PancreatitisPhase 4NCT02281799
Thiopurine Induced Pancreatitis in IBD Patients
A Phase 4 study testing Azathioprine in people with Pancreatitis and Inflammatory Bowel Diseases, run by Shaare Zedek Medical Center at 1 site in Israel.
Trial summary
Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) were developed over 50 years ago by Gertrude Elion and George Hitchings and were initially used clinically in the management of childhood leukemia and organ transplantation. Read more about this study
- Who is it for?
- Ages 5 to 60 years
- Conditions the study is for
- Pancreatitis, Inflammatory Bowel Diseases
- What is being tested?
- Azathioprine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteIsrael
- Study dates
- Mar 2015to Jan 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Patients diagnosed with IBD, treated previously with thiopurines, and ceased treatment due to suspected thiopurine-induced pancreatitis
- Ability to consent to and participate in the study and follow study procedures
- Age 5-60 years
Who cannot join
- Previous severe pancreatitis requiring prolonged hospital admission or intensive care involvement, or Ranson's criteria ≥ 3
- No clinical need to reintroduce a thiopurine for management of IBD at the time of the study (e.g. stable on another medication, or mild phenotype of disease), based on clinical assessment of treating gastroenterologist
- Diagnosis of recurrent pancreatitis syndrome
- Diabetes mellitus or any other neuropathy which may dampen the clinical presentation of pancreatitis
- Known or suspected allergy or intolerance to thiopurines, besides previous pancreatitis
- Any other laboratory or clinical condition that the investigator considers clinically significant that could impact the outcome of the study or the safety of the patient.
Trial locations and contacts
1 site in 1 country.
About this study
Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) were developed over 50 years ago by Gertrude Elion and George Hitchings and were initially used clinically in the management of childhood leukemia and organ transplantation.
The first case report of 6-MP use in inflammatory bowel disease (IBD) was from 1962 , and since then the use of thiopurines has been well established in the management of moderate to severe IBD.
Read more
Thiopurines offer an inexpensive and effective treatment option for maintenance of remission of IBD in comparison to biological agents which may be 30 times more expensive .
Although 50-60% of IBD patients respond to thiopurines, a significant proportion of patients will not tolerate them due to various adverse effects . The adverse effects of thiopurines may be dose related, patient related or idiosyncratic.
The immunosuppressive effects of thiopurines also increase the rates of opportunistic infections.
Thiopurines are also associated with a higher rate of malignancies, particularly a malignant Burkitt-like lymphoma, related to Epstein-Barr virus infection . Other adverse effects of thiopurine relate to allergic phenomenon.
An idiosyncratic adverse effect of thiopurine use is acute pancreatitis (AP).
Acute inflammation of the pancreas defined by INSPPIRE criteria:
requiring 2 of:
- Abdominal pain compatible with AP
- Serum amylase and/or lipase ≥ 3 times upper limits of normal
- Imaging findings of AP
Drug induced AP is the assumed diagnosis when no other cause of AP can be found, the patient is taking a drug known to be associated with AP, and symptoms resolve after drug discontinuation. If pancreatitis re-occurs on re-exposure, the drug is definitely considered the cause.
While drugs are considered a rare cause of AP and most cases are mild and self limited , there is an 8 fold higher risk of AP in IBD patients treated with AZA . Thiopurine induced AP is usually detected within 4 weeks of starting treatment.
However in the case of thiopurine induced AP, there has been no clear understanding of the mechanism.
Thiopurine induced AP is generally considered an indication to cease thiopurine therapy, due to the assumed risk of recurrence of AP on reintroduction.
There exists several case reports and anecdotal evidence that reintroducing thiopurines following an assumed thiopurine associated AP can be well tolerated.
The investigators hypothesize that AZA and/or 6-MP can be safely reintroduced in the management of IBD patients following thiopurine-induced pancreatitis.
If in the past the patients were treated with AZA, they will now be commenced on 6-MP, and if in the past they were treated with 6-MP, they will be commenced on AZA.
Read the detailed description
The research protocol extends for up to 3.5 months, during which the participant will attend 5 clinic visits at Shaare Zedek Medical Centre: screening visit, week 0, week 4, week 8 and week 12.
During the screening visit, all patients identified who meet the exclusion and inclusion criteria and who agree to participate in the study, will have their medical records reviewed for previous clinical or biochemical evidence of pancreatitis, both related, and unrelated to thiopurine use.
Patients will undergo a physical examination, baseline blood tests including measurement of lipase and/or amylase, liver biochemistry and fasting lipid profile. If not already tested, the patients TPMT activity will be tested. Participants will also have a baseline abdominal ultrasound to confirm normal anatomy and absence of cholelithiasis At week 0, if there are no clinical, biochemicals or ultrasound suggestions of pancreatitis, the participant will be commenced on an alternative thiopurine from what was used in the past. That is, if in the past they were treated with AZA, they will now be commenced on 6-MP, and if in the past they were treated with 6MP, they will be commenced on AZA. The medications will be commenced at standard dose (ie AZA 2.5mg/kg/day, 6MP 1.5mg/kg/day). Depending on the specific situation, and assuming all relevant information is available, the screening visit may be merged with the week 0 visit.
In weeks 1, 2, 3 and 6 will have blood tests (full blood count and liver biochemistry) performed at a local clinic, and the investigator will be in telephone contact with the participant to discuss the results and to discuss if there are any adverse effects of the medication.
In weeks 4, 8 and 12 the participant will attend clinic with the investigator for a medical history, clinical examination and review of blood tests (blood count and liver enzymes).
In the event of any new onset upper abdominal pain or emesis, patients will be instructed to present to their nearest medical facility for blood tests (including serum amylase and/or lipase) and an ultrasound, if clinically indicated, to contact the investigator and to consider cessation of the thiopurine.
At the end of the 3 month period, if patients show no sign of pancreatitis, they will revert to regular monitoring of thiopurine therapy as per their treating gastroenterologist.
- Conditions
- Pancreatitis, Inflammatory Bowel Diseases
- Being tested
- Azathioprine
- Keywords
- Azathioprine (AZA), 6-mercaptopurine (6-MP), Thiopurine-S-methyltransferase (TPMT), Xanthine oxidase (XO), 6-thioguanine (6-TGN), 6-methyl-mercaptopurine (6-MMP), inflammatory bowel disease (IBD), acute pancreatitis (AP), inosine triphosphate pyrophosphohydrolase (ITPA), rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), Crohn's disease (CD), ulcerative colitis (UC)
- Medical subject headings
- Pancreatitis, Inflammatory Bowel Diseases, Arthritis, Rheumatoid, Crohn Disease, Colitis, Ulcerative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzathioprineDrug
Also called 6-mercaptopurine
Patients will be commenced on an alternative thiopurine to that used initially, according to the standard dosing schedule used by their IBD clinician.
For example, if the initial thiopurine-related pancreatitis occurred while taking Azathioprine, the patient will be restarted on 6-MP, and vice versa.
| Study group | Role | What they receive |
|---|---|---|
| Open label | Experimental | 10 patients diagnosed with IBD, treated previously with thiopurines and ceased treatment due to suspected thiopurine-induced pancreatitis.
Patients will be commenced on an alternative thiopurine to that used initially,. The medications will be commenced at standard dose (ie Azathioprine 2.5mg/kg/day, 6-MP 1.5mg/kg/day). Receives: Drug: Azathioprine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants demonstrating biochemical or clinical evidence of pancreatitis
Measured: 3 month period following intervention
Secondary outcomes (1)
Number of participants with adverse events or hospitalization experienced as a result of intervention
Measured: 3 month period following intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2014 (estimated)
- Study startMar 2015
- Primary completionJan 2018
- Study completionJan 2018
Why it stopped: No Participants Enrolled
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PancreatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shaare Zedek Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Sydney Children's Hospitals Network, Christchurch Hospital
- Responsible party
- Sponsor
- Investigators
- Oren Ledder, MD, Principal investigator, Shaare Zedek Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02281799
- Sponsor's protocol ID
- Thiopurine_Pancreatitis
- Status last verified
- Oct 2017
- First submitted
- 23 Oct 2014
- Last updated
- 18 Mar 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Thiopurine Induced Pancreatitis in IBD Patients
- ClinicalTrials.gov ID
- NCT02281799
- Acronym / sponsor ID
- Thiopurine_Pancreatitis
- Conditions
- Pancreatitis, Inflammatory Bowel Diseases
- Keywords
- Azathioprine (AZA), 6-mercaptopurine (6-MP), Thiopurine-S-methyltransferase (TPMT), Xanthine oxidase (XO), 6-thioguanine (6-TGN), 6-methyl-mercaptopurine (6-MMP), inflammatory bowel disease (IBD), acute pancreatitis (AP)
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: No Participants Enrolled
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Shaare Zedek Medical CenterUniversity, hospital or other
- Collaborators
- Sydney Children's Hospitals Network, Christchurch Hospital
- Study start
- Mar 2015
- Primary completion
- Jan 2018 (actual)
- Study completion
- Jan 2018 (actual)
- First posted
- 4 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) were developed over 50 years ago by Gertrude Elion and George Hitchings and were initially used clinically in the management of childhood leukemia and organ transplantation.
The first case report of 6-MP use in inflammatory bowel disease (IBD) was from 1962 , and since then the use of thiopurines has been well established in the management of moderate to severe IBD.
Thiopurines offer an inexpensive and effective treatment option for maintenance of remission of IBD in comparison to biological agents which may be 30 times more expensive .
Although 50-60% of IBD patients respond to thiopurines, a significant proportion of patients will not tolerate them due to various adverse effects . The adverse effects of thiopurines may be dose related, patient related or idiosyncratic.
The immunosuppressive effects of thiopurines also increase the rates of opportunistic infections.
Thiopurines are also associated with a higher rate of malignancies, particularly a malignant Burkitt-like lymphoma, related to Epstein-Barr virus infection . Other adverse effects of thiopurine relate to allergic phenomenon.
An idiosyncratic adverse effect of thiopurine use is acute pancreatitis (AP).
Acute inflammation of the pancreas defined by INSPPIRE criteria:
requiring 2 of:
- Abdominal pain compatible with AP
- Serum amylase and/or lipase ≥ 3 times upper limits of normal
- Imaging findings of AP
Drug induced AP is the assumed diagnosis when no other cause of AP can be found, the patient is taking a drug known to be associated with AP, and symptoms resolve after drug discontinuation. If pancreatitis re-occurs on re-exposure, the drug is definitely considered the cause.
While drugs are considered a rare cause of AP and most cases are mild and self limited , there is an 8 fold higher risk of AP in IBD patients treated with AZA . Thiopurine induced AP is usually detected within 4 weeks of starting treatment.
However in the case of thiopurine induced AP, there has been no clear understanding of the mechanism.
Thiopurine induced AP is generally considered an indication to cease thiopurine therapy, due to the assumed risk of recurrence of AP on reintroduction.
There exists several case reports and anecdotal evidence that reintroducing thiopurines following an assumed thiopurine associated AP can be well tolerated.
The investigators hypothesize that AZA and/or 6-MP can be safely reintroduced in the management of IBD patients following thiopurine-induced pancreatitis.
If in the past the patients were treated with AZA, they will now be commenced on 6-MP, and if in the past they were treated with 6-MP, they will be commenced on AZA.
Detailed description
The research protocol extends for up to 3.5 months, during which the participant will attend 5 clinic visits at Shaare Zedek Medical Centre: screening visit, week 0, week 4, week 8 and week 12.
During the screening visit, all patients identified who meet the exclusion and inclusion criteria and who agree to participate in the study, will have their medical records reviewed for previous clinical or biochemical evidence of pancreatitis, both related, and unrelated to thiopurine use.
Patients will undergo a physical examination, baseline blood tests including measurement of lipase and/or amylase, liver biochemistry and fasting lipid profile. If not already tested, the patients TPMT activity will be tested. Participants will also have a baseline abdominal ultrasound to confirm normal anatomy and absence of cholelithiasis At week 0, if there are no clinical, biochemicals or ultrasound suggestions of pancreatitis, the participant will be commenced on an alternative thiopurine from what was used in the past. That is, if in the past they were treated with AZA, they will now be commenced on 6-MP, and if in the past they were treated with 6MP, they will be commenced on AZA. The medications will be commenced at standard dose (ie AZA 2.5mg/kg/day, 6MP 1.5mg/kg/day). Depending on the specific situation, and assuming all relevant information is available, the screening visit may be merged with the week 0 visit.
In weeks 1, 2, 3 and 6 will have blood tests (full blood count and liver biochemistry) performed at a local clinic, and the investigator will be in telephone contact with the participant to discuss the results and to discuss if there are any adverse effects of the medication.
In weeks 4, 8 and 12 the participant will attend clinic with the investigator for a medical history, clinical examination and review of blood tests (blood count and liver enzymes).
In the event of any new onset upper abdominal pain or emesis, patients will be instructed to present to their nearest medical facility for blood tests (including serum amylase and/or lipase) and an ultrasound, if clinically indicated, to contact the investigator and to consider cessation of the thiopurine.
At the end of the 3 month period, if patients show no sign of pancreatitis, they will revert to regular monitoring of thiopurine therapy as per their treating gastroenterologist.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open label | Experimental | Drug: Azathioprine10 patients diagnosed with IBD, treated previously with thiopurines and ceased treatment due to suspected thiopurine-induced pancreatitis. Patients will be commenced on an alternative thiopurine to that used initially,. The medications will be commenced at standard dose (ie Azathioprine 2.5mg/kg/day, 6-MP 1.5mg/kg/day). |
Who may qualify
- Ages
- 5 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- Patients diagnosed with IBD, treated previously with thiopurines, and ceased treatment due to suspected thiopurine-induced pancreatitis
- Ability to consent to and participate in the study and follow study procedures
- Age 5-60 years
Key exclusion criteria (6 listed)
- Previous severe pancreatitis requiring prolonged hospital admission or intensive care involvement, or Ranson's criteria ≥ 3
- No clinical need to reintroduce a thiopurine for management of IBD at the time of the study (e.g. stable on another medication, or mild phenotype of disease), based on clinical assessment of treating gastroenterologist
- Diagnosis of recurrent pancreatitis syndrome
- Diabetes mellitus or any other neuropathy which may dampen the clinical presentation of pancreatitis
- Known or suspected allergy or intolerance to thiopurines, besides previous pancreatitis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzathioprineAlso: 6-mercaptopurinePatients will be commenced on an alternative thiopurine to that used initially, according to the standard dosing schedule used by their IBD clinician. For example, if the initial thiopurine-related pancreatitis occurred while taking Azathioprine, the patient will be restarted on 6-MP, and vice versa. | Drug | Open label |
Primary outcome
Number of participants demonstrating biochemical or clinical evidence of pancreatitis
Time frame: 3 month period following intervention
1 secondary outcome
Number of participants with adverse events or hospitalization experienced as a result of intervention
Time frame: 3 month period following intervention
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Oren Ledder, MD principal investigator
Shaare Zedek Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Azathioprine in people with Pancreatitis and Inflammatory Bowel Diseases, run by Shaare Zedek Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 18 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants demonstrating biochemical or clinical evidence of pancreatitis (time frame: 3 month period following intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2021.