An Open-Label Extension Study of Fazirsiran

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

24 Jul 2023 → ongoing

Decision date (initial)

2023-07-17

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center America Inc, United State

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis, Therapy, Pharmacokinetic, Safety, Efficacy, Pharmacodynamic

The primary objective of the study is to evaluate the safety and tolerability of the long-term treatment of fazirsiran in participants with AATD-LD.

Secondary objectives 2

1. • To evaluate the effect of long-term treatment with fazirsiran on liver histology with a particular focus on the progression or regression of METAVIR stage fibrosis as well as histologic evidence of portal inflammation and Z-alpha-1 antitrypsin (Z-AAT) polymer burden in the liver.
2. • To evaluate the effect of fazirsiran on changes in noninvasive measures of fibrosis over time compared with baseline during the study.

Conditions and MedDRA coding

Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

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 1

1. The participant enrolling in this OLE study will have participated in a previously qualifying study, and will be considered for eligibility based on the following study-specific criteria: -AROAAT2001: – Participants with fibrosis may roll over into this OLE study after they reach their next regularly scheduled, Q12W visit. – Participants with fibrosis who have completed the AROAAT2001 study may be enrolled into the OLE study. -AROAAT2002: – Participants in Cohorts 1 and 1b may roll over after completing the 24 week primary study period. –Participants in Cohort 2 may roll over after completing the 48 week primary study period. – Participants who have completed the study may be enrolled into the OLE study. Note: If the first dose of fazirsiran in the OLE study will be delayed by more than 24 weeks after the last dose in AROAAT2001 or AROAAT2002, the rollover should be discussed with the medical monitor.

Exclusion criteria 1

1. 1. The participant is likely to require major surgery. Major surgery typically requires at least 1 night in the hospital. Examples include laparoscopic surgery (except cholecystectomy and tubal ligation); GI tract surgery including 1 or more segments of the colon or terminal ileum; open resection of organs; large joint replacements; mastectomy with reconstruction; and spine, thoracic, vascular, or intracranial surgery. Note: participants who are awaiting a liver transplant may roll over into this study and receive treatment until the last regularly scheduled study visit, or 4 weeks before the procedure, whichever occurs later. In an urgent situation, a transplant should not be withheld due to timing of last dose. 2. 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. 3. The participant has abnormal finding(s) of clinical relevance during the evaluation before the first study dosing that, in the opinion of the investigator, could adversely impact participant safety during the study or adversely impact study results. 4. The participant had major protocol deviation(s) (as determined by the sponsor) in AROAAT2001 or AROAAT2002 that would affect the conduct of this study. 5. The participant permanently discontinued investigational product because of an AE, adjudicated as related to the study intervention, in AROAAT2001 or AROAAT2002. 6. Female participants who became pregnant during Study AROAAT2001 or AROAAT2002, female participants who are lactating or planning to become pregnant during the study period; or males or female participants of childbearing potential not agreeing to continue using appropriate contraception methods (that is, highly effective methods for female and medically appropriate methods for male study participants) through the conclusion of study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. The primary safety endpoints for this study to be assessed over time and through the end of study (EOS) are: •AEs and SAEs including any pulmonary AEs or SAEs indicative of worsening pulmonarycondition or function (for example, pulmonary exacerbation, respiratory infection, significant pulmonary function test [PFT] decline.)
2. •Change from baseline in pulmonary function parameters: – FEV1 (L) and percent predicted forced expiratory volume in the first second of expiration (ppFEV1 [%]). – FVC; L and percent predicted FVC (ppFVC; %). – FEV1/FVC ratio. – Diffusing capacity of lung for carbon monoxide (DLCO; mL/min/mm Hg) and percent predicted DLCO (ppDLCO; %). – DLCOhgb; mL/min/mm Hg and percent predicted DLCOhgb (ppDLCOhgb; %).
3. Translation PT
4. •Vital signs.
5. •Change from baseline in clinical laboratory values (hematology, biochemistry including liver tests, coagulation, and urinalysis results).

Secondary endpoints 6

1. •No progression from baseline of at least 1 stage of histologic fibrosis (by METAVIR staging) on liver biopsy at Week 102 (Yes/No)
2. •In participants with baseline fibrosis of F1 or higher, a decrease from baseline of at least 1 stage of histologic fibrosis (by METAVIR staging) on liver biopsy at Week 102 (Yes/No)
3. •Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by periodic acid Schiff plus diastase (PAS+D) staining in liver biopsy at Week 102.
4. •Change from baseline in intrahepatic portal inflammation in Week 102 liver biopsy.
5. •Change from baseline in liver stiffness assessed by magnetic resonance elastography (MRE) (at select sites).
6. •Change from baseline in liver stiffness assessed by vibration-controlled transient elastography (VCTE).

Investigational products

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

Test 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 20

Locations

3 EU/EEA countries · 3 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 33 files

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

Application history

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