A Trial of BTT1023 in Patients With Primary Sclerosing Cholangitis (BUTEO)

• Sponsor: University of Birmingham
• Collaborators: Biotie Therapies Corp.; University Hospital Birmingham; National Institute for Health Research, United Kingdom
• Information provided by (Responsible Party): University of Birmingham

Study Description

Brief Summary:

This is a phase II study to determine the safety and preliminary efficacy of a human monoclonal antibody (BTT1023) which targets the vascular adhesion protein (VAP-1) and its use in the treatment of patients with primary sclerosing cholangitis (PSC).

Condition or disease	Intervention/treatment	Phase
Primary Sclerosing Cholangitis	Drug: BTT1023	Phase 2

Detailed Description:

Primary sclerosing cholangitis is a progressive immune mediated biliary disease characterised by bile duct inflammation and fibrosis, and accompanying hepatic fibrosis. For patients with elevated alkaline phosphatase (ALP) in particular, progressive disease is predicted, that currently results in a need for liver transplantation in the majority. No current medical therapy has as yet been shown to be effective in altering the natural history of disease. For this reason patients with PSC with elevated ALP values will be recruited to this study, to evaluate the impact of Vap-1 blockade by BTT1023, in an early phase study focused on biochemical efficacy and safety.

This is an early phase study of BTT1023 in immune mediated liver disease, with the rationale to identify biochemical efficacy of effect (reduction in ALP) and safety, in an orphan disease indication for PSC that presently lacks any other medical therapy. The study design therefore focuses on identifying early biochemical efficacy signals to justify larger scale, randomised controlled studies over longer duration.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	41 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Single Arm, Two-stage, Multi-centre, Phase II Clinical Trial Investigating the Safety and Activity of the Use of BTT1023 Targeting Vascular Adhesion Protein (VAP-1), in the Treatment of Patients With Primary Sclerosing Cholangitis (PSC).
Actual Study Start Date :	September 8, 2015
Estimated Primary Completion Date :	January 2019
Estimated Study Completion Date :	March 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: BTT1023; BTT1023 8mg/kg IV infusion, every 14 days (total of 7 infusion). Duration 1-2 hours per infusion.	Drug: BTT1023; IV (in the vein) Investigational Medicinal Product (IMP)

Outcome Measures

Primary Outcome Measures :

1. To determine the activity of the anti-Vap-1 antibody BTT1023 in patients with PSC as measured by a decrease in alkaline phosphatase levels (primary endpoint) with secondary endpoints to include various measures of liver injury and fibrosis. [ Time Frame: 99 days ]
   Vap-1 levels will be measured at multiple times from initiation of treatment, during treatment (78 days) and post treatment.
2. To evaluate the safety and tolerability of BTT1023 in patients with PSC [ Time Frame: 120 days ]
   Biochemical blood tests will be measured throughout the study period, as well as additional cardiology assessments (ECG). The results of these tests will be contribute to the safety evaluation of BTT1023.

Secondary Outcome Measures :

1. To determine the mechanisms of action of BTT1023 through in vivo assessment of SSAO enzyme activity and immune cell function. [ Time Frame: 120 days ]
   SSAO and immune cell assay function will be performed throughout the entire period.
2. To evaluate the potential of a novel MRI based assessment of liver fibrosis and biliary strictures for assessing therapeutic outcome in PSC. [ Time Frame: Baseline and day 120 ]
   MRI imaging of the liver will be performed at two time points (baseline, day 120). This imaging will be assessed using a novel analytical method.
3. Assess the use of sVap-1 as a biomarker to monitor disease progression in PSC. [ Time Frame: 120 days ]
   Multiple measures of the known potential biomarker (sVAP-1) wiil be taken and correlated against clinical outcome throughout the period of the trial.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Males and females 18 - 75 years of age who are willing and able to provide informed, written consent and comply with all study requirements.
• Clinical diagnosis of PSC as evident by chronic cholestasis of more than six months duration with either a consistent MRI showing sclerosing cholangitis or a liver biopsy consistent with PSC in the absence of a documented alternative aetiology for sclerosing cholangitis.
• In those on treatment with UDCA, therapy must be stable for at least 8 weeks, and at a dose not greater than 20mg/kg/day.
• Serum ALP greater than 1.5xULN.
• Female subjects of childbearing potential must have a negative serum pregnancy test prior to starting study treatment. For the purposes of this study, a female subject of childbearing potential is a woman who has not had a hysterectomy, bilateral oophorectomy, or medically-documented ovarian failure. Women ≤ 50 years of age with amenorrhea of any duration will be considered to be of childbearing potential.
• All sexually active women of childbearing potential must agree to use two forms of highly effective method of contraception from the Screening Visit throughout the study period and for 99 days following the last dose of study drug. If using hormonal agents the same method must have been used for at least 1 month before study dosing and subjects must use a barrier method as the other form of contraception. Lactating women must agree to discontinue breast feeding before study investigational medicinal product administration
• Men, if not vasectomized, must agree to use barrier contraception (condom plus spermicide) during heterosexual intercourse from screening through to study completion and for 99 days from the last dose of study investigational medicinal product.

Exclusion Criteria:

• Presence of documented secondary sclerosing cholangitis on prior clinical investigations.
• Presence of alternative causes of liver disease, that are considered by the Investigator to be the predominant active liver injury at the time of screening, including viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis. Patients with possible overlap syndrome with autoimmune hepatitis are excluded if the Investigator considers autoimmune hepatitis as the predominant liver injury.
• AST and ALT > 10 x ULN or Bilirubin >3xULN or INR>1.3 in the absence of anti-coagulants.
• Serum creatinine >130μmol/L or Platelet count <50x109/L.
• Any evidence of hepatic decompensation past or present, including ascites, episodes of hepatic encephalopathy, variceal bleeding.
• Pregnancy or breast feeding.
• Harmful alcohol consumption as evaluated by the investigator.
• Flare in colitis activity within last 90 days requiring intensification of therapy beyond baseline maintenance treatment; use of oral prednisolone >10mg/day, biologics and or hospitalisation for colitis within 90 days.
• Diagnosed cholangiocarcinoma or high clinical suspicion over dominant stricture.
• Active malignancy (within 3 years of diagnosis), other than non-melanomatous skin cancer.
• Major surgical procedure within 30 days of screening or prior organ transplantation.
• Known hypersensitivity to the investigation product or any of its formulation excipients.
• Participation in an investigational trial of a drug or device either within 60 days of screening or 5 half-lifes of the last dose of investigational drug, where the study drug half life is greater than 12 days.
• Any other condition that in the opinion of the investigator renders the subject a poor risk for inclusion into the subject a poor risk for inclusion into the study.
• Positive screening test for tuberculosis (including T-SPOT.TB TB test), unless respiratory review confirms false positive test results.
• Receipt of live vaccination within 6 weeks prior to baseline visit.
• Known HIV positive status.

Contacts and Locations

Contacts

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Contact: Gideon Hirschfield, MD	+44 121 414 3823	g.hirschfield@bham.ac.uk
Contact: Anna Rowe, PhD	+44 121 371 8117	a.l.rowe@bham.ac.uk

Locations

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United Kingdom
Queens Medical Centre	Recruiting
Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
Principal Investigator: Guruprasad Aithal, MD
University Hospitals Birmingham NHS Foundation Trust	Recruiting
Birmingham, West Midlands, United Kingdom, B15 2TH
Principal Investigator: Gideon Hirschfield, MD
Sub-Investigator: Prof David Adams, MD
Royal Victoria Infirmary	Recruiting
Newcastle, United Kingdom
Principal Investigator: Mark Hudson, MD
John Radcliffe	Recruiting
Oxford, United Kingdom
Principal Investigator: Ellie Barnes, MD

Sponsors and Collaborators

University of Birmingham

Biotie Therapies Corp.

University Hospital Birmingham

National Institute for Health Research, United Kingdom

Investigators

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Principal Investigator:	Gideon Hirschfield, MD	University of Birmingham

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Arndtz K, Corrigan M, Rowe A, Kirkham A, Barton D, Fox RP, Llewellyn L, Athwal A, Wilkhu M, Chen YY, Weston C, Desai A, Adams DH, Hirschfield GM; BUTEO trial team. Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): A single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol. BMJ Open. 2017 Jul 3;7(6):e015081. doi: 10.1136/bmjopen-2016-015081.

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Responsible Party:	University of Birmingham
ClinicalTrials.gov Identifier:	NCT02239211 History of Changes
Other Study ID Numbers:	RG_13-027; 2014-002393-37 ( EudraCT Number )
First Posted:	September 12, 2014
Last Update Posted:	June 14, 2017
Last Verified:	June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by University of Birmingham:

BUTEO; Primary sclerosing cholangitis; PSC	VAP-1; BTT1023; Human monoclonal antibody

Additional relevant MeSH terms:

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Cholangitis; Cholangitis, Sclerosing; Bile Duct Diseases; Biliary Tract Diseases	Digestive System Diseases; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs