year]
Secondary outcome measures (12)
  • Part 1 (Dose Escalation): Proportion of participants who have serum levels of total AAT greater than or equal to LLN after TSRA-196 treatment [Time frame: 1 Year]
  • Part 2 (Dose Expansion): Incidence of TEAEs and SAEs [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Proportion of participants who have serum levels of total AAT greater than or equal to 11 μM after TSRA-196 treatment [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change in serum levels of total AAT from baseline over time [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Incidence of Adverse Event of Special Interest (AESI) from day of dosing through end of study [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change over time in safety measures, including clinical laboratory parameters, vital signs, and ECG parameters [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Pharmacokinetic (PK) parameter: Area under the blood concentration time curves (AUC) of TSRA-196 [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Maximum observed blood concentration (Cmax) of TSRA-196 [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Time to Cmax (tmax) of TSRA-196 [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Half-life (t1/2) of TSRA-196 [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Clearance (CL) of TSRA-196 [Time frame: 1 Year]
  • Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: The volume of distribution at terminal stage (Vz) of TSRA-196 [Time frame: 1 Year]

Eligibility criteria

Inclusion criteria

  • Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent
  • Body mass index of 18 to 37 kg/m2, inclusive
  • Confirmed diagnosis of AATD and PiZZ genotype
  • At least one previous measure of blood total AAT level <11 µmol/L
  • Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration
  • Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels for 5 half-lives or at least 4 weeks, whichever is longer, before TSRA-196 administration

Parts 1A and 2A (AATD lung disease with no or minimal liver fibrosis)

  • Clinically significant lung disease, defined as 1) evidence of emphysema or bronchiectasis by computed tomography or 2) DLCO <70% of the predicted value or 3) ppFEV1 <80%
  • ppFEV1 ≥35%
  • METAVIR fibrosis score F0 or F1 confirmed by liver biopsy at screening, or a liver stiffness measure by FibroScan ≤7 kPa at screening
  • FIB-4 index score ≤3.25 at screening
  • ALT and/or AST <ULN at screening

Parts 1B and 2B (AATD liver disease with significant or severe liver fibrosis, with or without AATD lung disease)

  • METAVIR fibrosis score F2 or F3 confirmed by liver biopsy at screening. A liver biopsy conducted within 12 months before screening is acceptable as a substitute.
  • Liver stiffness measure by FibroScan >7 and ≤15 kPa at screening
  • ALT and/or AST <2 x ULN at screening

Exclusion criteria

  • Presence of genetic variation in SERPINA1 gene that may disrupt the function of TSRA-196, determined by screening genotyping
  • History of liver disease unrelated to AATD, or history of or clinical signs of cirrhosis
  • Significant lung disease not attributable to manifestations of AATD, as determined by the investigator
  • History of one or more hospitalizations due to severe exacerbation of underlying lung disease during the year before screening or received IV antibiotics for treatment of a pulmonary infection within 6 months before screening
  • Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis
  • Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period
  • Documented chronic need for positive airway pressure therapy beyond nocturnal use
  • Seropositive for human immunodeficiency virus (HIV) (HIV-1 or HIV-2)
  • Seropositive for hepatitis B (hepatitis B surface antigen \[HBsAg\] or hepatitis B core antibody \[HBcAb\] positive) with detectable HBV DNA
  • Hepatitis C virus (HCV) RNA positive at screening (Parts 1A and 2A), or HCV RNA positive and/or HCV antibody positive at screening (Parts 1B and 2B)
  • Has received an organ transplant or is on a waiting list for an organ transplant
  • Prior treatment with gene therapy using viral vectors or intended to permanently change the patient's DNA
  • Any investigational products within 30 days before dosing or plan to take an investigational product before the end of study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation
N/A
Model
Single group
Masking
Open label
Primary purpose
Treatment

Study locations

United States · 3 centers
  • Clinical Study Center — Boston
  • Clinical Study Center — Charleston
  • Clinical Study Center — Seattle
Australia · 1 center
  • Clinical Study Center — Fitzroy

Identifiers

NCT: NCT07227207 · TSRA196-AAT-201

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗