Primary Sclerosing Cholangitis
Conditions
Keywords
PSC, Primary Sclerosing Cholangitis
Brief summary
This study will test a drug called A3907 to see how safe and tolerated it is for treating people with Primary Sclerosing Cholangitis (PSC).
Detailed description
This study will test a drug called A3907 to see how safe and tolerated it is for treating people with Primary Sclerosing Cholangitis (PSC). Detailed Description: The primary goal of this study in participants with PSC with and without a Clinically Relevant Stricture (CRS) who are treated with A3907 is to assess the safety and tolerability of A3907 following repeat doses. Secondary goals include evaluation of the pharmacokinetic properties of A3907 (the study of how the body interacts with A3907 for the entire duration of exposure) and changes in safety parameters via laboratory testing such as liver enzymes, bile acid levels and markers of bile acid synthesis
Interventions
DRUGRitivixibat
10mg tablet A3907 administered orally
Sponsors
Albireo, an Ipsen Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: 1. Adults between 18 and 75 years of age (inclusive) 2. Clinical diagnosis of large-duct PSC as evidenced by chronic cholestasis 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. Women of nonchildbearing potential (WONCBP) have a confirmatory follicle-stimulating hormone \[FSH\] level ≥ 40 mIU/mL 5. Alkaline phosphatase Phosphatase (ALP) value \> 1.5 × upper limit of normal (ULN) but ≤ 10 × ULNULN 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 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 Key
Exclusion criteria
1. Presence of documented secondary sclerosing cholangitis, small duct PSC, known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis or other causes of chronic liver disease 2. Arm 1-3 Only: Biliary intervention within 3 months prior to study enrollment or planned. 3. Arm 4 Only: Planned Biliary intervention between the Screening Period and baseline. 4. Presence of alternative causes of chronic liver disease, including alcohol-associated liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis, autoimmune hepatitis, or active hepatitis B or C. 5. 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. 6. History of human immunodeficiency virus infection or any other known relevant infection (e.g. tuberculosis). 7. History of ileectomy, colostomy or colectomy. 8. History of malignancy, including hepatocellular carcinoma and cholangiocarcinoma 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. 9. Alpha-fetoprotein (AFP) \> 20 ng/mL (at the Screening Visit) with 4-phase liver CT or MRI suggesting presence of liver cancer. 10. History of transplants, including liver transplantation, or currently on active transplantation list (Arms 1 3). Arm 4 may be on an active liver transplantation list. 11. Current or a history of hepatic decompensation events including, but not limited to ascites, encephalopathy, or history of esophageal variceal bleeding. 12. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis. 13. Small duct PSC (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography) without large duct PSC. 14. Liver cirrhosis as assessed by any of the following: 1. historical liver histology. 2. liver stiffness measurement, assessed by FibroScan (FibroScan value \> 14.4 kPa), in addition to clinical assessment and biochemical markers at the discretion of the investigator. 3. signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal haemorrhage, and/or hepatic encephalopathy). 15. History of bacterial cholangitis within 60 days prior to the Screening Period, or if the patient is on antibiotics for prophylaxis of recurrent cholangitis. 16. Females who are pregnant, lactating, or breast feeding. 17. 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. 18. Hypersensitivity to investigational medicinal product (A3907) and its excipients. 19. Presence of any contraindication for undergoing MRCP (e.g. pacemaker). 20. Any other condition or abnormality 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. 21. Administration of medications that slow gastrointestinal motility. 22. Treatment with rifampicin. 23. Exposure to oral drugs that are strong inhibitors or inducers of CYP3A4 enzymes (e.g. grapefruit juice, ritonavir, itraconazole, ketoconazole, troleandomycin, rifampin, St John's wort, etc.) within 14 days prior to the Screening Period, or 5 half-lives of the drug, whichever is longer. 24. Exposure to oral drugs that are substrates of CYP3A4 enzymes (e.g. codeine, ciclosporin \[cyclosporin\], diazepam, etc.) during the study. 25. Treatment with vitamin D or fibrates, unless patient is on a stable dose ≥ 6 months prior to baseline. 26. Exposure to an investigational drug, biologic agent, or medical device within 30 days prior to the Screening Period, or 5 half-lives of the study agent, whichever is longer. 27. Platelet count \< 150 000/mm3 28. Albumin level \< 3.0 g/dL 29. INR \> 1.3 (the patient may be treated with vitamin K intravenously, and if INR is ≤ 1.3 at resampling, the patient may be enrolled). 30. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget's disease). A GGT or ALP isoenzymes should be obtained for confirmation of biliary origin; 31. Glomerular filtration rate \[GFR\] \< 60 mL/min/1.73 m2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From first dose of study drug (Day 1) up to 14 days post last dose, approximately 112 days | An adverse event (AE) was any untoward medical occurrence in an enrolled participant regardless of causal relationship with study drug. An SAE was defined as any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or an important medical event. A TEAE was any AE or worsening of an existing disease that occurred after the first dose of study drug and within the 14-day follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of A3907 | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-dose on Days 0 and 98 | Blood samples were collected at specified timepoints to assess Cmax of A3907. The pharmacokinetic (PK) analysis was conducted after single dose (Day 0) and repeated dose administration (Day 98). |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time t (Time of Last Quantifiable Plasma Concentration) (AUC0-t) of A3907 | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10 hours post-dose on Days 0 and 98 | Blood samples were collected at specified timepoints to assess AUC0-t of A3907. |
| Change From Baseline to Week 12 in Serum and Urine Individual and Total Bile Acid Levels | Baseline (Day 1) and Week 12 | Blood and urine samples were collected at specified timepoints to assess serum and urine individual and total bile acid levels. Baseline=average of all screening results and results on day of planned single dose if both results were available. Otherwise, baseline=last non-missing assessment prior to study drug administration of planned single dose. CA=Cholic Acid; LCA=lithocholic acid; DCA=deoxycholic acid; CDCA=chenodeoxycholic acid; UDCA= ursodeoxycholic acid; GCA=glycocholic acid; GLCA=glycolithocholic acid; GDCA=glycodeoxycholic acid; GCDCA=glycochenodeoxycholic acid; GUDCA= glycoursodeoxycholic acid; TCA=taurocholic acid; TCDCA=taurochenodeoxycholic acid; TDCA=taurodeoxycholic acid; TLCA=taurolithocholic acid; TUDCA=tauroursodeoxycholic acid; S=sulfate. Calculated total bile acids without all UDCA bile acids is the sum of all individual bile acids excluding all UDCAs (UDCA, GUDCA, TUDCA). Conjugated bile acids include GCA, GLCA, GDCA, GCDCA, GUDCA, TCA, TCDCA, TDCA, TLCA, TUDCA. |
| Change From Baseline to Week 12 in Liver Biochemical Tests (LBTs): Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase (GGT) and Alkaline Phosphatase (ALP) | Baseline (Day 1) and Week 12 | Blood samples were collected at specified timepoints to assess LBTs. Baseline was defined as the average of all screening results and results on the day of the planned single dose if both results were available. Otherwise, baseline was defined as the last non-missing assessment prior to the study drug administration of planned single dose. |
| Change From Baseline to Week 12 in Liver Biochemical Tests: Total and Direct Bilirubin Levels | Baseline (Day 1) and Week 12 | Blood samples were collected at specified timepoints to assess LBTs. Baseline was defined as the average of all screening results and results on the day of the planned single dose if both results were available. Otherwise, baseline was defined as the last non-missing assessment prior to the study drug administration of planned single dose. |
| Change From Baseline to Week 12 in 7α-hydroxy-4-cholesten-3-one (C4) | Baseline (Day 1) and Week 12 | Blood samples were collected at specified timepoints to assess C4. Baseline was defined as the assessment performed on the day of the planned single dose. |
| Change From Baseline to Week 12 in Fibroblast Growth Factor 19 (FGF-19) | Baseline (Day 1) and Week 12 | Blood samples were collected at specified timepoints to assess FGF-19. Baseline was defined as the assessment performed on the day of the planned single dose. |
Countries
France, Italy, Poland, Spain
Contacts
STUDY_DIRECTORIpsen Medical Director
Ipsen
Participant flow
Recruitment details
This Phase II, open-label study was conducted at 8 investigational sites in 4 countries in adults with primary sclerosing cholangitis (PSC). A total of 18 participants were enrolled in the study.
Pre-assignment details
The study consisted of a 2-week screening period followed by administration of a single dose of A3907 followed by a 2-week period to confirm if the target exposure was reached before beginning a treatment period of 12 weeks. The study was terminated early due to Sponsor decision, not due to any safety concerns. No participant was enrolled in A3907 30 milligram (mg) twice daily (BID) without clinically relevant stricture (CRS) arm as the study was terminated prior to enrollment in that arm.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 10.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 5 / 8 | 6 / 6 | 3 / 4 |
| serious Total, serious adverse events | 0 / 8 | 1 / 6 | 0 / 4 |
Outcome results
None listed