Hematologic Diseases, Anemia, Sickle Cell
Conditions
Keywords
Blood Diseases, Sickle Cell Anemia
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).
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.
Interventions
Intravenous ketorolac
DRUGIbuprofen
Ibuprofen, taken orally
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Texas Southwestern Medical Center
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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) |
| 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 |
| 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 |
| 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. |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| IV Ketorolac / Oral Placebo Intravenous ketorolac and oral placebo | 6 |
| IV Placebo / Oral Ibuprofen Intravenous placebo abd oral ibuprofen | 4 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Hospital discharge before study drug | 0 | 1 |
Baseline characteristics
| Characteristic | IV Placebo / Oral Ibuprofen | IV Ketorolac / Oral Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 17.7 years | 15.4 years | 16.7 years |
| Region of Enrollment United States | 4 participants | 6 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 4 |
Outcome results
Primary
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
Time frame: Measured every 4 hours during hospitalization, over a mean hospitalization duration of 81.5 hours.
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Time to a 50% Reduction in Reported Pain Intensity | 58.4 hours |
| IV Placebo / Oral Ibuprofen | Time to a 50% Reduction in Reported Pain Intensity | 68.0 hours |
Secondary
Bleeding
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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Bleeding | 0 Participants |
| IV Placebo / Oral Ibuprofen | Bleeding | 0 Participants |
Secondary
Duration of Hospitalization
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.
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Duration of Hospitalization | 80.7 hours |
| IV Placebo / Oral Ibuprofen | Duration of Hospitalization | 83.0 hours |
Secondary
Dyspepsia
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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Dyspepsia | 0 Participants |
| IV Placebo / Oral Ibuprofen | Dyspepsia | 0 Participants |
Secondary
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)
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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Fluid Retention | 0 Participants |
| IV Placebo / Oral Ibuprofen | Fluid Retention | 0 Participants |
Secondary
Gastrointestinal Ulceration
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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Gastrointestinal Ulceration | 0 Participants |
| IV Placebo / Oral Ibuprofen | Gastrointestinal Ulceration | 0 Participants |
Secondary
Hematuria
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.
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Hematuria | 4 Participants |
| IV Placebo / Oral Ibuprofen | Hematuria | 1 Participants |
Secondary
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.
Time frame: The duration of the entire hospitalization, over a mean hospitalization duration of 81.5 hours.
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Occurrence of Azotemia | 0 Participants |
| IV Placebo / Oral Ibuprofen | Occurrence of Azotemia | 0 Participants |
Secondary
Total Parenteral Opioid Usage
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.
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| IV Ketorolac / Oral Placebo | Total Parenteral Opioid Usage | 225.2 milligrams (mg) of morphine equivalents |
| IV Placebo / Oral Ibuprofen | Total Parenteral Opioid Usage | 264.6 milligrams (mg) of morphine equivalents |