Observational Study to Evaluate Efficacy, Safety and Biomarkers of Bulevirtide Treatment in Patients with Chronic hepatitis D

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karolinska University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

19 Jun 2023 → ongoing

Decision date (initial)

2023-05-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To assess the percentage of patients with virological response of HDV RNA < limit of detection (LoD) at follow-up (FU) 12 months after end of treatment (EOT).

Secondary objectives 24

1. To assess the percentage of patients with virological response of HDV RNA < LoD at month 1, 3 and every 3 months after treatment start, and FU month 3, 6, and 9 after EOT.
2. To assess the percentage of patients with HBsAg < LoD at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
3. To evaluate change of HBsAg from baseline every 3 month during study period.
4. To assess the percentage of patients with HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline, at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
5. To assess the percentage of patients with virological relapse, defined as HDV RNA < LoD at EOT and increase of HDV RNA to > LoD after EOT, at FU month 3, 6, 9 and 12 after EOT.
6. To assess the percentage of patients with appearance of hepatitis B surface antibody (anti-HBs) at EOT, and FU month 3, 6, 9 and 12 after EOT.
7. To assess the percentage of patients with hepatitis B virus (HBV) DNA level < LoD every 3 months during study period.
8. To assess the percentage of patients with biochemical response, defined as normalization of alanine transaminase (ALT), at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
9. To assess the percentage of patients with combined response, defined as HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline and ALT normalization, at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT
10. To evaluate change of liver elasticity measurement level from baseline compared to the level at every 6 months during on-treatment, EOT, and FU month 6, and 12 after EOT.
11. To evaluate AE of special interest: 1. Liver-related event, defined as new diagnoses of liver cirrhosis, HCC, or hepatic decompensation (ascites, variceal bleeding or hepatic encephalopathy); 2. Event of ≥ grade 3 hematological AE (in IFN treated); 3. Event of thyroid disorder (in IFN treated); 4. Event of injection site reaction; 5. Event of≥ grade 3 ALT increase
12. To assess the adherence to BLV treatment through quantification of missed doses.
13. To assess the percentage of patients with early discontinuation of treatment and the reasons.
14. To assess the percentage of patients with serious adverse event (SAE).
15. EXPLORATORY OBJECTIVES: To evaluate change of hepatitis B core-related antigen (HBcrAg) from baseline every 3 months during study period.
16. To evaluate change of HBV RNA level from baseline every 3 months during study period.
17. To evaluate change of fibrosis stage in pre-treatment liver biopsy, compared to fibrosis stage in on- or post-treatment liver biopsy.
18. To evaluate change of inflammation grade in pre-treatment liver biopsy, compared to inflammation grade in on- or post-treatment liver biopsy.
19. To evaluate change of quality of life pre-treatment from baseline, compared to every six months after treatment start, EOT and FU 12 months.
20. To evaluate change of innate or adaptive immunological marker/signature in BLV (PBMC) from baseline, compared to months 1, 6, and every 6 months, EOT, FU month 6 and 12.
21. To investigate if any innate or adaptive immunological marker/signature in PBMC, associated with on-treatment or off-treatment virological and/or biochemical response.
22. To investigate if any intrahepatic immune marker/signature in pre-treatment liver biopsy, associated with on- or off-treatment virological and/or biochemical response.
23. To investigate if any biomarker in serum, associated with on-treatment or off-treatment virological and/or biochemical response.
24. To evaluate if any changes in oral or fecal microbiome, or other features in saliva or feces from baseline during and after treatment.

Conditions and MedDRA coding

hepatitis D

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age > 18 years
2. Diagnosis of chronic HBV/HDV co-infection
3. Have compensated liver disease (presence of portal hypertension without ongoing hepatic decompensation, as ascites, variceal bleeding and hepatic encephalopathy, is allowed)
4. Have indication for treatment of BLV, or already treated with BLV.
5. For female participants: a. Postmenopausal for at least one year, or b. Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, staples, or another type of sterilization), or c. Abstinence from heterosexual intercourse throughout the treatment period, or d. Willingness to use highly effective contraception (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive) throughout the treatment period and for 6 months after last dose of the drugs in the study.
6. Male participants must agree to use a highly effective contraception (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive used by female partners) throughout the treatment period and for 6 months after the last dose of the drugs in the study.
7. Participants who are willing to give written informed consent.

Exclusion criteria 4

1. Any contra-indications to treatment with BLV, including any intolerance or hypersensitivity to the active ingredient or other components of BLV.
2. Pregnant or breast-feeding women
3. Patients with predictable difficulties of FU according to the investigator
4. Any other condition that, in the opinion of Investigator, precludes the patient from taking part in this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients with virological response of HDV RNA < LoD at FU 12 months after EOT.

Secondary endpoints 24

1. Percentage of patients with virological response of HDV RNA < LoD at month 1, 3 and every 3 months during treatment, and FU month 3, 6 and 9 after EOT.
2. Percentage of patients with HBsAg < LoD at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
3. Change of HBsAg from baseline every 3 months during study period.
4. Percentage of patients with HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline, at month 1 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
5. Percentage of patients with virological relapse, defined as HDV RNA < LoD at EOT and increase of HDV RNA to > LoD after EOT, after EOT, at FU month 3, 6, 9 and 12 after EOT.
6. Percentage of patients with appearance of hepatitis B surface antibody (anti-HBs) at EOT, and FU month 3, 6, 9 and 12 after EOT.
7. Percentage of patients with HBV DNA level < LoD every 3 months during study period.
8. Percentage of patients with biochemical response, defined as normalization of alanine transaminase (ALT), at month 1, 3 and every 3 months during treatment, and FU month 3, 6, 9 and 12 after EOT.
9. Percentage of patients with combined response, defined as HDV RNA < LoD or HDV RNA reduction of at least 2 log10 compared to baseline and ALT normalization, at month 1, 2 and 3, and every 3 months after treatment start, and FU month 3, 6, 9 and 12 after EOT.
10. Change of liver elasticity measurement level from baseline compared to the level at every 6 months during on-treatment, EOT, and FU month 6 and 12 after EOT
11. Percentage of AE of special interest: 1. Liver-related event, defined as new diagnoses of liver cirrhosis, HCC, or hepatic decompensation (ascites, variceal bleeding or hepatic encephalopathy); 2. Event of ≥ grade 3 hematological AE (in IFN treated); 3. Event of thyroid disorder (in IFN treated); 4. Event of injection site reaction; 5. Event of≥ grade 3 ALT increase.
12. Percentage of missed BLV doses during treatment.
13. Percentage of patients with early discontinuation of treatment and the reasons.
14. Percentage of patients with SAE.
15. EXPLORATORY ENDPOINTS: Change of HBcrAg from baseline every 3 months during study period.
16. Change of HBV RNA level from baseline every 3 months during study period.
17. Change of fibrosis stage in pre-treatment liver biopsy, compared to fibrosis stage in on- or post-treatment liver biopsy.
18. Change of inflammation grade in pre-treatment liver biopsy, compared to inflammation grade in on- or post-treatment liver biopsy.
19. Change of quality of life pre-treatment from baseline, compared to every 6 months after treatment start, EOT and FU month 6 and 12.
20. Change of innate or adaptive immunological marker/signature in PBMC from baseline, compared to month 1, 6, and every 6 months, EOT, FU month 6 and 12.
21. Identification of any innate or adaptive immunological marker/signature in PBMC, associated with on- or off-treatment virological and/or biochemical response.
22. Identification of any intrahepatic immune marker/signature in pre-treatment liver biopsy, associated with on-treatment or off-treatment virological and/or biochemical response
23. Identification of any biomarker in serum, associated with on- or off-treatment virological and/or biochemical response.
24. Identification of any changes in oral or fecal microbiome, or other features in saliva or feces from baseline during and after treatment.

Investigational products

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

Test 3

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska University Hospital

Sponsor organisation

Karolinska University Hospital

Address

Halsovagen, Flemingsberg Flemingsberg

City

Huddinge

Postcode

141 86

Country

Sweden

Scientific contact point

Organisation

Karolinska University Hospital

Contact name

SOO ALEMAN

Public contact point

Organisation

Karolinska University Hospital

Contact name

SOO ALEMAN

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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