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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
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Acyclovir is a drug used to treat herpes simplex virus (HSV) infections in babies. Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been adequately studied in full-term or premature neonates. HSV is a very serious infection in babies <6 months of age and often results in death or profound mental retardation. HSV leads to profound mental retardation in young infants because the virus attacks the central nervous system.
The investigators hypothesize that the currently recommended dose of acyclovir is inadequate to produce adequate blood levels to combat herpes simplex infection. The investigators propose to study acyclovir levels in the blood of babies who are placed on acyclovir to treat a suspected HSV infection. This will allow them to determine the appropriate dose in premature infants. This is an unmet public health need because it is likely that the drug behaves differently in premature infants than it does in term infants and older children. Premature babies have more body water and less body tissue. Their kidneys are more immature and do not function as well as full term infants. Premature neonates are also at the greatest risk from herpes infection because they have poorly functioning immature immune systems. Early and appropriate treatment with acyclovir has resulted in improved outcome in term infants.
Neonatal herpes infection carries a major risk of death if untreated. Prognosis is related to disease extent and timing of therapy, making early diagnosis crucial. Mortality in the pre-antiviral era was 90% for disseminated disease and 50% for central nervous system (CNS) disease. Institution of high-dose (60 mg/kg/day) antiviral therapy with acyclovir has reduced mortality to 31% for disseminated disease and 6% for CNS disease.1 Although acyclovir has reduced mortality dramatically, morbidity remains high.
Study population: Infants < 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age:
Group-1: 23-29 weeks gestational age, <14 days postnatal age Group-2: 23-29 weeks gestational age, 14-44 days postnatal age Group-3: 30-34 weeks gestational age, <45 days postnatal age
Intravenous acyclovir will be administered for 3 days.
Timing of PK sample collection will be with respect to the end of each IV infusion. Timed PK sampling will be drawn at doses 1, and doses 5, 6, 7, 8, or 9.
Dose 1:
0-15 minutes after completion of the 1st dose; Within 30 minutes prior to administration of 2nd dose
Steady state [doses 5 or 6 (groups 1 and 2), doses 8 or 9 (group 3)]:
Within 30 minutes prior to dose; 0-15 minutes after completion of the dose; 2-3 hours after completion of the dose; Within 30 minutes prior to administration of the next dose
Last dose:
6-7 hours after the last dose (groups 1 and 2)and 10-11 hours after the last dose (group 3)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12 | Active Comparator | Gestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8 |
|
| Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12 | Active Comparator | Gestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8 |
|
| Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8 | Active Comparator | Gestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4 |
|
| Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h | Other | All patients in protocol V1 were to be dosed with 500 mg/m2 IV q8h. Protocol V1 Group 1: Gestational Age: 23-29 Weeks; PNA: <14 days; Protocol V1 Group 2: Gestational Age: 30-42 Weeks; PNA: <14 days; Protocol V1 Group 3: Gestational Age: 23-29 Weeks; PNA: 14-60 days; Protocol V1 Group 4: Gestational Age: 30-42 Weeks; PNA: 14-60 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acyclovir | Drug | Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days). |
| Measure | Description | Time Frame |
|---|---|---|
| Clearance (CL) | Timeframe: Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose | V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose |
| Volume of Distribution (V) | up to 3 days of study drug administration and 10 days of safety monitoring | |
| Half-life (T1/2) | up to 3 days of study drug administration and 10 days of safety monitoring | |
| Maximum Steady State Concentration (Cmaxss) | up to 3 dasy of study drug administration and 10 days of safety monitoring | |
| Steady State Concentration at 50% of the Dosing Interval (C50ss) | up to 3 days of study drug administration and 10 days of safety monitoring | |
| Minimum Steady State Concentration (Cminss) | up to 3 days of study drug administration and 10 days of safety monitoring |
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The investigator or other study site personnel will document in the source documents (e.g., the hospital chart) that informed consent was obtained. Laboratory tests or non-pharmacologic treatment procedures that were performed as standard of care within 72 hours prior to first dose of study drug may be used for screening procedures and recorded in the CRF.
Inclusion Criteria
< 45 days of age at the time of initial study drug administration.
Sufficient venous access to permit administration of study medication.
Availability and willingness of the parent/legal guardian to provide written informed consent.
Suspected HSV sepsis OR At least two (2) of the following
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Phillip B Smith, M.D. | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wesely Medical Center | Wichita | Kansas | 67214-4976 | United States | ||
| Tulane School of Medicine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12118847 | Background | Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. doi: 10.1053/spid.2002.29752. | |
| 11483782 | Background | Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong SJ, Kiell J, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001 Aug;108(2):230-8. doi: 10.1542/peds.108.2.230. |
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Total enrollment is 32. 32 for safety analysis and 30 in PK population (28 included in final PK analysis).
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| ID | Title | Description |
|---|---|---|
| FG000 | Acyclovir Study Enrollment | Two open-label PK studies contributed the data for this report. Version 1 was single-center and Version >=2 was multi-center. Acyclovir was administered intravenously as a 1-hour infusion for up to 3 days. Dosing in Study 1 was 500 mg/m2 every 8 hours. Dosing in Study 2 was determined by GA and PNA: 10 mg/kg every 12 hours (23-29 weeks GA and <14 days PNA); 20 mg/kg every 12 hours (23-29 weeks GA and 14-44 days PNA); and 20 mg/kg every 8 hours (30-34 weeks GA and <45 days PNA). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Acyclovir Study Design | Two open-label PK studies contributed the data for this report. Version 1 was single-center and Version >=2 was multi-center. Acyclovir was administered intravenously as a 1-hour infusion for up to 3 days. Dosing in Study 1 was 500 mg/m2 every 8 hours. Dosing in Study 2 was determined by GA and PNA: 10 mg/kg every 12 hours (23-29 weeks GA and <14 days PNA); 20 mg/kg every 12 hours (23-29 weeks GA and 14-44 days PNA); and 20 mg/kg every 8 hours (30-34 weeks GA and <45 days PNA). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Clearance (CL) | Timeframe: Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | L/h/kg | V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose |
|
Up to 3 days of study drug administration and 10 days of safety monitoring
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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 | Acyclovir Study Design | Two open-label PK studies contributed the data for this report. Version 1 was single-center and Version >=2 was multi-center. Acyclovir was administered intravenously as a 1-hour infusion for up to 3 days. Dosing in Study 1 was 500 mg/m2 every 8 hours. Dosing in Study 2 was determined by GA and PNA: 10 mg/kg every 12 hours (23-29 weeks GA and <14 days PNA); 20 mg/kg every 12 hours (23-29 weeks GA and 14-44 days PNA); and 20 mg/kg every 8 hours (30-34 weeks GA and <45 days PNA). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | General disorders | Systematic Assessment | 1 infant died due to nonketotic hyperglycinaemia and 1 infant dies due to sepsis. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haemolytic anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| P. Brian Smith, MD MPH MHS | Duke Clinical Research Institute | 919-668-8951 | brian.smith@duke.edu |
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| ID | Term |
|---|---|
| D006561 | Herpes Simplex |
| D000071074 | Neonatal Sepsis |
| D047928 | Premature Birth |
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D006566 | Herpesviridae Infections |
| D004266 | DNA Virus Infections |
| D014777 | Virus Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D000212 | Acyclovir |
| ID | Term |
|---|---|
| D006147 | Guanine |
| D007042 | Hypoxanthines |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 |
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|
| New Orleans |
| Louisiana |
| 70112 |
| United States |
| Duke University | Durham | North Carolina | 27713 | United States |
| 7048912 | Background | Lietman PS. Acyclovir clinical pharmacology. An overview. Am J Med. 1982 Jul 20;73(1A):193-6. doi: 10.1016/0002-9343(82)90089-4. |
| 2066845 | Background | Englund JA, Fletcher CV, Balfour HH Jr. Acyclovir therapy in neonates. J Pediatr. 1991 Jul;119(1 Pt 1):129-35. doi: 10.1016/s0022-3476(05)81053-4. |
| 7048911 | Background | Blum MR, Liao SH, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med. 1982 Jul 20;73(1A):186-92. doi: 10.1016/0002-9343(82)90088-2. |
| 6285713 | Background | Hintz M, Connor JD, Spector SA, Blum MR, Keeney RE, Yeager AS. Neonatal acyclovir pharmacokinetics in patients with herpes virus infections. Am J Med. 1982 Jul 20;73(1A):210-4. doi: 10.1016/0002-9343(82)90093-6. |
| 6285712 | Background | Yeager AS. Use of acyclovir in premature and term neonates. Am J Med. 1982 Jul 20;73(1A):205-9. doi: 10.1016/0002-9343(82)90092-4. |
| Background | Pickering LK. Red Book. 28th ed. Elk Grove Village, Illinois: American Academy of Pediatrics; 2009. |
| 18639724 | Background | Kimberlin DW. When should you initiate acyclovir therapy in a neonate? J Pediatr. 2008 Aug;153(2):155-6. doi: 10.1016/j.jpeds.2008.04.027. No abstract available. |
| 7251524 | Background | Brigden D, Bye A, Fowle AS, Rogers H. Human pharmacokinetics of acyclovir (an antiviral agent) following rapid intravenous injection. J Antimicrob Chemother. 1981 Apr;7(4):399-404. doi: 10.1093/jac/7.4.399. No abstract available. |
| 3335815 | Background | Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis. 1988 Feb;157(2):385-8. doi: 10.1093/infdis/157.2.385. No abstract available. |
| 18846389 | Result | Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76. doi: 10.1007/s00467-008-0997-5. Epub 2008 Oct 10. |
| days |
|
| Age, Continuous | Median | Full Range | weeks |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Birthweight | Median | Full Range | grams |
|
|
|
| Primary | Volume of Distribution (V) | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | L/kg | up to 3 days of study drug administration and 10 days of safety monitoring |
|
|
|
| Primary | Half-life (T1/2) | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | h | up to 3 days of study drug administration and 10 days of safety monitoring |
|
|
|
| Primary | Maximum Steady State Concentration (Cmaxss) | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | mg/L | up to 3 dasy of study drug administration and 10 days of safety monitoring |
|
|
|
| Primary | Steady State Concentration at 50% of the Dosing Interval (C50ss) | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | mg/L | up to 3 days of study drug administration and 10 days of safety monitoring |
|
|
|
| Primary | Minimum Steady State Concentration (Cminss) | 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis. | Posted | Median | Full Range | mg/L | up to 3 days of study drug administration and 10 days of safety monitoring |
|
|
|
| 4 |
| 32 |
| 21 |
| 32 |
|
| Neuroblastoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Neonatal asphyxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Cardiomegaly | Cardiac disorders | Systematic Assessment |
|
| Atrial septal defect | Congenital, familial and genetic disorders | Systematic Assessment |
|
| Congenital cardiovascular anomaly | Congenital, familial and genetic disorders | Non-systematic Assessment |
|
| Nonketotic hyperglycinaemia | Congenital, familial and genetic disorders | Systematic Assessment |
|
| Patent ductus arteriosus | Congenital, familial and genetic disorders | Systematic Assessment |
|
| Ventricular septal defect | Congenital, familial and genetic disorders | Systematic Assessment |
|
| Adrenal insufficiency | Endocrine disorders | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | Systematic Assessment |
|
| Hyperbilirubinaemia neonatal | Hepatobiliary disorders | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Blood creatinine abnormal | Investigations | Systematic Assessment |
|
| Blood creatinine increased | Investigations | Systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | Systematic Assessment |
|
| Electrolyte imbalance | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Neonatal hyponatraemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Intraventricular haemorrhage neonatal | Nervous system disorders | Systematic Assessment |
|
| Renal failure | Renal and urinary disorders | Systematic Assessment |
|
| Apnoea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Chronic respiratory disease | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Infantile apnoeic attack | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dermatitis diaper | Skin and subcutaneous tissue disorders |
|
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| D017193 |
| Skin Diseases, Viral |
| D012874 | Skin Diseases, Infectious |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |