Ketorolac Versus Ibuprofen to Treat Painful Episodes of Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT00115336
• Recruitment Status: Terminated
• First Posted: June 22, 2005
• Results First Posted: October 8, 2020
• Last Update Posted: October 8, 2020
• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Children's Hospital Medical Center, Cincinnati

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 (Clinical Trial)
• 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: January 2005
• Actual Primary Completion Date: August 2008
• Actual Study Completion Date: December 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 Name: Toradol
Active Comparator: 2-Intravenous placebo and oral ibuprofen; Intravenous placebo and oral ibuprofen	Drug: Ibuprofen; Ibuprofen, taken orally; Other Name: Motrin, Advil

Outcome Measures

Primary Outcome Measures :

1. Time to a 50% Reduction in Reported Pain Intensity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ 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) ]
   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 [ Time Frame: 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 [ 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) ]
   Number of participants who reported discomfort in the stomach related to eating or drinking
7. 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) ]
   Number of participants who had gastrointestinal ulceration.
8. Bleeding [ 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) ]
   Number of participants who had clinically overt bleeding from any site. This excludes microscopic hematuria only.

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Texas

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

More Information

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT00115336
• Other Study ID Numbers: 191; U54HL070588 ( U.S. NIH Grant/Contract )
• First Posted: June 22, 2005
• Results First Posted: October 8, 2020
• Last Update Posted: October 8, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• 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; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Genetic Diseases, Inborn; Ibuprofen; Ketorolac; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action