An Open Label Study to Evaluate A3907 in Adults with Primary Sclerosing Cholangitis (PSC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Albireo AB, Albireo AB

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

2 Jan 2023 → 10 Jul 2025

Decision date (initial)

2022-12-19

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Albireo AB

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Others, Pharmacokinetic

To evaluate the safety and tolerability of A3907 in patients with PSC with and without a Clinically Relevant Stricture (CRS)

Secondary objectives 1

1. To evaluate the pharmacokinetics (PK) of A3907 To evaluate the effect of A3907 on bile acid levels To evaluate the effect of A3907 on liver health To evaluate the effect of A3907 on bile acid synthesis

Conditions and MedDRA coding

Primary Sclerosing Cholangitis (PSC)

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants. Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board. Supporting Information Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1. Adults between 18 and 75 years of age (inclusive). 2. Have a clinical diagnosis of large-duct PSC with evidence of more than 6 months duration with either a consistent magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis and historical evidence of elevated alkaline phosphatase (ALP). 3. Willing to sign informed consent. 4. Women of childbearing potential (WOCBP) and males with female partners of childbearing potential must agree to use contraception as detailed in Section 9.3.18. Women of nonchildbearing potential (WONCBP) must meet the definition in Section 9.3.18 and have a confirmatory follicle stimulating hormone [FSH] level ≥ 40 mIU/mL . 5. Alkaline Phosphatase (ALP) value > 1.5 × upper limit of normal (ULN) but ≤ 10 ×ULN at Visit 1 (Screening Period). Before starting 12 weeks treatment variability of < 30% between ALP values at Visit 1 and Visit 2 must be confirmed. If variability is > 30 % a third ALP value may be obtained. If the third ALP value meets >1.5 × ULN but ≤ 10 × ULN the patient can start the 12-week treatment period. 6. Arms 1-3 Only: Total bilirubin < 1.5 × ULN (unless due to Gilberts Syndrome or hemolysis) and normal direct bilirubin. 7. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN 8. Serum bile acid level > ULN 9. Arms 1 - 3 Only: An MRCP or equivalent imaging modality performed within 6 months before the Screening Period that is consistent with PSC without a clinically relevant stricture. 10. Arm 4 Only: An MRCP or equivalent imaging modality performed within 6 months before the Screening Period that is consistent with PSC with a clinically relevant stricture, or clinically relevant bile duct obstruction (see Inclusion # 12 for additional information). 11. Use of ursodeoxycholic acid (UDCA) with a total daily dose ≤ 23 mg/kg/day, or bile acid-binding resins are permitted, with a minimum of 3 months of stable treatment prior to the Screening Period, and expected to remain on a stable dose through the 12-week treatment period; or a minimum of 3 months off UDCA prior to the Screening Period if UDCA was recently discontinued. 12. If a patient has inflammatory bowel disease (IBD) with a minimum disease duration of 4 weeks, this diagnosis should be documented. Inflammatory bowel disease should be in clinical remission or mildly active according to Crohn’s Disease Activity Index (CDAI), partial Mayo score for Crohn’s Disease (CD) and ulcerative colitis (UC), respectively (i.e., patients with CDAI score < 220 and Mayo score < 5, respectively). Patients with IBD should have had a colonoscopy performed within one year prior to the Screening Period with results showing no evidence of dysplasia or cancer.
2. 13. Clinically stable for at least 3 months prior to the Screening Period. 14. Arm 4 Only: One stable clinically relevant biliary stricture of at least 4 weeks duration on contrast enhanced MRI/MRCP with > 75% reduction of duct diameter in the common bile duct or hepatic duct without suspicion of cholangiocarcinoma (further established by imaging and stable CA 19-9 below ULN repeated twice over 1 month), or cholelithiasis. Subjects may have signs or symptoms of worsening obstructive cholestasis (increasing jaundice, nausea, anorexia, steatorrhea and worsening or new onset pruritus), deterioration of liver function (i.e., decreasing platelet count, increasing international normalized ratio [INR]) and/could be listed for liver transplantation due to their clinically relevant biliary stricture. 15. Arm 4 Only: MELD Score < 35

Exclusion criteria 1

1. Medical History - 1. Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis). 2. Biliary intervention within 3 months prior to study enrollment or planned. 3. Presence of alternative causes of chronic liver disease, including alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis, or active hepatitis B or C. 4. IBD with uncontrolled moderate to severe activity and/or on treatment with any immunosuppressive, immunomodulator, or biologic agent for treatment of IBD (i.e. azathioprine, 6 mercaptopurine, tacrolimus, methotrexate, infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, ozanimod). Treatment with corticosteroids (including budesonide, budesonide MMX and beclomethasone) in the previous 4 weeks. 5. History of human immunodeficiency virus infection or any other known relevant infection (e.g., tuberculosis). 6. History of colostomy or colectomy. 7. History of malignancy, including hepatocellular carcinoma within the past 10 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. 8. History of transplants, including liver transplantation, or currently on active transplantation list. 9. Current or a history of ascites, encephalopathy, or history of esophageal variceal bleeding. 10. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis. 11. Small duct PSC (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography). 12. Liver cirrhosis as assessed by any of the following: a. historical liver histology • suspected liver fibrosis, defined by liver stiffness measurement, assessed by FibroScan (FibroScan value > 14.4 kPa). b. signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal haemorrhage, and/or hepatic encephalopathy). 13. Are female of childbearing potential, including those who are pregnant or lactating 14. History of alcohol or substance abuse in the previous 2 years. Patients must agree to refrain from illicit drug (including marijuana) and alcohol use during the study 15. Hypersensitivity to investigational medicinal product (A3907) and excipients. 16. Presence of any contraindication for undergoing MRCP (e.g., pacemaker). Treatment - 17. Administration of medications that slow gastrointestinal motility (Section 8.6.2). 18. Treatment with rifampicin 19. Treatment with CYP3A4 substrates acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. 20. Treatment with vitamin D or fibrates, unless patient is on a stable dose ≥ 6 months prior to baseline. 21. Exposure to an investigational drug, biologic agent, or medical device within 30 days prior to Screening, or 5 half-lives of the study agent, whichever is longer. Laboratory Exclusions - 22. Platelet count < 150 000/mm3. 23. Albumin level < 3.0 g/dL. 24. International normalised ratio (INR) > 1.4 (the patient may be treated with vitamin K intravenously, and if INR is ≤ 1.4 at resampling, the patient may be enrolled). 25. Advanced renal disease (glomerular filtration rate [GFR] < 70 mL/min/1.73 m2 ) Miscellaneous - 26. Any other conditions or abnormalities which, in the opinion of the investigator (or designee), may compromise the safety of the patient or interfere with the patient participating in or completing the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is safety and tolerability as determined by the incidence of treatment-emergent adverse events (TEAEs) through Week 12

Secondary endpoints 1

1. • PK parameters for A3907 including, but not limited to, Cmax, and area under the plasma AUC • Change from Baseline to Week 12 in serum and urine individual and total bile acid levels • Change from baseline to Week 12 in liver transaminases (ALT and AST), GGT, ALP and total and direct bilirubin levels. • Change from Baseline to Week 12 in 7α-hydroxy-4-cholesten-3-one (C4)

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Albireo AB

Sponsor organisation

Albireo AB

Address

Arvid Wallgrens Backe 20, Goteborgs Annedal Goteborgs Annedal

City

Goteborg

Postcode

413 46

Country

Sweden

Scientific contact point

Organisation

Albireo AB

Contact name

Jan P. Mattsson

Public contact point

Organisation

Albireo AB

Contact name

Jan P. Mattsson

Third parties 19

Albireo AB

Sponsor organisation

Albireo AB

Address

S Annedal, Arvid Wallgrens Backe 20, Goteborgs Annedal Arvid Wallgrens Backe 20 Goteborgs Annedal

City

Goteborg

Postcode

413 46

Country

Sweden

Third parties 19

Locations

4 EU/EEA countries · 8 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 74 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