Pyridoxine in primary sclerosing cholangitis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

19 Jun 2024 → ongoing

Decision date (initial)

2023-11-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Regional Health Authority of South-Eastern Norway (Helse Sør-Øst) · European Research Council

External identifiers

EU CT number

2023-505155-47-00

WHO UTN

U1111-1294-5024

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To show the superiority of pyridoxine compared to placebo in the treatment of PSC as assessed by reduction of alkaline phosphatase levels

Secondary objectives 10

1. Evaluate the impact of pyridoxine treatment on markers of vitamin B6 storage and deficiency
2. Determine the effect of pyridoxine on other liver enzymes and liver function tests
3. Determine the impact of pyridoxine treatment on markers of fibrosis
4. Determine the impact of pyridoxine treatment on markers of inflammation
5. Evaluate the effect of pyridoxine on clinical risk scores in PSC
6. To assess the effect of pyridoxine on quality of life
7. To assess the effect of pyridoxine on fatigue and pruritus
8. Determine the safety and tolerability of 40 mg pyridoxine in PSC
9. Evaluate the impact of lower dose pyridoxine treatment (corresponding to daily recommended intake) on markers of vitamin B6 storage and deficiency
10. To assess the effect on alkaline phosphatase levels of 40 mg pyridoxine for 12 weeks followed by 1.6 mg for 12 weeks

Conditions and MedDRA coding

Primary sclerosing cholangitis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participant must be > 18 years of age and < 75 years of age at the time of signing the informed consent.
2. Participants with a confirmed diagnosis of large-duct PSC, verified by retrograde, operative, percutaneous or magnetic resonance cholangiography demonstrating intrahepatic and/or extrahepatic biliary duct changes such as beading or narrowing consistent with PSC.
3. Alkaline phosphatase > upper limit of normal reference (105 U/L) at screening.
4. All patients must have been investigated by colonoscopy at least once. Patients with concomitant IBD must have colonoscopy available within the last 24 months prior to screening.
5. If concomitant IBD, any colitis should be in remission or show mild activity over 12 weeks prior to screening.
6. Participants on treatment with biologics, immunosuppressives or corticosteroids must be taking a stable dose for at least 12 weeks prior to screening and expected to remain on the same medication for the duration of the study.
7. Participants with ursodeoxycholic acid or bezafibrate treatment on a stable dose for at least 12 weeks prior to screening
8. If concomitant autoimmune hepatitis, a stable dose of immunosuppression over the last 12 months is required (e.g., prednisone, budesonide, azathioprine).
9. Capable of giving written informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
10. Capable of responding to patient questionnaires
11. Must be able to understand Norwegian

Exclusion criteria 18

1. History or presence of other competing liver diseases including a. Positive hepatitis B or C serology b. Primary biliary cholangitis c. Wilson’ disease d. Hemochromatosis e. Biopsy verified non-alcoholic steatohepatitis (NASH) f. Cholangiocarcinoma g. Chronic alcohol consumption defined as a daily consumption of 3 units/day (36 gr/d) for males and 2 units/day (24gr/day) for females h. α1-antitrypsin deficiency i. congenital biliary disease
2. Current or history of colonic cancer or all-grade dysplasia described at the last colonoscopy.
3. History of other malignancy of extra-hepatic origin within the last 3 years (recent localized treatment of squamous or non-invasive basal skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screening).
4. Any severe competing cardiovascular, renal, endocrine, or psychiatric disorder, which of the opinion of the investigator might have an influence on the patient’s compliance or the interpretation of the results.
5. Drug abuse, regular use of recreational drugs within the last year, or any conditions associated with poor compliance.
6. Vitamin B6 supplementation, any form or dose including standard multivitamins, previous 12 weeks to inclusion.
7. Ongoing therapy with levodopa, isoniazid, hydralazine or penicillamine due to drug interactions
8. Previous liver transplantation or anticipated need for liver transplantation within 6 months or listing for liver transplantation.
9. Endoscopic treatment for bile duct stenosis 12 weeks prior to screening or planned within 12 weeks after inclusion.
10. Secondary causes of sclerosing cholangitis such as iatrogenic bile duct injury, IgG4- associated cholangitis, sepsis, and burns.
11. Small duct cholangitis in the absence of large duct disease.
12. Liver cirrhosis with a Child-Pugh B or C classification as defined by; history of variceal bleeding, hepatic encephalopathy, or resistant ascites.
13. History of bacterial cholangitis with hospitalization within 12 weeks prior to screening.
14. Colectomy or any other colorectal resections.
15. Breastfeeding or pregnancy.
16. Diagnosis of HIV.
17. Hepatocellular carcinoma or other hepatobiliary malignancy.
18. 18. Participants concurrently, or within last 12 weeks, receiving study medication while included in other clinical trials.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Difference in mean change of alkaline phosphatase (ALP) between the 12-week pyridoxine phase and the 12-week placebo phase

Secondary endpoints 11

1. Difference in mean change in PLP levels and HKratio between the 12-week pyridoxine phase and the 12-week placebo phase
2. Changes in ALAT, ASAT, GGT, total bilirubin between the 12-week pyridoxine phase and the 12-week placebo phase
3. Difference in mean change in the Enhanced Liver Fibrosis test (ELF) between the 12-week pyridoxine phase and the 12-week placebo phase
4. Difference in mean change in interleukin-8 and neopterin between the 12-week pyridoxine phase and the 12-week placebo phase
5. Difference in mean change in PSC-specific revised Mayo risk score; the Amsterdam-Oxford model (AOM); PREsTo; between the 12-week pyridoxine phase and the 12-week placebo phase
6. Difference in mean change in SF-36 Physical summary scale and Mental summary scale between the 12-week pyridoxine phase and the 12-week placebo phase
7. Difference in mean change of fatigue, evaluated by the Fatigue Impact Scale (FIS) fatigue and a fatigue numerical rating scale (NRS) between the 12-week pyridoxine phase and the 12-week
8. Difference in mean change of a pruritus numerical rating scale (NRS) between the 12-week pyridoxine phase and the 12-week placebo phase
9. Number of adverse events and serious adverse advents during the study period
10. Change in PLP levels and HKratio after open label treatment 12 weeks of 40 mg pyridoxine and 12 weeks of 1.6 mg pyridoxine
11. Change in alkaline phosphatase levels after open label treatment 12 weeks of 40 mg pyridoxine and 12 weeks of 1.6 mg pyridoxine

Investigational products

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

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Johannes R Hov

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Johannes R Hov

Locations

1 EU/EEA country · 2 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