Efficacy and Safety Study of Caldolor (IV Ibuprofen) in Hospitalized Adult Orthopedic Patients

• Sponsor: Cumberland Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00470600
• Collaborator: (none)
• Enrollment: 185
• Locations: 9
• Arms: 2
• Duration (Months): 16.1
• Patients Per Site: 20.6
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The primary objective of this study of Caldolor (IV ibuprofen) administered to post-operative hospitalized adult orthopedic patients every 6 hours for at least 24 hours is to determine the efficacy of Caldolor (IV ibuprofen) compared to placebo for the treatment of post-operative pain by patients self-assessment of pain.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Caldolor; Other: Normal Saline	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 185 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF IBUPROFEN INJECTION (IVIb) FOR TREATMENT OF PAIN IN POST-OPERATIVE ORTHOPEDIC ADULT PATIENTS
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Normal Saline 250 milliliters normal saline as a placebo comparator was administered every 6 hours for a total of five doses over the first 24 hours. Those patients who received the initial five doses could continue to receive additional doses as needed every 6 hours through the 120-hour treatment period.	Other: Normal Saline; Placebo comparator; Other Names: NS
Experimental: Intravenous ibuprofen 800 mg of intravenous ibuprofen diluted in 250 milliliters normal saline was administered every 6 hours for a total of five doses over the first 24 hours. Those patients who received the initial five doses could continue to receive additional doses as needed every 6 hours through the 120-hour treatment period.	Drug: Caldolor; 800 milligrams intravenous; Other Names: Ibuprofen

Outcome Measures

Primary Outcome Measures

1. AUC-VAS With Movement (Post-operative Period, Hour-6-28) [Study hour-6 through hour-28]

   Measurement of the patient's self assessment of pain with movement using the validated visual analog scale (VAS) during the post-operative period (study hour-6 through hour-28). VAS assessments document the patient's self reported level of pain from "No pain" (0 mm) to "Worst possible pain" (100 mm) on a 100 mm line. VAS assessments were performed immediately following surgery [variable since every surgery has a unique length of time even if it is the same procedure] and at hours 6, 8, 12, 16, 20, 24 and 28 (for the primary endpoint).

Secondary Outcome Measures

1. Secondary Endpoint: AUC-VAS at Rest (Post-operative Period, Hours 6-28) [Study hour-6 through hour-28]

   Measurement of the patient's self assessment of pain at rest using a visual analog scale (VAS) during the post-operative period (study hour-6 through hour-28). VAS assessments document the patient's self reported level of pain from "No pain" (0 mm) to "Worst possible pain" (100 mm) on a 100 mm line. VAS assessments were performed immediately following surgery and at hours 6, 8, 12, 16, 20, 24 and 28 (for the primary endpoint).

2. Patient Demand of Narcotic Use (Post-operative Period, From Hour 6 to 28). [Study hour-6 to hour-28]

   Patient demand of narcotic used by patients in each treatment group for analgesia, post-surgery.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Scheduled for elective hip or knee replacement, reconstruction or arthroplasty surgery with anticipated need for post-operative intravenous (IV) morphine analgesia with anticipated use of (greater than or equal to (≥) 28 hours.

2. Adequate IV access

3. Anticipated hospital stay ≥ 28 hours

Exclusion Criteria:

1. Be unable to make a reliable self-report of pain intensity to pain relief

2. Less than 18 years of age

3. Greater than 80 years of age

4. Use of analgesics, muscle relaxants, NSAIDS and sedatives less than 12 hours prior to clinicaltrial material(CTM) administration with the following exceptions: paracetamol (acetaminophen) can be administered until 6 hours prior to surgery; tramadol can be administered until midnight the evening prior to surgery; muscle relaxants working at the neuromuscular junction used for intubation and/or anesthesia administration for the surgical procedure prior to CTM administration; and sedatives (i.e., midazolam) used as a co-induction agent for the surgical procedure prior to CTM administration

5. Patients taking warfarin, lithium, combination of angiotension converting enzyme(ACE)-inhibitors and furosemide

6. Patients with anemia (active, clinically significant anemia) and/or a history or evidence of asthma or heart failure

7. History of allergy or hypersensitivity to any component of Caldolor, aspirin (or aspirin related products), NSAIDs, or COX-2 inhibitors

8. Pregnant or nursing

9. History of severe head trauma that required current hospitalization, intracranial surgery or stroke within the previous 30 days, or any history of intracerebral arteriovenous malformation, cerebral aneurysm or CNS mass lesion

10. Weigh less than 30 kilogram

11. Have a history of congenital bleeding diathesis (e.g. hemophilia) or any active clinically significant bleeding, or have underlying platelet dysfunction including (but not limited to) idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, or congenital platelet dysfunction

12. Have gastrointestional (GI) bleeding that required medical intervention within the previous 6 weeks (unless definitive surgery has been performed)

13. Have a platelet count less than 30,000 mm^3 determined within the 28 days prior to surgery

14. Pre-existing dependence on narcotics or known tolerance to opioids

15. Inability to understand the requirements of the study, be willing to provide written informed consent (as evidenced by signature on an informed consent document approved by an Institutional Review Board [IRB]), and agree to abide by the study restrictions and to return for the required assessments

16. Refusal to provide written authorization for use and disclosure of protected health information

17. Be on dialysis, have oliguria or creatinine greater than 3.0 milligram/deciliter.

18. Inability to achieve hemostasis or inability to close surgical incision, prior to Operating Room discharge

19. Operative procedure includes organ transplant

20. Pre or intra-operative procedure utilized for the prevention of pre- or post-operative pain (i.e. epidural or nerve blocks)

21. Be receiving full dose anticoagulation therapy or Activated Protein C within 6 hours before dosing (Prophylaxis with subcutaneous heparin is acceptable)

22. Have received another investigational drug within the past 30 days

23. Be otherwise unsuitable for the study in the opinion of the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wilmax Clinical Research Inc.	Mobile	Alabama	United States	336608
2	Teton Research, LLC	Little Rock	Arkansas	United States	72205
3	Clinical Management Services, Inc.	Arcadia	California	United States	91007
4	Southeastern Center for Clinical Trials	Atlanta	Georgia	United States	30350
5	Research Concepts, Inc	Houston	Texas	United States	77054
6	Research Concepts, Inc.	Houston	Texas	United States	77401
7	Johannesburg General Hospital	Johannesburg		South Africa
8	Krugersdorp Private Hospital	Krugersdorp		South Africa
9	Eugene Marais Hospital	Pretoria		South Africa

Sponsors and Collaborators

• Cumberland Pharmaceuticals

Investigators

• Principal Investigator: Neil Singla, MD, Lotus Clinical Research/Methodist Hospital of Southern CA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cumberland Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00470600
• Other Study ID Numbers: CPI-CL-008C
• First Posted: May 8, 2007
• Last Update Posted: Aug 21, 2015
• Last Verified: Aug 1, 2015

• Additional relevant MeSH terms: Ibuprofen

Study Results

Participant Flow

Arm/Group Title	Placebo	800mg IV Ibuprofen (Caldolor)
Arm/Group Description	250 mL of normal saline.	8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.
Period Title: Overall Study
STARTED	86	99
COMPLETED	86	99
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	800mg IV Ibuprofen (Caldolor)	Total
Arm/Group Description	250 mL of normal saline.	8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.	Total of all reporting groups
Overall Participants	86	99	185
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (9.9)	62 (10.3)	61 (10.2)
Age, Customized (participants) [Number]
<45years	6 7%	3 3%	9 4.9%
>= 45 years	80 93%	96 97%	176 95.1%
Sex: Female, Male (Count of Participants)
Female	55 64%	65 65.7%	120 64.9%
Male	31 36%	34 34.3%	65 35.1%
Region of Enrollment (participants) [Number]
United States	61 70.9%	70 70.7%	131 70.8%
South Africa	25 29.1%	29 29.3%	54 29.2%

Outcome Measures

1. Primary Outcome

Title	AUC-VAS With Movement (Post-operative Period, Hour-6-28)
Description	Measurement of the patient's self assessment of pain with movement using the validated visual analog scale (VAS) during the post-operative period (study hour-6 through hour-28). VAS assessments document the patient's self reported level of pain from "No pain" (0 mm) to "Worst possible pain" (100 mm) on a 100 mm line. VAS assessments were performed immediately following surgery [variable since every surgery has a unique length of time even if it is the same procedure] and at hours 6, 8, 12, 16, 20, 24 and 28 (for the primary endpoint).
Time Frame	Study hour-6 through hour-28

Outcome Measure Data

Analysis Population Description

Efficacy analyses were performed on the Intent to Treat (ITT) population and the Efficacy Evaluable Population (EEP). All randomized patients who received at least a partial dose of CTM were included in the ITT analyses. All data below represents the ITT analyses.

Arm/Group Title	Placebo	800mg IV Ibuprofen (Caldolor)
Arm/Group Description	250 mL of normal saline.	8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.
Measure Participants	84	95
Least Squares Mean (Standard Error) [AUC-VAS pain v. time (mm*hr)]	1326.1 (82.0)	1005.0 (81.5)

2. Secondary Outcome

Title	Secondary Endpoint: AUC-VAS at Rest (Post-operative Period, Hours 6-28)
Description	Measurement of the patient's self assessment of pain at rest using a visual analog scale (VAS) during the post-operative period (study hour-6 through hour-28). VAS assessments document the patient's self reported level of pain from "No pain" (0 mm) to "Worst possible pain" (100 mm) on a 100 mm line. VAS assessments were performed immediately following surgery and at hours 6, 8, 12, 16, 20, 24 and 28 (for the primary endpoint).
Time Frame	Study hour-6 through hour-28

Outcome Measure Data

Analysis Population Description

Efficacy analyses were performed on the Intent to Treat (ITT) population and the Efficacy Evaluable Population (EEP). All randomized patients who received at least a partial dose of CTM were included in the ITT analyses. All data below represents the ITT analyses.

Arm/Group Title	Placebo	800mg IV Ibuprofen (Caldolor)
Arm/Group Description	250 mL of normal saline.	8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.
Measure Participants	84	95
Least Squares Mean (Standard Error) [AUC-VAS pain v. time (mm*hr)]	997.0 (83.6)	728.0 (83.0)

3. Secondary Outcome

Title	Patient Demand of Narcotic Use (Post-operative Period, From Hour 6 to 28).
Description	Patient demand of narcotic used by patients in each treatment group for analgesia, post-surgery.
Time Frame	Study hour-6 to hour-28

Outcome Measure Data

Analysis Population Description

Demand of narcotic use was determined by PCA records or by chart if patient requested and not via PCA.

Arm/Group Title	Placebo	800mg IV Ibuprofen (Caldolor)
Arm/Group Description	250 mL of normal saline.	8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.
Measure Participants	84	95
Mean (Standard Deviation) [milligrams]	59.5 (29.9)	41.1 (27.3)

Adverse Events

Arm/Group Title	Placebo		800mg IV Ibuprofen (Caldolor)
Arm/Group Description	250 mL of normal saline.		8 mL of IV Ibuprofen (Caldolor) added with 250 mL of normal saline to give 800 mg dose.
All Cause Mortality
	Placebo		800mg IV Ibuprofen (Caldolor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		800mg IV Ibuprofen (Caldolor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/86 (3.5%)		8/99 (8.1%)
Cardiac disorders
Atrial fibrillation	0/86 (0%)	0	1/99 (1%)	1
Gastrointestinal disorders
Abdominal pain	0/86 (0%)	0	1/99 (1%)	1
Colitis	0/86 (0%)	0	1/99 (1%)	1
Hepatobiliary disorders
Acute hepatic failure	0/86 (0%)	0	1/99 (1%)	1
Infections and infestations
Gastroenteritis	1/86 (1.2%)	1	0/99 (0%)	0
Post procedural pneumonia	0/86 (0%)	0	1/99 (1%)	1
Psychiatric disorders
Altered mental status	0/86 (0%)	0	1/99 (1%)	1
Renal and urinary disorders
Acute renal failure	0/86 (0%)	0	1/99 (1%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema	1/86 (1.2%)	1	0/99 (0%)	0
Pulmonary embolism	0/86 (0%)	0	1/99 (1%)	1
Vascular disorders
Deep vein thrombosis	1/86 (1.2%)	1	0/99 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		800mg IV Ibuprofen (Caldolor)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/86 (86%)		90/99 (90.9%)
Blood and lymphatic system disorders
Anemia	10/86 (11.6%)	10	10/99 (10.1%)	10
Cardiac disorders
Tachycardia	3/86 (3.5%)	3	4/99 (4%)	4
Gastrointestinal disorders
Vomiting	12/86 (14%)	13	27/99 (27.3%)	28
Constipation	11/86 (12.8%)	11	20/99 (20.2%)	20
Dyspepsia	4/86 (4.7%)	5	0/99 (0%)	0
Nausea	30/86 (34.9%)	37	44/99 (44.4%)	47
General disorders
Pyrexia	15/86 (17.4%)	16	14/99 (14.1%)	18
Oedema Peripheral	2/86 (2.3%)	2	3/99 (3%)	6
Injury, poisoning and procedural complications
anaemia postoperative	0/86 (0%)	0	3/99 (3%)	3
Investigations
Body temperature increased	11/86 (12.8%)	11	8/99 (8.1%)	10
Urine output decreased	8/86 (9.3%)	9	5/99 (5.1%)	5
Haemaglobin decreased	0/86 (0%)	0	4/99 (4%)	4
Metabolism and nutrition disorders
Hypokalemia	3/86 (3.5%)	3	5/99 (5.1%)	5
Musculoskeletal and connective tissue disorders
Muscle spasms	4/86 (4.7%)	4	1/99 (1%)	1
Nervous system disorders
Headache	5/86 (5.8%)	7	3/99 (3%)	4
Dizziness	3/86 (3.5%)	4	4/99 (4%)	4
Psychiatric disorders
Insomnia	2/86 (2.3%)	2	7/99 (7.1%)	7
Agitation	1/86 (1.2%)	1	3/99 (3%)	3
Renal and urinary disorders
Urinary retention	2/86 (2.3%)	2	9/99 (9.1%)	10
Dysuria	5/86 (5.8%)	6	2/99 (2%)	2
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	1/86 (1.2%)	1	3/99 (3%)	3
Skin and subcutaneous tissue disorders
Pruritis	17/86 (19.8%)	22	10/99 (10.1%)	13
Rash	3/86 (3.5%)	3	1/99 (1%)	1
Vascular disorders
Hypotension	6/86 (7%)	6	8/99 (8.1%)	9
Hypertension	3/86 (3.5%)	3	3/99 (3%)	4
Deep vein thrombosis	3/86 (3.5%)	3	1/99 (1%)	1

Limitations/Caveats

[Not Specified]

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.