Sickle Cell Disease
Conditions
Keywords
Pain control
Brief summary
This is a phase II double-blind placebo-controlled clinical trial evaluating the effect of gabapentin when added to standard pain management for patients with sickle cell disease experiencing acute pain crisis in the ambulatory care setting. Sickle cell pain is different for every patient. Some patients get complete relief from routine pain medicines, and others need more time or more doses of pain medicines before the pain goes away completely. It is known that humans have many types of pain, including something called neuropathic pain. Neuropathic pain in other conditions (such as diabetes) has been treated successfully with a medicine called gabapentin. The investigators in this study suspect that some sickle cell pain is a combination of pain types. They would like to see if adding gabapentin to the usual pain medicines makes pain go away faster or more completely. Primary Objective: * To assess the analgesic efficacy of gabapentin vs. placebo for pain during vaso-occlusive crisis (VOC) in participants with sickle cell disease (SCD). A response to study drug will be defined by a decrease in pain score of ≥ 33% between presentation to the acute care setting and assessment at 3 hours post administration of study drug. Secondary Objective: * To compare the total morphine equivalent dose (mg/kg) used to control pain during VOC between presentation to the acute care setting and assessment at 3 hours post administration of study drug in the gabapentin vs. placebo groups.
Detailed description
Upon participant enrollment, study staff will randomize the participant to one of 2 possible treatment arms: a single dose of gabapentin or a single dose of placebo. Morphine or other opioid and non-steroidal anti-inflammatory drugs will be available to both groups as needed for pain and will be administered according to the current standard of care for pain in VOC from the Department of Hematology at St. Jude Children's Research Hospital (SJCRH). Randomization will be performed in the SJCRH pharmacy by a pharmacist. The randomization will be stratified by three age categories (1-3 years of age, 4-6 years, and 7 years or older) for which distinct pain assessment tools are applied and for 2 pain score categories at assessment at presentation (4-6 and 7-10, respectively). A block randomization with block sizes varying randomly between 4 and 6 will be used in each stratum. Pain scores will be obtained at presentation to the acute care setting and 3 hours (± 15 minutes) post administration of study drug. Participants who were discharged will be contacted by study staff between 24 and 72 hours following administration of study drug to see if there have been any side effects. Patients who were admitted after administration of the study drug will be monitored through hospital record to determine if any unexpected events occurred. After this follow up, participation in the study is complete.
Interventions
DRUGGabapentin
Gabapentin is supplied as an oral suspension. Patients randomized to the gabapentin arm will receive a single dose of gabapentin as soon after enrollment as feasible. The gabapentin dose will be given orally and will be approximately 15 mg/kg with a maximum dose of 900 mg.
DRUGPlacebo
Placebo will be prepared by the SJCRH pharmacy and will be similar in appearance, quantity and taste to the gabapentin drug. Patients randomized to the placebo arm will receive a single dose of placebo as soon after enrollment as feasible. The placebo dose will be given orally and will be approximately 15 mg/kg with a maximum dose of 900mg.
Sponsors
Scan | Design Foundation
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to 20 Years
Healthy volunteers
No
Inclusion criteria
* Participant must have sickle cell disease (any genotype) documented in the St. Jude medical record. * Participant must be seeking care for acute vaso-occlusive pain at St. Jude Children's Research Hospital. * Participant age must be ≥1 year and \<21 years.
Exclusion criteria
* Prior randomization in this study. * Mild pain (score \<4) or pain for which treatment with opioid is not indicated. * Pregnant or lactating female. * Decreased glomerular filtration rate (GFT) (\<60ml/min/1.73m\^2) as estimated by the revised Schwartz equation. * Current treatment with gabapentinoid drugs (gabapentin or pregabalin). * Known seizure disorder. * Current treatment with antiepileptic agents. * Pain in combination with other clinical symptoms that require additional interventions, including fever with focus, acute chest syndrome, acute injury, or splenic sequestration. * Allergy to gabapentin. * Current participation in another research study with an investigational new drug/device (IND/IDE) agent. * Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug | Baseline and 3 hours (±30 minutes) post administration of study drug. The 3-hour pain assessment time-period was extended for subjects that were sleep until the first available measurement. | Pain scales used are the numerical rating system, the Faces Pain Scale, and the Faces, Legs, Arms, Cry and Consolability (FLACC) pain scale (for patients 7 years or older, ages 4-6 years, or less than 4 years, respectively). For each patient, if the reduction of the pain scores (0=no pain and 10=worst possible pain) between presentation to the acute care setting and 3 hours post administration of study drug is 33% or greater, then this patient will be defined as having a successful intervention. The proportions of successful interventions in the gabapentin and placebo groups will be estimated and compared using Z-test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Morphine Equivalent Doses Administered From Presentation to 3-hours Post Treatment With Gabapentin/Placebo | The 3-hour pain assessment was the pain assessment closest in time to the 3-hour time and was typically within 30 minutes of target. The time period was extended for 12 patients that were sleeping. | The equivalent dose of morphine in mg |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hospital Admission | From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours. | To compare the rate of admission related to pain management, in the gabapentin vs. placebo groups. (Outcome: binary response - admitted or discharged) |
| Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home | From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours. | For each patient, if the reduction of the pain scores (0=no pain and 10=worst possible pain) between presentation to the acute care setting and Point of decision for either hospital admission or discharge to home is 33% or greater, then this patient will be defined as having a successful intervention. |
| Absolute Change in Pain, Study Drug to Hospital Discharge Decision | From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours. | To compare the change in pain score from time of administration of study drug to the point of decision for either admission or discharge to home, in the gabapentin and placebo groups. (0=no pain and 10=worst possible pain) |
| Absolute Change in Pain From Study Drug to 3 Hours Post Administration of Study Drug | Study drug administration to 3-hours post study drug administration | To compare the change in pain score from time of administration of study drug to assessment at 3 hours post administration of study drug in the gabapentin vs. placebo groups. (0=no pain and 10=worst possible pain) |
| Morphine Equivalent Doses Administered From Presentation to the Point of Decision for Either Admission or Discharge to Home | From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours. | To compare the total morphine equivalent dose (mg/kg) used to control pain during VOC between presentation to the acute care setting and the point of decision for either admission or discharge to home, in the gabapentin and placebo groups. |
Countries
United States
Participant flow
Recruitment details
Participants meeting eligibility criteria were enrolled between 10/7/2013 to 1/3/2018. They were randomized to either gabapentin or placebo.
Pre-assignment details
The study was stopped early due to slow accrual when there were 82 patients with evaluable pain assessments available for the primary objective. Patients asleep at pain assessment times led to missing pain assessments.
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin Participants were randomized to receive one dose of gabapentin.
Gabapentin: Gabapentin is supplied as an oral suspension. Patients randomized to the gabapentin arm received a single dose of gabapentin as soon after enrollment as feasible, given orally, approximately 15 milligram/kilogram (mg/kg) with a maximum dose of 900 milligram (mg). | 42 |
| Placebo Participants were randomized to receive one dose of placebo.
Placebo: Placebo was prepared by the SJCRH pharmacy, similar in appearance, quantity and taste to the gabapentin drug. Patients randomized to the placebo arm received a single dose of placebo as soon after enrollment as feasible, given orally, in a volume that matched the active medication arm. | 44 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Gabapentin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 42 Participants | 39 Participants | 81 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Continuous | 11.8 years STANDARD_DEVIATION 5.3 | 11.8 years STANDARD_DEVIATION 4.5 | 11.8 years STANDARD_DEVIATION 4.9 |
| Pain at presentation (before randomization) | 7.7 units on a scale STANDARD_DEVIATION 1.9 | 8.0 units on a scale STANDARD_DEVIATION 1.6 | 7.8 units on a scale STANDARD_DEVIATION 1.8 |
| Pain score category at presentation 4-6 | 12 Participants | 10 Participants | 22 Participants |
| Pain score category at presentation 7-10 | 32 Participants | 32 Participants | 64 Participants |
| Race/Ethnicity, Customized Black | 44 Participants | 42 Participants | 86 Participants |
| Race/Ethnicity, Customized Non-Spanish speaking Non Hispanic | 44 Participants | 40 Participants | 84 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 44 participants | 42 participants | 86 participants |
| Sex: Female, Male Female | 22 Participants | 13 Participants | 35 Participants |
| Sex: Female, Male Male | 22 Participants | 29 Participants | 51 Participants |
| Sickle cell genotype Hemoglobin SC | 15 Participants | 10 Participants | 25 Participants |
| Sickle cell genotype Hemoglobin SS | 26 Participants | 18 Participants | 44 Participants |
| Sickle cell genotype Other | 1 Participants | 8 Participants | 9 Participants |
| Sickle cell genotype SBeta Zero Thalassemia | 2 Participants | 6 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 44 |
| other Total, other adverse events | 5 / 42 | 2 / 44 |
| serious Total, serious adverse events | 0 / 42 | 0 / 44 |
Outcome results
Primary
Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug
Pain scales used are the numerical rating system, the Faces Pain Scale, and the Faces, Legs, Arms, Cry and Consolability (FLACC) pain scale (for patients 7 years or older, ages 4-6 years, or less than 4 years, respectively). For each patient, if the reduction of the pain scores (0=no pain and 10=worst possible pain) between presentation to the acute care setting and 3 hours post administration of study drug is 33% or greater, then this patient will be defined as having a successful intervention. The proportions of successful interventions in the gabapentin and placebo groups will be estimated and compared using Z-test.
Time frame: Baseline and 3 hours (±30 minutes) post administration of study drug. The 3-hour pain assessment time-period was extended for subjects that were sleep until the first available measurement.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital. A total of 4 subjects were missing the pain assessment at 3 hours (2 in each arm). The resulting sample sizes were n=40 (Gabapentin arm) and n=42 (placebo arm), for a total sample size of n=82.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gabapentin | Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug | No | 13 Participants |
| Gabapentin | Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug | Yes | 27 Participants |
| Placebo | Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug | No | 17 Participants |
| Placebo | Number of Participants With Successful Pain Interventions by Arm Between Presentation and 3 Hours Post Administration of Study Drug | Yes | 25 Participants |
p-value: 0.227z-test Proportion
Secondary
Morphine Equivalent Doses Administered From Presentation to 3-hours Post Treatment With Gabapentin/Placebo
The equivalent dose of morphine in mg
Time frame: The 3-hour pain assessment was the pain assessment closest in time to the 3-hour time and was typically within 30 minutes of target. The time period was extended for 12 patients that were sleeping.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gabapentin | Morphine Equivalent Doses Administered From Presentation to 3-hours Post Treatment With Gabapentin/Placebo | 0.12 mg/kg |
| Placebo | Morphine Equivalent Doses Administered From Presentation to 3-hours Post Treatment With Gabapentin/Placebo | 0.13 mg/kg |
p-value: 0.897Wilcoxon (Mann-Whitney)
Other Pre-specified
Absolute Change in Pain From Study Drug to 3 Hours Post Administration of Study Drug
To compare the change in pain score from time of administration of study drug to assessment at 3 hours post administration of study drug in the gabapentin vs. placebo groups. (0=no pain and 10=worst possible pain)
Time frame: Study drug administration to 3-hours post study drug administration
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital. Placebo arm: 6 subjects missed pain assessments at treatment; 2 missed pain assessment at 3h. Gabapentin arm: 7 missed pain assessment at treatment; 2 of the 7 also missed the assessment at 3h.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gabapentin | Absolute Change in Pain From Study Drug to 3 Hours Post Administration of Study Drug | 0 score on a scale |
| Placebo | Absolute Change in Pain From Study Drug to 3 Hours Post Administration of Study Drug | 0.5 score on a scale |
p-value: 0.739Wilcoxon (Mann-Whitney)
Other Pre-specified
Absolute Change in Pain, Study Drug to Hospital Discharge Decision
To compare the change in pain score from time of administration of study drug to the point of decision for either admission or discharge to home, in the gabapentin and placebo groups. (0=no pain and 10=worst possible pain)
Time frame: From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital. Placebo arm: 6 subjects missed pain assessments at treatment. Gabapentin arm: 7 subjects missed pain assessment at treatment; 2 of the 7 missed the assessment at hospital discharge decision.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gabapentin | Absolute Change in Pain, Study Drug to Hospital Discharge Decision | 1.0 score on a scale |
| Placebo | Absolute Change in Pain, Study Drug to Hospital Discharge Decision | 0.5 score on a scale |
p-value: 0.388Wilcoxon (Mann-Whitney)
Other Pre-specified
Hospital Admission
To compare the rate of admission related to pain management, in the gabapentin vs. placebo groups. (Outcome: binary response - admitted or discharged)
Time frame: From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gabapentin | Hospital Admission | No | 32 Participants |
| Gabapentin | Hospital Admission | Yes | 10 Participants |
| Placebo | Hospital Admission | No | 32 Participants |
| Placebo | Hospital Admission | Yes | 12 Participants |
p-value: 0.713Chi-squared
Other Pre-specified
Morphine Equivalent Doses Administered From Presentation to the Point of Decision for Either Admission or Discharge to Home
To compare the total morphine equivalent dose (mg/kg) used to control pain during VOC between presentation to the acute care setting and the point of decision for either admission or discharge to home, in the gabapentin and placebo groups.
Time frame: From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gabapentin | Morphine Equivalent Doses Administered From Presentation to the Point of Decision for Either Admission or Discharge to Home | 0.13 mg/kg |
| Placebo | Morphine Equivalent Doses Administered From Presentation to the Point of Decision for Either Admission or Discharge to Home | 0.13 mg/kg |
p-value: 0.73Wilcoxon (Mann-Whitney)
Other Pre-specified
Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home
For each patient, if the reduction of the pain scores (0=no pain and 10=worst possible pain) between presentation to the acute care setting and Point of decision for either hospital admission or discharge to home is 33% or greater, then this patient will be defined as having a successful intervention.
Time frame: From time of presentation to the acute care setting until time of either discharge to home or admission to the hospital, up to 8 hours.
Population: Patients with Sickle cell disease (any genotype) ages ≥1 year and \<21 years seeking care for acute vaso-occlusive pain at St Jude Children's Hospital. There were 2 subjects in the Gabapentin group that did not have a pain assessment admit/discharge decision. N=84 patients had assessments at both presentation and admit/discharge.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gabapentin | Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home | No | 10 Participants |
| Gabapentin | Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home | Yes | 30 Participants |
| Placebo | Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home | Yes | 27 Participants |
| Placebo | Number of Participants With Successful Pain Interventions by Arm Between Presentation and Point of Decision for Either Hospital Admission or Discharge to Home | No | 17 Participants |
p-value: 0.181Chi-squared