Not yet recruitingRare disease

Safety and Efficacy of TSRA-196 (rnaivt9315 and rnacs24757) in Adults with Lung or Liver Disease due to Alpha‑1 Antitrypsin Deficiency

Fast replyInvestigationalNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

People with the PiZZ genotype of Alpha-1 Antitrypsin Deficiency often have low levels of a protein that protects the lungs and liver, which can lead to breathing problems, similar to chronic lung disease, and to liver damage. The study uses an investigational medicine called TSRA-196, given as an intravenous (through the vein) infusion, designed to increase the amount of this protective protein in the blood.

The main goal of the study is to see whether a single dose of the medicine is safe and whether it can raise protein levels to a normal range, with some participants receiving a second dose later to assess longer‑term effects. Participants will receive the infusion, then attend regular visits over several months during which blood samples and simple health checks are performed.

Researchers will watch for any side effects, measure the amount of the protective protein in the blood, and test how well it works using a laboratory test called a elastase inhibition assay. They will also check lung function and liver health through routine exams and questionnaires to understand how the treatment impacts overall well‑being.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Baseline assessment
After enrollment, you will undergo a series of baseline tests. these include blood samples to measure your current alpha-1 antitrypsin (a protein that protects the lungs and liver), lung function testing, and other safety checks such as vital signs and electrocardiogram (ecg). the purpose is to record your health status before receiving any study medication.
Step 2
First dose administration
You will receive a single intravenous infusion of tsra-196. the medication is delivered through a vein using a solution for infusion. the exact amount is determined by the study protocol and is given only once at this stage.
Step 3
Short‑term safety monitoring
Following the infusion, you will be observed for several hours in the clinic for any immediate reactions. you will also be asked to report any side effects, known as treatment‑emergent adverse events (teae) or serious adverse events (sae), for at least the first week after dosing.
Step 4
Month 3 follow‑up
Approximately three months after the first infusion, you will return for a follow‑up visit. blood will be drawn to check whether your serum alpha-1 antitrypsin level is at or above the lower limit of normal (lln) and whether it reaches at least 11 µM, a level considered potentially therapeutic. additional safety assessments will also be performed.
Step 5
Month 6 follow‑up
Around six months after the first dose, another visit will occur. the same blood tests for alpha-1 antitrypsin levels and safety evaluations will be repeated. data from month 3 and month 6 are used to assess the effectiveness of the single dose.
Step 6
Second dose (optional, part 3)
If you are assigned to the part 3 cohort, a second intravenous infusion of tsra-196 may be given after the initial assessment period. the timing of the second dose follows the study schedule and is intended to evaluate the effect of a repeat administration.
Step 7
Month 12 final assessment
Approximately twelve months after the first (or second, if applicable) infusion, you will have a final visit. comprehensive blood tests will measure long‑term alpha-1 antitrypsin levels, functional activity of the protein, and any changes from baseline. safety checks, including laboratory parameters, vital signs, and ecg, will also be completed.

Who can join the trial?

11 criteria

Be a man or woman who is between 18 and 70 years old when you sign the consent form.
If you have lung disease with little or no liver scarring (called minimal liver fibrosis), you must have a noticeable lung problem that is not extremely severe, and your liver must show no or only minimal scarring based on a liver biopsy or a non‑invasive test.
If you have liver disease with moderate or severe scarring (called moderate‑to‑severe liver fibrosis), the scarring must be confirmed by a liver biopsy, and you may also have lung disease.
Your body mass index (BMI) must be between 18 and 37 kg/m². BMI is a measure that compares your weight to your height.
You must have a confirmed diagnosis of Alpha‑1 Antitrypsin Deficiency (AATD) and carry the PiZZ genotype, which is a specific genetic pattern linked to this condition.
At least one blood test must have shown a total AAT level lower than 11 μmol/L. This indicates a very low amount of the protective protein.
You must have not smoked for at least 6 months before screening and must stay a non‑smoker for the whole study.
You must avoid alcohol for 14 days before receiving the study drug and for 30 days after the dose, and you should not drink significant amounts of alcohol at any other time during the study.
Your screening blood test must show a total bilirubin level that meets the study’s limits, even if you have Gilbert’s syndrome (a harmless condition that can raise bilirubin).
All other laboratory and blood‑cell (hematology) test results must fall within the ranges set by the study protocol.
You must be either new to any AAT therapy (treatment‑naïve) or have stopped (a washout) all investigational or approved treatments that change AAT levels before starting the trial.

Who cannot join the trial?

18 criteria

Having a DNA change near the PiZ variant that might affect the study drug, found through genetic testing.
Having serious lung disease that is not caused by Alpha‑1 Antitrypsin Deficiency, as judged by the doctor.
Being hospitalized one or more times for a severe worsening of lung disease in the past year, or receiving IV (intravenous) antibiotics for a lung infection in the last 6 months.
Having unstable COPD related to AATD, or having severe bronchiectasis (a condition where the airways become permanently widened and scarred).
Having had lung volume reduction surgery within the past year, or planning to have this surgery during the study period.
Needing continuous positive airway pressure therapy (CPAP) beyond just using it at night.
Having received an organ transplant or being on a waiting list for an organ transplant.
Being dependent on continuous supplemental oxygen.
Receiving a live‑attenuated vaccine (a weakened form of a virus) within 30 days before the study dose, or any other vaccine within 14 days before dosing.
Having previously received gene therapy that uses viruses to permanently change DNA, or planning to do so (RNA‑based treatments are allowed).
Testing positive for HIV, active hepatitis B, or hepatitis C (meaning the virus is present in the blood).
Having a history of blood‑clot disease, heart attack, or stroke within the past 6 months.
Having uncontrolled high blood pressure as defined by the study protocol.
Having had a severe reaction (grade 3 or higher) to lipid‑nanoparticle (LNP) substances used in medicines.
Having an active cancer diagnosed within the past 5 years, except for certain skin cancers, treated cervical pre‑cancer, or low‑grade prostate cancer that is only being observed.
Having a null or loss‑of‑function mutation in the SERPINA1 gene, identified by genetic testing.
Having liver disease that is not related to Alpha‑1 Antitrypsin Deficiency.
Having signs of cirrhosis (such as swollen veins in the esophagus called varices or fluid buildup in the abdomen called ascites).

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Karolinska University Hospital
Verified
Solna, Sweden
Leids Universitair Medisch Centrum (LUMC)
Responsive
Leiden, The Netherlands
Queen Silvia Childrens Hospital - Sahlgrenska University Hospital - Vaestra Goetalandsregionen
Verified
Gothenburg, Sweden

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Investigated drugs

TSRA-196 is an experimental medication being tested in this study. It is given through a vein (intravenous infusion) as a liquid solution. The product contains two special RNA molecules, called RNAIVT9315 and RNACS24757, which are designed to help the body produce more functional alpha‑1 antitrypsin, a protein that protects the lungs and liver. In the trial, participants with severe alpha‑1 antitrypsin deficiency receive a single dose of TSRA‑196, and some may receive a second dose later. Researchers are looking at how safe the medication is and whether it improves the health of the lungs and liver in these patients.

What is already known about the treatment

TSRA-196 - This medication is supplied as a sterile solution for infusion and is given by slow intravenous injection into a vein. It is currently an investigational drug being studied in a Phase 1/2 clinical trial for safety and effectiveness. The main use being tested is to treat lung and/or liver disease caused by severe Alpha‑1 Antitrypsin Deficiency. It works by delivering specially designed RNA molecules that help liver cells make more normal alpha‑1 antitrypsin protein, and it is classified as an RNA‑based gene‑therapy product.

Investigated diseases

Alpha-1 Antitrypsin Deficiency - Alpha-1 antitrypsin deficiency is an inherited condition that results in low levels of a protein that protects the lungs and liver. Without enough of this protein, the lungs become more sensitive to damage from inhaled particles, leading to a gradual loss of breathing capacity. Over time, this can cause persistent shortness of breath and reduced ability to exercise. In the liver, the missing protein can accumulate, causing a slow buildup of scar tissue and reduced liver function. The condition typically worsens slowly over many years.