Pentoxifylline Treatment in Acute Pancreatitis (AP)

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02487225
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 83
• Location: 1
• Arms: 2
• Duration (Months): 30
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the effects (good and bad) of giving a drug called pentoxifylline to patients with acute pancreatitis.

Condition or Disease	Intervention/Treatment	Phase
Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)	Drug: Pentoxifylline; Drug: Placebo	Phase 3

Detailed Description

Participants were randomized to either the treatment group (Pentoxifylline medication) or the control group (Placebo).

Participant took a pill orally, starting from the time of admission. Participants received a total of 9 doses over the three days of hospitalization (72 hours).

Research blood draws were done at baseline and on 5 successive days or until the time of discharge, whichever occured earlier. The study gathered clinical follow up information up to 4 months following hospitalization regarding the diagnosis of acute pancreatitis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pentoxifylline Treatment in Acute Pancreatitis: A Double-Blind Placebo - Controlled Randomized Trial
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Apr 30, 2017
• Actual Study Completion Date: Oct 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pentoxifylline Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses.	Drug: Pentoxifylline; Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits Tumor Necrosis Factor (TNF) and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors; Other Names: Trental Pentox Pentoxil Flexital
Placebo Comparator: Placebo Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses.	Drug: Placebo; A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug

Outcome Measures

Primary Outcome Measures

1. Change in C-reactive Protein (C-RP) From Admission Baseline at One Week. [Admission (baseline), day 5]

   C-reactive protein is a substance produced by the liver in response to inflammation. Normal C-RP levels are below 3.0 mg/L.Units: mg/L

2. Change in Tumor Necrosis Factor-alpha (TNF-a) Levels From Admission Baseline at One Week. [Admission (baseline), day 5]

   Tumor Necrosis Factor Alpha is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. TNF is important to the body because it helps regulate the response of the immune system to a foreign object, especially to the present cancerous tumor. It promotes inflammation, produces other cells used in the inflammatory response, and can help cells heal. The normal range is 5 to 27.2 pg/ml.Units: pg/ml

3. Change in Interleukin-6 (IL-6) Levels From Admission Baseline at One Week. [Admission (baseline), day 5]

   Interleukin-6 (IL-6) may be used to help evaluate a person who has a condition associated with inflammation, such as lupus or rheumatoid arthritis, or with infection, such as sepsis. It may also be used in the evaluation of diabetes or cardiovascular disease. IL-6 is a cytokine, a protein produced by immune cells that acts on other cells to help regulate and/or promote an immune response. It also stimulates the production of acute phase reactants, proteins that increase in the blood with conditions that cause inflammation or tissue injury. Circulating IL-6 can be found in the blood of normal individuals in the 1 pg/mL range, with slight elevations during the menstrual cycle, modest elevations in certain cancers (melanoma) (10 pg/mL), and large elevations after surgery (30-430 pg/mL).Units: pg/ml

4. Change in Interleukin-8 (IL-8) Levels From Admission Baseline at One Week. [Admission (baseline), day 5]

   IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. Units: pg/mL

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria

• Enrollment within 72 hours of diagnosis of acute pancreatitis (AP)

• Ability to give informed consent or a Legal Adult Representative (LAR) able to give informed consent for subject when needed as defined buy LAR use guidelines.

• Adult subjects of age ≥18 years.

Exclusion Criteria:

• Moderate or severe congestive heart failure

• History of seizure disorders or demyelinating disease

• Nursing mothers

• Pregnancy

• History of prior tuberculosis or risk factors for tuberculosis

• Evidence of non- corticosteroid immunosuppression (such as malignancy, chronic renal failure, chemotherapy within 60 days, and HIV)

• Evidence of active hemorrhage

• Paralytic ileus with severe nausea and vomiting

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Santhi Swaroop Vege, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 9, 2017

More Information

Publications

None provided.

• Responsible Party: Santhi Swaroop Vege, M.D., PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02487225
• Other Study ID Numbers: 15-001710; 1R21DK101889-01A1
• First Posted: Jul 1, 2015
• Last Update Posted: Jan 23, 2019
• Last Verified: Jan 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Santhi Swaroop Vege, M.D., PI, Mayo Clinic: Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis
• Additional relevant MeSH terms: Pancreatitis; Pancreatitis, Chronic; Gallstones; Pancreatitis, Alcoholic; Hypertriglyceridemia; Pentoxifylline

Study Results

Participant Flow

Recruitment Details	Subjects were recruited at Mayo Clinic in Rochester, Minnesota.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
Period Title: Overall Study
STARTED	45	38
COMPLETED	18	8
NOT COMPLETED	27	30

Baseline Characteristics

Arm/Group Title	Pentoxifylline	Placebo	Total
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug	Total of all reporting groups
Overall Participants	45	38	83
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.0	55.5	59.0
Sex: Female, Male (Count of Participants)
Female	21 46.7%	21 55.3%	42 50.6%
Male	24 53.3%	17 44.7%	41 49.4%
Race/Ethnicity, Customized (Count of Participants)
Hispanic/Latino	2 4.4%	0 0%	2 2.4%
White	41 91.1%	36 94.7%	77 92.8%
Other	2 4.4%	2 5.3%	4 4.8%
Region of Enrollment (Count of Participants)
United States	45 100%	38 100%	83 100%
Bedside Index of Severity in Acute Pancreatitis (BISAP) Score (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	1.0	0.5	1.0
Systematic Inflammatory Response Syndrome (SIRS) score on admission (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	1.0	1.0	1.0

Outcome Measures

1. Primary Outcome

Title	Change in C-reactive Protein (C-RP) From Admission Baseline at One Week.
Description	C-reactive protein is a substance produced by the liver in response to inflammation. Normal C-RP levels are below 3.0 mg/L.Units: mg/L
Time Frame	Admission (baseline), day 5

Outcome Measure Data

Analysis Population Description

Eighteen (18) of forty-five subjects (45) in the treatment arm and eight (8) of thirty-eight (38) subjects in the placebo arm completed the study. Additionally, subjects had blood collections for 5 days or until dismissal. Many subjects were dismissed at 2-3 days.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
Measure Participants	45	38
Admission (baseline)	86.2 (81.5)	75.8 (83.1)
Day 5	116.4 (100.4)	127.2 (97.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Admission (baseline)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5796
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Day 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8415
	Comments
	Method	Kruskal-Wallis
	Comments

2. Primary Outcome

Title	Change in Tumor Necrosis Factor-alpha (TNF-a) Levels From Admission Baseline at One Week.
Description	Tumor Necrosis Factor Alpha is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. TNF is important to the body because it helps regulate the response of the immune system to a foreign object, especially to the present cancerous tumor. It promotes inflammation, produces other cells used in the inflammatory response, and can help cells heal. The normal range is 5 to 27.2 pg/ml.Units: pg/ml
Time Frame	Admission (baseline), day 5

Outcome Measure Data

Analysis Population Description

Eighteen (18) of forty-five subjects (45) in the treatment arm and eight (8) of thirty-eight (38) subjects in the placebo arm completed the study. Additionally, subjects had blood collections for 5 days or until dismissal. Many subjects were dismissed at 2-3 days.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
Measure Participants	40	37
Admission (baseline)	1.9 (0.9)	1.8 (1.3)
Day 5	4.3 (6.3)	1.9 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Admission (baseline)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1109
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4619
	Comments
	Method	Kruskal-Wallis
	Comments

3. Primary Outcome

Title	Change in Interleukin-6 (IL-6) Levels From Admission Baseline at One Week.
Description	Interleukin-6 (IL-6) may be used to help evaluate a person who has a condition associated with inflammation, such as lupus or rheumatoid arthritis, or with infection, such as sepsis. It may also be used in the evaluation of diabetes or cardiovascular disease. IL-6 is a cytokine, a protein produced by immune cells that acts on other cells to help regulate and/or promote an immune response. It also stimulates the production of acute phase reactants, proteins that increase in the blood with conditions that cause inflammation or tissue injury. Circulating IL-6 can be found in the blood of normal individuals in the 1 pg/mL range, with slight elevations during the menstrual cycle, modest elevations in certain cancers (melanoma) (10 pg/mL), and large elevations after surgery (30-430 pg/mL).Units: pg/ml
Time Frame	Admission (baseline), day 5

Outcome Measure Data

Analysis Population Description

Eighteen (18) of forty-five subjects (45) in the treatment arm and eight (8) of thirty-eight (38) subjects in the placebo arm completed the study. Additionally, subjects had blood collections for 5 days or until dismissal. Many subjects were dismissed at 2-3 days.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
Measure Participants	42	35
Admission (baseline)	107.9 (124.8)	89.1 (138.2)
Day 5	81.8 (97.4)	88.6 (85.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Admission (baseline)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1236
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Day 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9468
	Comments
	Method	Kruskal-Wallis
	Comments

4. Primary Outcome

Title	Change in Interleukin-8 (IL-8) Levels From Admission Baseline at One Week.
Description	IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. It is released from several cell types in response to an inflammatory stimulus. Units: pg/mL
Time Frame	Admission (baseline), day 5

Outcome Measure Data

Analysis Population Description

Eighteen (18) of forty-five subjects (45) in the treatment arm and eight (8) of thirty-eight (38) subjects in the placebo arm completed the study. Additionally, subjects had blood collections for 5 days or until dismissal. Many subjects were dismissed at 2-3 days.

Arm/Group Title	Pentoxifylline	Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors	Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
Measure Participants	42	36
Admission (baseline)	43.7 (29.4)	31.5 (26.1)
Day 5	45.9 (43.2)	32.1 (23.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Admission (baseline)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.157
	Comments
	Method	Kruskal-Wallis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pentoxifylline, Placebo
	Comments	Day 5
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3173
	Comments
	Method	Kruskal-Wallis
	Comments

Adverse Events

Time Frame	4 months
Arm/Group Title	Pentoxifylline		Placebo
Arm/Group Description	Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Pentoxifylline: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors		Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. Placebo: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug
All Cause Mortality
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/45 (4.4%)		0/38 (0%)
Serious Adverse Events
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)		0/38 (0%)
Psychiatric disorders
Hospitalized for psychological evaluation, considered a danger to self	1/45 (2.2%)	1	0/38 (0%)	0
Other (Not Including Serious) Adverse Events
	Pentoxifylline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/45 (26.7%)		5/38 (13.2%)
Cardiac disorders
Angina	2/45 (4.4%)	2	0/38 (0%)	2
Gastrointestinal disorders
Abdominal Pain	0/45 (0%)	0	1/38 (2.6%)	1
Necrosis due to disease progression	1/45 (2.2%)	1	1/38 (2.6%)	1
Infected cystic duct leak	1/45 (2.2%)	1	0/38 (0%)	0
Nausea	2/45 (4.4%)	2	1/38 (2.6%)	1
General disorders
Sepsis due to disease progression	2/45 (4.4%)	2	0/38 (0%)	0
Headache/Migraine	1/45 (2.2%)	1	2/38 (5.3%)	2
Musculoskeletal and connective tissue disorders
Hip pain and gait dysfunction	1/45 (2.2%)	1	0/38 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/45 (2.2%)	1	0/38 (0%)	0
Upper respiratory infection	1/45 (2.2%)	1	0/38 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.