Ketorolac Versus Ibuprofen to Treat Painful Episodes of Sickle Cell Disease

Ketorolac Versus Ibuprofen for the Painful Crisis of Sickle Cell Disease - Southwestern Comprehensive Sickle Cell Center

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).

Study Overview

• Status: Terminated
• Conditions: Hematologic Diseases; Anemia, Sickle Cell
• Intervention / Treatment: Drug: Intravenous Ketorolac; Drug: Ibuprofen

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to a 50% Reduction in Reported Pain Intensity	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	Measured every 4 hours during hospitalization, over a mean hospitalization duration of 81.5 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Hospitalization	Time between admission to the hospital and discharge from the hospital	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.
Total Parenteral Opioid Usage	Sum of all parenteral opioids used during the study period in milligrams (mg) of morphine or morphine equivalents.	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.
Occurrence of Azotemia	Participants who had measured values of blood urea nitrogen (BUN), serum creatinine, or both that were above the upper limit of normal for age.	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.
Fluid Retention	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)	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)
Hematuria	Number of participants who had microscopic hematuria as determined by urinalysis	The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.
Dyspepsia	Number of participants who reported discomfort in the stomach related to eating or drinking	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)
Gastrointestinal Ulceration	Number of participants who had 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)
Bleeding	Number of participants who had clinically overt bleeding from any site. This excludes microscopic hematuria only.	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)

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: 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 record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: June 21, 2005
• First Submitted That Met QC Criteria: June 21, 2005
• First Posted (Estimate): June 22, 2005

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Sickle Cell Anemia; Blood Diseases
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Hematologic Diseases; Anemia, Sickle Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketorolac; Ibuprofen
• Other Study ID Numbers: 191; U54HL070588 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No