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Trial registered on ANZCTR


Registration number
ACTRN12619001373167
Ethics application status
Approved
Date submitted
3/09/2019
Date registered
9/10/2019
Date last updated
9/10/2019
Date data sharing statement initially provided
9/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Using a plant metabolite (quercetin) to optimise medication (mesalazine) metabolism to treat Primary Sclerosing Cholangitis
Scientific title
Quercetin as an Adjunct to Primary Sclerosing Cholangitis Therapy with 5-ASA through Inhibition of N-acetylation
Secondary ID [1] 299022 0
None
Universal Trial Number (UTN)
Trial acronym
QAPTAIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
primary sclerosing cholangitis 314029 0
inflammatory bowel disease 314030 0
ulcerative colitis 314031 0
Condition category
Condition code
Oral and Gastrointestinal 312416 312416 0 0
Inflammatory bowel disease
Oral and Gastrointestinal 312417 312417 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Inflammatory and Immune System 312418 312418 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pharmacokinetic Pilot Study

Mesalazine (5-ASA) is an effective first-line therapy for patients with UC however there are no reports, positive or negative, of efficacy in PSC. 5-ASA is known to be rapidly N-acetylated once it is absorbed in the colon and released into the blood. N-acetylation inactivates 5-ASA, likely negating its effect before it reaches the biliary duct. Some 5-ASA escapes the intestine without being metabolized and is subsequently acetylated in the liver. The enzyme responsible for the N-acetylation is N- acetyltransferase 1, or NAT-1. NAT-1 is present in the lining of the intestine as well as in the liver.

Quercetin is a flavonoid found in fruits and vegetables that has been shown to inhibit NAT-1. Quercetin was reviewed by the Food and Drug Administration (FDA) in 2010 and was given “generally recognised as safe” (GRAS) designation at a dose of 1500mg/d.

We propose that 5-ASA may be an effective therapy for primary sclerosing cholangitis (PSC). However, 5-ASA is metabolized to an inactive form preventing active 5-ASA to be able exert a therapeutic effect on the liver and biliary tree in PSC. Quercetin has been shown to inhibit N-acetyl transferase 1, the enzyme that metabolizes 5-ASA. Quercetin may also be therapeutic in PSC based on its anti-inflammatory properties. This pilot study aims to test if quercetin has a therapeutic potential in PSC by inhibiting NAT-1 and delivering active 5-ASA at a higher concentration to the liver. If successful, subsequent studies will examine its therapeutic potential in PSC.

Participants already taking 5-ASA (4g daily, oral tablets or granules) will be enrolled. After the initial visit for screening and consent, participants will be instructed to continue their oral 5-ASA 4g tablets or granules, once a day in the morning before food.

For baseline results without quercetin supplmentation, participants will return to the study centre on day 7 after continuing their prescribed 5-ASA regimen to complete two questionnaires (disease activity & quality of life) and have blood tests & stool tests collected.

During the intervention period, participants will continue their oral 5-ASA 4g daily and in addition, take oral quercetin 1500mg daily for 7 days (split dosing 1000mg in the morning 1 hour after 5-ASA and 500mg in the evening, formulated as encapsulated powder). For post-intervention results, participants will return to the study centre on day 14 of the study after having taken 7 days of 5-ASA and quercetin to complete two questionnaires (disease activity & quality of life) and have blood tests & stool tests collected.

Adherence to 5-ASA & quercetin during the study will be monitored through the use of a medication diary. A food diary will be maintained to account for unexpected significant variations in quercetin levels. Participants do not need to modify their usual diet for this study.

The intervention involves adding quercetin supplement to the usual medication regimen. There is no washout period.
Intervention code [1] 315288 0
Treatment: Drugs
Comparator / control treatment
Participants will serve as their own control
Levels of quercetin, 5-ASA and n-acetyl-5-ASA will be measured at baseline and again after 7 days of intervention with quercetin 1500mg daily
Control group
Active

Outcomes
Primary outcome [1] 321067 0
Determine if there is a significant difference between the levels of 5-ASA and N-acetylated 5-ASA measured before and after addition of supplemental quercetin for seven days (quercetin oral 1500mg daily in addition to 5-ASA oral 4g daily)
Levels of 5-ASA, N-acetylated 5-ASA and quercetin will be measured in serum using high performance liquid chromatography.
Timepoint [1] 321067 0
Baseline levels will be measured on day 7 after 7 days without intervention (this is to allow medication & food diary data collection during the baseline period).
Post-intervention levels will be measured on day 14 after 7 days with intervention.
Secondary outcome [1] 373871 0
Measurement of absolute levels of serum quercetin using high performance liquid chromatography. This will examine
- the effect of quercetin supplementation on serum levels
- whether there is a dose-response relationship between the plasma levels of quercetin and the degree of inhibition of 5-ASA N-acetylation.
Timepoint [1] 373871 0
Baseline levels will be measured on day 7 after 7 days without intervention (this is to allow medication & food diary data collection during the baseline period).
Post-intervention levels will be measured on day 14 after 7 days with intervention.
Secondary outcome [2] 373872 0
Assessing change in faecal microbiome before and after taking quercetin for seven days
This will be assessed using metagenomic DNA sequencing, analysis of Shannon diversity (microbial diversity), principal component analysis.
Timepoint [2] 373872 0
Faecal specimens for microbiome analysis will be collected on
- day 7 after 7 days without intervention (this is to allow medication & food diary data collection during the baseline period)
- post-intervention levels will be measured on day 14 after 7 days with intervention.

Eligibility
Key inclusion criteria
1) Age>18
2) A diagnosis of UC
3) Disease in remission (SCCAI < 3 which is accepted as correlating with remission and has been confirmed in prospective validation cohorts, no specific duration of remission mandated)
4) On 5-ASA therapy, ideally on Mezavant at 4.8 g/day or Pentasa at 4 g/day.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Chronic renal impairment (eGFR< 60)
2) Significant liver disease defined as PSC or elevated liver function tests > 1.5 x upper limit of normal
3) Evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites, or
spontaneous hepatic encephalopathy
4) Findings highly suggestive of liver disease of an alternative or concomitant aetiology, including but
not limited to chronic alcoholic liver disease, chronic hepatitis B or C infection, haemochromatosis, Wilson’s disease, a1-antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or secondary sclerosing cholangitis
5) Pregnancy or lactation (due to unknown risk profile of quercetin in pregnancy)
6) Active illicit drug or alcohol abuse
7) Need for chronic use of antibiotics
8) History of cholangiocarcinoma, colon cancer
9) History of a colectomy with > 1/3 bowel resected
10) Taking a polyphenol supplement chronically including resveratrol, curcumin, green tea extract,
quercetin
11) Taking an immunosuppressant or biologic for IBD
12) Hypersensitivity to quercetin

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Nil additional relevant design features
Phase
Phase 0
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Statistical analysis for this pilot study will be done with testing for significance via the paired T-test

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
14/10/2019
Actual
Date of last participant enrolment
Anticipated
13/04/2020
Actual
Date of last data collection
Anticipated
13/07/2020
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 14551 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 27563 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 303554 0
Other Collaborative groups
Name [1] 303554 0
IBD Clinical Trials Unit, Mater Research Ltd.
Country [1] 303554 0
Australia
Funding source category [2] 303556 0
Hospital
Name [2] 303556 0
Crohn's & Colitis Center, Brigham & Women's Hospital
Country [2] 303556 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
IBD Clinical Trials Unit, Mater Research Ltd.
Address
IBD Clinical Trials Unit, Mater Research Ltd., Aubigny Place
Raymond Terrace
South Brisbane QLD
4101
Country
Australia
Secondary sponsor category [1] 303631 0
None
Name [1] 303631 0
Address [1] 303631 0
Country [1] 303631 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304086 0
Mater Misericordiae Ltd Human Research Ethics Committee (MML HREC) (EC00332)
Ethics committee address [1] 304086 0
Level 2, Aubigny Place
Raymond Terrace
South Brisbane QLD 4101
Ethics committee country [1] 304086 0
Australia
Date submitted for ethics approval [1] 304086 0
28/07/2019
Approval date [1] 304086 0
02/08/2019
Ethics approval number [1] 304086 0
HREC/MML/55758 (V2)

Summary
Brief summary
There is no medical treatment that has been shown to have clinical benefit in primary sclerosing cholangitis (PSC); a condition affecting the liver and bile ducts. Mesalazine (5-ASA) is a first-line medication used for treatment for ulcerative colitis. Ulcerative colitis has a strong association with PSC. 5-ASA is rapidly metabolised before reaching the liver and bile ducts which may restrict its potential benefit in PSC. This study investigates whether a naturally occurring flavonoid, quercetin, may inhibit metabolism of 5-ASA and lead to improved drug delivery to the liver and bile ducts. This study will also explore the impact of quercetin on the bacterial population in the faeces.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95766 0
Dr Jake Begun
Address 95766 0
IBD Clinical Trials Unit, Mater Research Ltd., Room 324 Aubigny Place
1 Raymond Terrace
South Brisbane QLD
4101
Country 95766 0
Australia
Phone 95766 0
+61 731638111
Fax 95766 0
+61731638213
Email 95766 0
[email protected]
Contact person for public queries
Name 95767 0
Jake Begun
Address 95767 0
IBD Clinical Trials Unit, Mater Research Ltd., Room 324 Aubigny Place
1 Raymond Terrace
South Brisbane QLD
4101
Country 95767 0
Australia
Phone 95767 0
+61 731638111
Fax 95767 0
+61731638213
Email 95767 0
[email protected]
Contact person for scientific queries
Name 95768 0
Jake Begun
Address 95768 0
IBD Clinical Trials Unit, Mater Research Ltd., Room 324 Aubigny Place
1 Raymond Terrace
South Brisbane QLD
4101
Country 95768 0
Australia
Phone 95768 0
+61 731638111
Fax 95768 0
+61731638213
Email 95768 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD sharing not planned in view of nature of study being a pilot study with 25 participants.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.