Ketorolac Versus Ibuprofen to Treat Painful Episodes of Sickle Cell Disease

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00115336
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), University of Texas Southwestern Medical Center (Other)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to compare ketorolac, a potent, non-steroidal anti-inflammatory drug (NSAID), with ibuprofen, a commonly used NSAID, for the treatment of the painful crisis of sickle cell disease (SCD).

Condition or Disease	Intervention/Treatment	Phase
Hematologic Diseases; Anemia, Sickle Cell	Drug: Intravenous Ketorolac; Drug: Ibuprofen	Phase 4

Detailed Description

BACKGROUND:

SCD is a common disorder among African Americans and other minority groups. It is characterized by chronic anemia and episodic vaso-occlusive crises. The most common of these crises is the painful crisis. Current treatment of the painful crisis includes rest, hydration, and analgesic medication. Morphine is the most commonly prescribed analgesic medication for moderate to severe painful episodes, but there are several side effects associated with its use, including somnolence, respiratory depression, constipation, dysphoria, and pruritus. Other analgesic medications, including NSAIDs, may improve pain control and decrease the need for morphine and other opioid drugs; however, more research is needed to confirm the benefits in individuals with SCD.

DESIGN NARRATIVE:

This study will enroll 120 children who will receive standard opioid and supportive therapy. In addition to this care, participants will be randomly assigned to receive one of the following: 1) intravenous ketorolac and oral placebo; or 2) intravenous placebo and oral ibuprofen. Outcome assessments will include the duration of hospitalization for opioid therapy; the degree of pain intensity and relief determined by validated pain scales; and the utilization of opioid medications during hospitalization. All participants will be monitored for potential adverse effects of the study medications by laboratory measurements and clinical assessments. Additionally, participants will self-report pain levels using the Oucher pain scale. Participants will be monitored for the development of adverse events, including gastrointestinal symptoms and deterioration of kidney function, as determined by daily kidney function tests including BUN, creatinine, and hematuria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Ketorolac Versus Ibuprofen for the Painful Crisis of Sickle Cell Disease - Southwestern Comprehensive Sickle Cell Center
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1-Intravenous ketorolac and oral placebo Intravenous ketorolac and oral placebo	Drug: Intravenous Ketorolac; Intravenous ketorolac; Other Names: Toradol
Active Comparator: 2-Intravenous placebo and oral ibuprofen Intravenous placebo and oral ibuprofen	Drug: Ibuprofen; Ibuprofen, taken orally; Other Names: Motrin, Advil

Outcome Measures

Primary Outcome Measures

1. Time to a 50% Reduction in Reported Pain Intensity [Measured every 4 hours during hospitalization, over a mean hospitalization duration of 81.5 hours.]

   The primary endpoint is the time to a 50% reduction in reported pain intensity. This endpoint is relative to the baseline pain intensity rating on the Oucher scale (minimum 0, maximum 10; higher scores indicate greater pain). The endpoint will be reached when the reported pain intensity is at least one-half of the baseline value on two consecutive measurements at least 4 hours apart. The time ascribed to the endpoint will be the time of the second of these two consecutive pain scales. Participants who do not have a 50% reduction in reported pain intensity, as defined above, before discharge from the hospital will be censored at the time of last rating on the Oucher pain scale before discharge from the hospital

Secondary Outcome Measures

1. Duration of Hospitalization [The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.]

   Time between admission to the hospital and discharge from the hospital

2. Total Parenteral Opioid Usage [The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.]

   Sum of all parenteral opioids used during the study period in milligrams (mg) of morphine or morphine equivalents.

3. Occurrence of Azotemia [The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.]

   Participants who had measured values of blood urea nitrogen (BUN), serum creatinine, or both that were above the upper limit of normal for age.

4. Fluid Retention [The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)]

   Number of participants who had clinically overt fluid retention as determined by history, physical examination, vital signs, and weight (e.g., peripheral edema, increase in weight)

5. Hematuria [The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.]

   Number of participants who had microscopic hematuria as determined by urinalysis

6. Dyspepsia [The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)]

   Number of participants who reported discomfort in the stomach related to eating or drinking

7. Gastrointestinal Ulceration [The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)]

   Number of participants who had gastrointestinal ulceration.

8. Bleeding [The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)]

   Number of participants who had clinically overt bleeding from any site. This excludes microscopic hematuria only.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of any form of SCD, including sickle cell anemia, sickle-hemoglobin C disease, and sickle-ß˖ or ß°-thalassemia

• Currently experiencing an acute painful episode (vaso-occlusive crisis), defined as acute pain in the extremities, back, abdomen, or chest that has lasted at least 4 hours and is presumed to be due to SCD, with no other identified cause

• Onset of severe pain in its current location(s) must have occurred within 72 hours of study entry

• Intensity of pain must be great enough to necessitate hospitalization for opioid analgesia (e.g., failure of home and outpatient therapy)

• Ability to comprehend and use patient-controlled analgesia (PCA)

• Score of 6 or greater on the baseline pain scale

Exclusion Criteria:

• Temperature greater than or equal to 38.5ºC at the time of study entry or in the preceding 12 hours

• Has a new lobar pulmonary infiltrate or a diagnosis of acute chest syndrome (i.e., a new lobar pulmonary infiltrate and two or more of the following: temperature greater than 38ºC, tachypnea, dyspnea, intercostal or supraclavicular retractions, nasal flaring, chest wall pain, and an oxygen saturation of less than 90% in room air by pulse oximetry)

• Diagnosis of acute splenic or hepatic sequestration crisis (i.e., liver or spleen enlarged from steady-state size and Hgb level decreased 2 g/dL or more from steady-state value)

• Currently experiencing priapism

• Pain caused by suspected or confirmed hepatobiliary disease (e.g., cholecystitis or cholelithiasis)

• Chronic pain caused by suspected or confirmed aseptic or avascular necrosis of the femoral or humeral heads

• Chronic pain syndrome characterized by opioid tolerance and defined by hospitalization for at least 30 days for the management of pain in a 1 year period prior to study entry

• Current participation (last transfusion given within the 2 months prior to study entry) in a program of chronic transfusions for the management of SCD; the use of hydroxyurea alone is permitted

• Allergy or history of anaphylactoid reactions to aspirin or other NSAIDs

• Kidney dysfunction (i.e., serum creatinine concentration greater than 1.5 times the upper limit of normal for age)

• History of gastrointestinal bleeding or ulceration requiring medical therapy

• Concomitant bleeding disorder (e.g., von Willebrand disease, hemophilia, or a qualitative platelet defect)

• Any other medical condition that would make it unsafe to receive NSAIDs, as determined by the study physician

• PCA not preferred

• Use of ketorolac in the 30 days prior to study entry

• Use of scheduled (e.g., "around the clock") opioid analgesics in the 5 days before the onset of current acute painful crisis

• Pregnant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• National Heart, Lung, and Blood Institute (NHLBI)
• University of Texas Southwestern Medical Center

Investigators

• Study Chair: Charles T. Quinn, MD, University of Texas Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT00115336
• Other Study ID Numbers: 191; U54HL070588
• First Posted: Jun 22, 2005
• Last Update Posted: Oct 8, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Children's Hospital Medical Center, Cincinnati: Blood Diseases; Sickle Cell Anemia
• Additional relevant MeSH terms: Anemia, Sickle Cell; Hematologic Diseases; Ibuprofen; Ketorolac

Study Results

Participant Flow

Recruitment Details	Planned enrollment for the trial was 120 subjects. Accrual was extremely slow; only 10 participants were randomized before the trial was closed in 2008 due to lack of accrual. Less than 10% of planned enrollment was achieved.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Period Title: Overall Study
STARTED	6	4
COMPLETED	6	3
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen	Total
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo abd oral ibuprofen	Total of all reporting groups
Overall Participants	6	4	10
Age (Count of Participants)
<=18 years	3 50%	4 100%	7 70%
Between 18 and 65 years	3 50%	0 0%	3 30%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	15.4	17.7	16.7
Sex: Female, Male (Count of Participants)
Female	3 50%	1 25%	4 40%
Male	3 50%	3 75%	6 60%
Region of Enrollment (participants) [Number]
United States	6 100%	4 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Time to a 50% Reduction in Reported Pain Intensity
Description	The primary endpoint is the time to a 50% reduction in reported pain intensity. This endpoint is relative to the baseline pain intensity rating on the Oucher scale (minimum 0, maximum 10; higher scores indicate greater pain). The endpoint will be reached when the reported pain intensity is at least one-half of the baseline value on two consecutive measurements at least 4 hours apart. The time ascribed to the endpoint will be the time of the second of these two consecutive pain scales. Participants who do not have a 50% reduction in reported pain intensity, as defined above, before discharge from the hospital will be censored at the time of last rating on the Oucher pain scale before discharge from the hospital
Time Frame	Measured every 4 hours during hospitalization, over a mean hospitalization duration of 81.5 hours.

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Mean (95% Confidence Interval) [hours]	58.4	68.0

2. Secondary Outcome

Title	Duration of Hospitalization
Description	Time between admission to the hospital and discharge from the hospital
Time Frame	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Mean (95% Confidence Interval) [hours]	80.7	83.0

3. Secondary Outcome

Title	Total Parenteral Opioid Usage
Description	Sum of all parenteral opioids used during the study period in milligrams (mg) of morphine or morphine equivalents.
Time Frame	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Mean (95% Confidence Interval) [milligrams (mg) of morphine equivalents]	225.2	264.6

4. Secondary Outcome

Title	Occurrence of Azotemia
Description	Participants who had measured values of blood urea nitrogen (BUN), serum creatinine, or both that were above the upper limit of normal for age.
Time Frame	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.

Outcome Measure Data

Analysis Population Description

Extremely slow accrual led to the trial closing in 2008. Because only 10% of planned enrollment was achieved, no analysis of the primary or secondary outcome data was performed because of lack of power and generalizability.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Count of Participants [Participants]	0 0%	0 0%

5. Secondary Outcome

Title	Fluid Retention
Description	Number of participants who had clinically overt fluid retention as determined by history, physical examination, vital signs, and weight (e.g., peripheral edema, increase in weight)
Time Frame	The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	Intravenous Ketorolac and Oral Placebo	Intravenous Placebo and Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo Intravenous Ketorolac: Intravenous ketorolac	Intravenous placebo and oral ibuprofen Ibuprofen: Ibuprofen, taken orally
Measure Participants	6	3
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Hematuria
Description	Number of participants who had microscopic hematuria as determined by urinalysis
Time Frame	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Count of Participants [Participants]	4 66.7%	1 25%

7. Secondary Outcome

Title	Dyspepsia
Description	Number of participants who reported discomfort in the stomach related to eating or drinking
Time Frame	The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Gastrointestinal Ulceration
Description	Number of participants who had gastrointestinal ulceration.
Time Frame	The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Count of Participants [Participants]	0 0%	0 0%

9. Secondary Outcome

Title	Bleeding
Description	Number of participants who had clinically overt bleeding from any site. This excludes microscopic hematuria only.
Time Frame	The entire study period (daily assessments during hospitalization [mean of 81.5 hours] and once at the 30-day follow-up visit, over a mean of 33.4 days)

Outcome Measure Data

Analysis Population Description

One participant was randomized but was discharged (unexpectedly early) from the hospital before study drug was administered. Thus, no primary or secondary outcome data are available for this one participant.

Arm/Group Title	IV Ketorolac / Oral Placebo	IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo	Intravenous placebo and oral ibuprofen
Measure Participants	6	3
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	All adverse events were systematically assessed at all study visits according to the study protocol by trained study personnel. Adverse events were recorded for up to 30 days from discharge from the hospital.
Arm/Group Title	IV Ketorolac / Oral Placebo		IV Placebo / Oral Ibuprofen
Arm/Group Description	Intravenous ketorolac and oral placebo		Intravenous placebo and oral ibuprofen
All Cause Mortality
	IV Ketorolac / Oral Placebo		IV Placebo / Oral Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/4 (0%)
Serious Adverse Events
	IV Ketorolac / Oral Placebo		IV Placebo / Oral Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	IV Ketorolac / Oral Placebo		IV Placebo / Oral Ibuprofen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/4 (100%)
Gastrointestinal disorders
Nausea	0/6 (0%)	0	1/4 (25%)	1
Vomiting	3/6 (50%)	3	1/4 (25%)	1
Immune system disorders
Fever	1/6 (16.7%)	1	1/4 (25%)	1
Renal and urinary disorders
Urinary Retention	1/6 (16.7%)	1	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	3/6 (50%)	3	2/4 (50%)	2
Acute chest syndrome	1/6 (16.7%)	1	0/4 (0%)	0

Limitations/Caveats

Extremely slow accrual led to the trial closing in 2008. Because less than 10% of planned enrollment was achieved, no statistical analysis of the primary or secondary outcome data was performed because of lack of power and generalizability.

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.