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The primary objective of this study is to characterize the pharmacokinetics and pharmacodynamics of hydromorphone oral solution in pediatric subjects aged 28 days to 16 years inclusive. The secondary objectives are to characterize the safety and efficacy of hydromorphone oral solution in pediatric subjects aged 28 days to 16 years inclusive.
Hydromorphone is an opioid analgesic that has been used for decades as an alternative to morphine in the treatment of moderate to severe malignant and nonmalignant pain. Only a small number of analgesics have been studied in children. The benefits to the subjects include contribution of knowledge that will provide for appropriate dosing regimen recommendations for future pediatric subjects.
Treatment consisted of both parenteral and oral hydromorphone. For up to 48 hours immediately following surgery, subjects were administered hydromorphone by IV PCA pump. Dosing with the oral hydromorphone HCl began when the subject was ready to take clear oral liquid. Subjects were administered oral hydromorphone HCl every 6 hours for up to 9 doses. The investigator determined the timing of the first dose based on each subject's clinical condition.
The duration of the treatment phase was up to 102 hours (up to 48 hours for the Parenteral Treatment Period and up to 54 hours for the Oral Treatment Period).
Efficacy was based on the oral hydromorphone treatment. Adverse events were collected for both the oral and parenteral treatments.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ≥ 28 Days to < 13 Months | Experimental | infant and toddler |
|
| ≥ 13 months to < 5 years | Experimental | young child |
|
| ≥ 5 years to < 12 years | Experimental | older child |
|
| ≥ 12 years to < 17 years | Experimental | adolescent |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydromorphone | Drug | Oral hydromorphone solution dosed every 6 hours up to 9 doses. Dose is determined based on the expected weight range for each age group. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model for Hydromorphone: Clearance (Cl) | Model was built using sparse blood samples: Sampling times: immediately predose, and between 0.25-0.75, 1-3, and 4-6 hours postdose for the first 2 doses of oral hydromorphone: predose for each dose of oral hydromorphone HCl thereafter; and at the end of study. Efficacy was based on Oral treatment only. | A maximum of 9 oral hydromorphone doses with potentially up to 54 hours duration. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean (SE) of Faces, Legs Activity, Cry, Consolability (FLACC) Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time [Ages >=28 Days to <5 Years] | There are 5 categories in this pediatric pain measurement: face, legs, activity, cry, and consolability. Responses in each category are scored between 0 and 2 (0 = normal, relaxed to 2 = upset, agitated), for a maximum total score of 10. The FLACC scale was used for children under the age of 3 years and older children who have limited verbal skills. |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol-specific inclusion/exclusion criteria may apply.
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| Name | Affiliation | Role |
|---|---|---|
| Gregory B. Hammer, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Arkansas Children's Hospital | Little Rock | Arkansas | 72202 | United States | ||
| Children's Hospital of Orange County - Pediatric Subspecialty |
Subjects who were anticipated to have acute, postoperative pain requiring oral opioid analgesics for at least 24 to 48 hours following postoperative parenteral analgesia.
23-Apr-2007 (first subject, first visit) to 03-May-2009 (last subject, last visit). Multicenter study conducted at 18 sites in the United States (US).
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| ID | Title | Description |
|---|---|---|
| FG000 | ≥ 28 Days to < 13 Months | Infant and toddler - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| FG001 | ≥ 13 Months to < 5 Years |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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|
| Immediately prior to first oral dose, up to 54 hours |
| Mean (SE) of Faces Pain Scale-Revised (FPS-R) [Ages >= 5 Years-< 12 Years] Pain Scores on Hydromorphone Alone (Oral/Supplemental)Over Time | Faces Pain Scale-Revised (FPS-R) consists of 6 facial expressions. Each face is 25 x 35 mm with 13 mm between faces. Each subject was asked to point to the face that reflected his or her pain. The end points are 0 = no pain and 10 = very much pain. The FPS-R scale was used for children over the age of 5 up to 12 years who have appropriate verbal skills. | Immediately prior to first oral dose with potentially up to 54 hours duration. |
| Mean (SE) of Visual Analog Scale (VAS) [Ages 12-16] Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time | The Visual Analog Scale (VAS), a 10-cm Color Analog Scale anchored by the descriptors of 0 = "no pain" and 10 = "most pain," was used by children ≥ 12 years of age. | Immediately prior to first oral dose, up to 54 hours |
| Orange |
| California |
| 92868 |
| United States |
| Stanford University Medical Center | Stanford | California | 94305 | United States |
| The Children's Hospital | Aurora | Colorado | 80218 | United States |
| Yale-New Haven Children's Hospital | New Haven | Connecticut | 06510 | United States |
| Jackson Memorial Hospital | Miami | Florida | 33136 | United States |
| University of Iowa Hospitals and Clinics | Iowa City | Iowa | 52242 | United States |
| Saint Louis University - Department of Neurology and Psychiatry | St Louis | Missouri | 63104 | United States |
| The University of North Carolina - CH | Chapel Hill | North Carolina | 27599-7221 | United States |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| Children's Hospital Medical Center of Akron | Akron | Ohio | 44308 | United States |
| Children's Medical Center | Dallas | Texas | 75235 | United States |
| Texas Children's Hospital / Baylor College of Medicine | Houston | Texas | 77030 | United States |
| The University of Texas, Health Sciences Center at Houston | Houston | Texas | 77030 | United States |
Young child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| FG002 | ≥ 5 Years to <12 Years | Older child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| FG003 | ≥ 12 Years to < 17 Years | Adolescent- received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | ≥ 28 Days to < 13 Months | Infant and toddler - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| BG001 | ≥ 13 Months to < 5 Years | Young child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| BG002 | ≥ 5 Years to < 12 Years | Older child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| BG003 | ≥ 12 Years to < 17 Years | Adolescent - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | months |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model for Hydromorphone: Clearance (Cl) | Model was built using sparse blood samples: Sampling times: immediately predose, and between 0.25-0.75, 1-3, and 4-6 hours postdose for the first 2 doses of oral hydromorphone: predose for each dose of oral hydromorphone HCl thereafter; and at the end of study. Efficacy was based on Oral treatment only. | The full analysis population for Pharmacokinetics/ Pharmacodynamics consisted of subjects who received at least 1 dose of oral hydromorphone HCl, and had at least 1 valid quantifiable PK sample. To be a valid sample, the time of administration of each dose of oral hydromorphone HCl, the dose, and the time of sample collection must be recorded. | Posted | Number | 95% Confidence Interval | L/hour | A maximum of 9 oral hydromorphone doses with potentially up to 54 hours duration. |
|
|
| |||||||||||||||||||||||||
| Secondary | Mean (SE) of Faces, Legs Activity, Cry, Consolability (FLACC) Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time [Ages >=28 Days to <5 Years] | There are 5 categories in this pediatric pain measurement: face, legs, activity, cry, and consolability. Responses in each category are scored between 0 and 2 (0 = normal, relaxed to 2 = upset, agitated), for a maximum total score of 10. The FLACC scale was used for children under the age of 3 years and older children who have limited verbal skills. | The Full Analysis Population for Efficacy consisted of subjects who received at least 1 dose of oral hydromorphone HCl and had at least 1 subsequent efficacy evaluation (pain measurement or supplemental pain medication). | Posted | Mean | Standard Error | units on a scale | Immediately prior to first oral dose, up to 54 hours |
| |||||||||||||||||||||||||||
| Secondary | Mean (SE) of Faces Pain Scale-Revised (FPS-R) [Ages >= 5 Years-< 12 Years] Pain Scores on Hydromorphone Alone (Oral/Supplemental)Over Time | Faces Pain Scale-Revised (FPS-R) consists of 6 facial expressions. Each face is 25 x 35 mm with 13 mm between faces. Each subject was asked to point to the face that reflected his or her pain. The end points are 0 = no pain and 10 = very much pain. The FPS-R scale was used for children over the age of 5 up to 12 years who have appropriate verbal skills. | The Full Analysis Population for Efficacy consisted of subjects who received at least 1 dose of oral hydromorphone HCl and had at least 1 subsequent efficacy evaluation (pain measurement or supplemental pain medication). | Posted | Mean | Standard Error | units on a scale | Immediately prior to first oral dose with potentially up to 54 hours duration. |
| |||||||||||||||||||||||||||
| Secondary | Mean (SE) of Visual Analog Scale (VAS) [Ages 12-16] Pain Scores on Hydromorphone Alone (Oral/Supplemental) Over Time | The Visual Analog Scale (VAS), a 10-cm Color Analog Scale anchored by the descriptors of 0 = "no pain" and 10 = "most pain," was used by children ≥ 12 years of age. | The Full Analysis Population for Efficacy consisted of subjects who received at least 1 dose of oral hydromorphone HCl and had at least 1 subsequent efficacy evaluation (pain measurement or supplemental pain medication). | Posted | Mean | Standard Error | unit on a scale | Immediately prior to first oral dose, up to 54 hours |
|
AEs that were ongoing or were reported during the 7 days following the subject's last dose of study drug were followed until resolution or for 30 days. SAEs were followed until the event resolved or the sequelae stabilized.
Adverse events were learned of through spontaneous reports and subject interview. The duration of treatment was up to 102 hours (up to 48 hours for the Parenteral Treatment Period and up to 54 hours for the Oral Treatment Period). Adverse events were collected for both parenteral and oral treatments.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Oral ≥ 28 Days to < 13 Months | Infant and toddler - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. | 2 | 39 | 21 | 39 | ||
| EG001 | Oral ≥ 13 Months to < 5 Years | Young child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. | 2 | 23 | 14 | 23 | ||
| EG002 | Oral ≥ 5 Years to <12 Years | Older child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. | 1 | 29 | 15 | 29 | ||
| EG003 | Oral ≥ 12 Years to < 17 Years | Adolescent - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. | 0 | 25 | 6 | 25 | ||
| EG004 | Parenteral ≥ 28 Days to < 13 Months | Infant and toddler - received parenteral analgesia up to 48 hours postsurgery. | 3 | 39 | 27 | 39 | ||
| EG005 | Parenteral ≥ 13 Months to < 5 Years | Young child - received parenteral analgesia up to 48 hours postsurgery. | 0 | 23 | 16 | 23 | ||
| EG006 | Parenteral ≥ 5 Years to < 12 Years | Older child - received parenteral analgesia up to 48 hours postsurgery. | 1 | 29 | 19 | 29 | ||
| EG007 | Parenteral ≥ 12 Years to < 17 Years | Adolescent - received parenteral analgesia up to 48 hours postsurgery. | 1 | 25 | 17 | 25 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Disseminated intravascular coagulation | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pericardial effusion - DEATH | Cardiac disorders | MedDRA (10.0) | Systematic Assessment | Pre-treatment |
|
| Vascular procedure complication - DEATH | Injury, poisoning and procedural complications | MedDRA (10.0) | Systematic Assessment |
| |
| Chylothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Laryngeal oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Streptococcus pneumonia | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
| |
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pulmonary hypertensive crisis | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Respiratory depression | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypovolaemic shock | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Sedation | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Chylothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Respiratory alkalosis | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Respiratory depression | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Anaemia | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Urine output decreased | Investigations | MedDRA (10.0) | Systematic Assessment |
| |
| Oxygen saturation decreased | Investigations | MedDRA (10.0) | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypovolaemia | Metabolism and nutrition disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Agitation | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Restlessness | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Stridor | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Lymphopenia | Blood and lymphatic system disorders | MedDRA (10.0) | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (10.0) | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Executive Medical Director | Purdue Pharma L.P. | 800-733-1333 |
| ID | Term |
|---|---|
| D010149 | Pain, Postoperative |
| ID | Term |
|---|---|
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D004091 | Hydromorphone |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
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| Male |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| Unknown or Not Reported |
|
| Oral ≥ 5 Years to < 12 Years |
Older child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| OG003 | Oral ≥ 12 Years to < 17 Years | Adolescent (Data for this group not collected. Test not appropriate for this age) |
|
|
Older child - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
| OG003 | Oral ≥ 12 Years to < 17 Years | Adolescent (Data for this group not collected. Test not appropriate for this age) |
|
|
Adolescent - received oral hydromorphone HCl every 6 hours, for a total of up to 9 doses, according to the dosing schedule. Starting doses were determined based on weight for this age group. |
|
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