Study to learn about the safety of fazirsiran and if it can help people with alpha-1 antitrypsin liver disease with mild liver scarring (fibrosis)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

18 Apr 2024 → ongoing

Decision date (initial)

2024-04-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the long-term safety and tolerability of fazirsiran compared with placebo, with an emphasis on lung safety, including measures of pulmonary function.

Secondary objectives 5

1. 1. Evaluate the PD effect of fazirsiran via measurement of serum Z-AAT.
2. 2. Evaluate the efficacy of fazirsiran compared with placebo at reducing liver Z-AAT levels.
3. 3. Evaluate the efficaccy of fazirsiran compared with placebo at reducing histologic evidence of Z-AAT polymer burden and portal inflammation in the liver.
4. 4. Evaluate the efficacy of fazirsiran compared with placebo at modulating progression of liver fibrosis assessed by liver biopsy at Week 106.
5. 5. Evaluate the efficacy of fazirsiran compared with placebo using noninvasive measures of liver injury and fibrosis (including imaging tests and biomarkers).

Conditions and MedDRA coding

Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda’s data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5 ). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. The participant must have a diagnosis of the PiZZ genotype AATD. A diagnosis of PiZZ from source- verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.
2. 2. The participant, of any sex, is aged 18 to 75 years, inclusive.
3. 3. The participant has evidence of METAVIR stage 1 liver fibrosis, evaluated by a centrally-read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading from a previous biopsy conducted within 1 year before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
4. 4. The participant has a pulmonary status meeting the protocol requirements

Exclusion criteria 9

1. 1. Evidence of ≥ F2 fibrosis based on liver biopsy during the screening period.
2. 2. The participant has a history of liver decompensating events (overt hepatic encephalopathy documented by a physician or trained professional, clinically significant ascites, spontaneous bacterial peritonitis, gastrointestinal (GI) bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy).
3. 3. The participant has evidence of other forms of chronic liver diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis. Additional diagnosis will be allowed as per the protocol.
4. 4. The participant has a history of malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with curatively treated malignancies who have no evidence of metastatic disease and a greater than 1 year disease-free interval may be enrolled after approval by the medical monitor.
5. 5. The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study such as may occur with occupational exposure to mineral dusts or metals.
6. 6. The participant has a recent lower respiratory tract infection, such as pneumonia, within the last 6 months before screening. The participant may be screened earlier based on principal investigator (PI) assessment of clinical recovery and return to baseline pulmonary function in discussion with the medical monitor.
7. 7. The participant has a history of frequent pulmonary exacerbations (≥2 moderate or severe exacerbations within 52 weeks before screening).
8. 8. The participant is experiencing a pulmonary exacerbation at the time of screening (participant may be rescreened after the clinical resolution of an exacerbation).
9. 9. The participant is receiving long-term, around-the-clock oxygen supplementation, or supplemental oxygen with continuous positive airway pressure (CPAP) or bilevel positive airway pressure for acute respiratory failure. The following conditions are allowable for the participant to enter screening: short-term use of oxygen supplementation (eg, for the management of acute chronic obstructive pulmonary disease [COPD] exacerbation) or CPAP for obstructive sleep apnea.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. AEs and SAE including any pulmonary AEs or SAEs indicative of worsening pulmonary condition/function (eg, pulmonary exacerbation, respiratory infection, significant PFT decline).
2. Change from baseline over time to EOS in pulmonary function parameters at scheduled visits
3. Change from baseline in whole lung 15th percentile density as measured by computed tomography (CT) lung densitometry over time to Week 100.
4. Vital signs.
5. ECG measurements.
6. Clinical laboratory values (hematology, biochemistry including liver tests, coagulation, and urinalysis results).

Secondary endpoints 9

1. Change from baseline in serum Z-AAT protein over time to Week 106.
2. Percent change from baseline in intrahepatic liver Z-AAT protein at Week 106.
3. Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining at Week 106.
4. No change or decrease from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining at Week 106.
5. Change from baseline in intrahepatic portal inflammation at Week 106.
6. No change or decrease from baseline in intrahepatic portal inflammation at Week 106.
7. No change or decrease from baseline in histologic fibrosis score (METAVIR staging) at Week 106.
8. Change from baseline in VCTE-derived liver stiffness over time to Week 106.
9. Change from baseline in markers of liver injury (alanine aminotransferase [ALT], aspartate aminotransferase [AST], γ-glutamyl transferase [GGT]) over time to Week 106.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 15

Locations

10 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 123 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

20 submissions — initial application plus substantial / non-substantial modifications