Immunomodulation, IL-1 Inhibition, and Postoperative Incisional Pain

• Sponsor: Stanford University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01466764
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The investigators hypothesize that perioperative administration of anakinra will reduce incisional pain by lowering the concentration of inflammatory mediators in surgical wounds. This knowledge is important because it suggests a new, previously unexplored pharmacological target for the control of postoperative incisional pain.

Condition or Disease	Intervention/Treatment	Phase
Pain; Inflammation	Drug: Anakinra; Other: Normal Saline	N/A

Detailed Description

This study will test whether administration of anakinra, an IL-1 receptor antagonist, will decrease pain and improve wound healing in patients undergoing vascular or orthopedic surgical procedures. The investigators will administer two doses of Anakinra via an injection under the skin, one dose one hour before surgery and a second dose on the first postoperative day (24 hours after surgery). The investigators will remove fluid from the surgical incisions using a small plastic catheter placed under skin during surgery and measure the amounts of pain- causing inflammatory mediators. The investigators will also measure the amount of pain the participant is experiencing using questions about pain intensity and by gently touching the incision to determine sensitivity of the incision site.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Immunomodulation, IL-1 Inhibition, and Postoperative Incisional Pain
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Anakinra Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery.	Drug: Anakinra; An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.; Other Names: Kineret
Placebo Comparator: Saline injection Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery.	Other: Normal Saline; An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.; Other Names: No other name

Outcome Measures

Primary Outcome Measures

1. Concentration Levels of Inflammatory Mediators IL-1 Receptor Antagonist (IL-1ra) Present in Human Wounds Following Surgery With and Without the Use of Anakinra. [Up to 72 hours following surgery]

   Tissue samples were collected at the surgical wound site at 3 time points during the 1st 72 hours following surgery. Tissue samples from subjects receiving placebo, and subjects receiving anakinra injections pre, and post op were analyzed for IL-1

Secondary Outcome Measures

1. Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery [Up to 72 hours following surgery]

   Analgesic consumption is reported as the count of participants receiving each analgesic type. Comparisons between the placebo and active drug groups were made at the conclusion of the study. PCA/IV: Patient controlled Analgesia/ Intravenous

2. Post-operative Pain Intensity [Up to 72 hours following surgery]

   Pain was measured on Day 1 and day 2 following surgery using a VAS scale at rest and on stimulation with Visual Analog Scale (VAS) of 1-10 (1=no pain and 10=worst pain)

3. Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital [Up to 72 hours following surgery plus 3 weeks follow-up]

   Evaluation of the surgical wound for symptoms of wound infection was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound infection.

4. Count of Participants With Venous Thrombosis After Surgery During Hospitalization [Up to 72 hours following surgery plus 3 weeks follow-up]

   Evaluation of the surgical wound for symptoms of venous thrombosis was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of venous thrombosis.

5. Assess Rates of Wound Dehiscence [Up to 72 hours following surgery plus 3 weeks follow-up]

   Evaluation of the surgical wound for symptoms of wound dehiscence was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound dehiscence.

6. Total Length of Hospital Stay [Up to approximately 5 days maximum (admittance to discharge)]

   Total length of hospital stay for patients enrolled in the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

-Patients 18 years of age and older presenting to the Stanford Preoperative Evaluation Clinic prior to elective orthopedic surgical procedures or elective vascular surgical procedures not involving the abdominal aorta or carotid arteries.

Exclusion Criteria:

Patients will be excluded from participation if they have one or more of the following conditions:

1. Evidence of active local or systemic infection as demonstrated by fever, leukocytosis (white blood cell count > 11,000/ul), productive cough, new infiltrate on chest x-ray, or purulent drainage from any source

2. End-stage renal disease

3. A history of diabetic neuropathy

4. A malignancy other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the previous 5 years

5. Leukopenia (white blood cell count < 2,000/ul)

6. Thrombocytopenia (platelet count < 100,000/ul)

7. Abnormal liver function test result (aspartate aminotransferase or alanine aminotransferase level ≥1.5-fold the upper limit of normal)

8. A history or infection with tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus

9. Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Hospital and Clinics	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Robert L Lobato, MD, Stanford U

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gary Peltz, Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT01466764
• Other Study ID Numbers: SU-10312011-8587
• First Posted: Nov 8, 2011
• Last Update Posted: Aug 9, 2017
• Last Verified: Jul 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Gary Peltz, Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University: biomarkers
• Additional relevant MeSH terms: Inflammation; Interleukin 1 Receptor Antagonist Protein

Study Results

Participant Flow

Pre-assignment Detail	13 were enrolled and 3 participants withdrew prior to randomization

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Anakinra	Saline Injection	Total
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.	Total of all reporting groups
Overall Participants	5	5	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	71.4	74	73
Sex: Female, Male (Count of Participants)
Female	3 60%	4 80%	7 70%
Male	2 40%	1 20%	3 30%
Region of Enrollment (Count of Participants)
United States	5 100%	5 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Concentration Levels of Inflammatory Mediators IL-1 Receptor Antagonist (IL-1ra) Present in Human Wounds Following Surgery With and Without the Use of Anakinra.
Description	Tissue samples were collected at the surgical wound site at 3 time points during the 1st 72 hours following surgery. Tissue samples from subjects receiving placebo, and subjects receiving anakinra injections pre, and post op were analyzed for IL-1
Time Frame	Up to 72 hours following surgery

Outcome Measure Data

Analysis Population Description

IL-1ra measurements were invalid due to cross-reaction with the assay platform.

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	0	0

2. Secondary Outcome

Title	Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery
Description	Analgesic consumption is reported as the count of participants receiving each analgesic type. Comparisons between the placebo and active drug groups were made at the conclusion of the study. PCA/IV: Patient controlled Analgesia/ Intravenous
Time Frame	Up to 72 hours following surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	5	5
PCA/IV - Dilaudid (mg)	5 100%	4 80%
PCA/IV - Fentanyl (mcg)	3 60%	1 20%
PCA/IV - Morphine	4 80%	4 80%
PO - Oxycontin(tab)	5 100%	4 80%
PO - Percocet(tab)	1 20%	1 20%
PO - Acetaminophen(tab)	3 60%	2 40%

3. Secondary Outcome

Title	Post-operative Pain Intensity
Description	Pain was measured on Day 1 and day 2 following surgery using a VAS scale at rest and on stimulation with Visual Analog Scale (VAS) of 1-10 (1=no pain and 10=worst pain)
Time Frame	Up to 72 hours following surgery

Outcome Measure Data

Analysis Population Description

Participants with available data were analyzed.

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	4	5
Pain Intensity at Rest Day One	2.25	2.8
Pain Intensity on Stimulation Day One	7	6.4
Pain Intensity at Rest Day Two	2.25	3.6
Pain Intensity on Stimulation Day Two	3.3	6.2

4. Secondary Outcome

Title	Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital
Description	Evaluation of the surgical wound for symptoms of wound infection was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound infection.
Time Frame	Up to 72 hours following surgery plus 3 weeks follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	5	5
Count of Participants [Participants]	0 0%	0 0%

5. Secondary Outcome

Title	Count of Participants With Venous Thrombosis After Surgery During Hospitalization
Description	Evaluation of the surgical wound for symptoms of venous thrombosis was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of venous thrombosis.
Time Frame	Up to 72 hours following surgery plus 3 weeks follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	5	5
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Assess Rates of Wound Dehiscence
Description	Evaluation of the surgical wound for symptoms of wound dehiscence was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound dehiscence.
Time Frame	Up to 72 hours following surgery plus 3 weeks follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	5	5
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Total Length of Hospital Stay
Description	Total length of hospital stay for patients enrolled in the study.
Time Frame	Up to approximately 5 days maximum (admittance to discharge)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anakinra	Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.	Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Measure Participants	5	5
Median (Standard Deviation) [hours]	75.06 (17.37)	87.76 (13.8)

Adverse Events

Time Frame	Up to 72 hours following surgery plus 3 weeks follow-up
Adverse Event Reporting Description	Adverse event collection was limited to incidence of wound infection, wound dehiscence, and venous thrombosis
Arm/Group Title	Anakinra		Saline Injection
Arm/Group Description	Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery. Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.		Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery. Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
All Cause Mortality
	Anakinra		Saline Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Anakinra		Saline Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Anakinra		Saline Injection
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)

Limitations/Caveats

The trial terminated early. We did not expect to see an effect in such a small number of subjects.

More Information

Certain Agreements

Principal Investigators are NOT 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.