A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)

• Sponsor: Phillip Brian Smith (Other)
• Overall Status: Completed
• CT.gov ID: NCT00942084
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 32
• Locations: 3
• Arms: 4
• Duration (Months): 9
• Patients Per Site: 10.7
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Herpes Simplex Virus; Neonatal Sepsis	Drug: Acyclovir	Phase 1

Detailed Description

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)

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12 Gestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8	Drug: Acyclovir; 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).
Active Comparator: Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12 Gestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8	Drug: Acyclovir; 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).
Active Comparator: Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8 Gestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4	Drug: Acyclovir; 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).
Other: Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h 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	Drug: Acyclovir; 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).

Outcome Measures

Primary Outcome Measures

1. Clearance (CL) [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]

   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

2. Volume of Distribution (V) [up to 3 days of study drug administration and 10 days of safety monitoring]

3. Half-life (T1/2) [up to 3 days of study drug administration and 10 days of safety monitoring]

4. Maximum Steady State Concentration (Cmaxss) [up to 3 dasy of study drug administration and 10 days of safety monitoring]

5. Steady State Concentration at 50% of the Dosing Interval (C50ss) [up to 3 days of study drug administration and 10 days of safety monitoring]

6. Minimum Steady State Concentration (Cminss) [up to 3 days of study drug administration and 10 days of safety monitoring]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 45 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. < 45 days of age at the time of initial study drug administration.

2. Sufficient venous access to permit administration of study medication.

3. Availability and willingness of the parent/legal guardian to provide written informed consent.

4. Suspected HSV sepsis OR At least two (2) of the following

• Signs of sepsis AND negative blood cultures for >24 hours7

• Respiratory distress8

• Lethargy8

• Fever ≥ 38.0°C7

• Skin lesions7,8

• Seizures (clinical OR EEG confirmed)7

• Irritability7

• AST OR ALT >2 X upper limit of normal7,8

• 20 WBCs/µL or >500 RBCs/µL7

Exclusion Criteria

1. History of anaphylaxis attributed to acyclovir.

2. Serum creatinine >1.7 mg/dL.

3. Urine output <0.5 mL/kg/hour over the previous 12 hours

4. Previous participation in the study.

5. Concomitant condition, which in the opinion of the investigator would preclude a participant's participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wesely Medical Center	Wichita	Kansas	United States	67214-4976
2	Tulane School of Medicine	New Orleans	Louisiana	United States	70112
3	Duke University	Durham	North Carolina	United States	27713

Sponsors and Collaborators

• Phillip Brian Smith
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Phillip B Smith, M.D., Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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. Review.
• 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.
• Englund JA, Fletcher CV, Balfour HH Jr. Acyclovir therapy in neonates. J Pediatr. 1991 Jul;119(1 Pt 1):129-35.
• Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis. 1988 Feb;157(2):385-8.
• 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.
• 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.
• 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.
• Lietman PS. Acyclovir clinical pharmacology. An overview. Am J Med. 1982 Jul 20;73(1A):193-6. Review.
• Pickering LK. Red Book. 28th ed. Elk Grove Village, Illinois: American Academy of Pediatrics; 2009.
• Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. Review.
• Yeager AS. Use of acyclovir in premature and term neonates. Am J Med. 1982 Jul 20;73(1A):205-9.

• Responsible Party: Phillip Brian Smith, Associate Professor of Pediatrics, Duke University
• ClinicalTrials.gov Identifier: NCT00942084
• Other Study ID Numbers: Pro00028772
• First Posted: Jul 20, 2009
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Phillip Brian Smith, Associate Professor of Pediatrics, Duke University: HSV; Acyclovir; Pharmacokinetics; Neonate; Premature; Sepsis
• Additional relevant MeSH terms: Herpes Simplex; Neonatal Sepsis; Premature Birth; Acyclovir

Study Results

Participant Flow

Recruitment Details	Total enrollment is 32. 32 for safety analysis and 30 in PK population (28 included in final PK analysis).

Arm/Group Title	Acyclovir Study Enrollment
Arm/Group Description	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).
Period Title: Overall Study
STARTED	32
COMPLETED	30
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Overall Participants	32
Age (days) [Median (Full Range) ]
Postnatal Age (days)	3.0
Age (weeks) [Median (Full Range) ]
Gestational Age (weeks)	30.5
Sex: Female, Male (Count of Participants)
Female	17 53.1%
Male	15 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 12.5%
Not Hispanic or Latino	28 87.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 34.4%
White	20 62.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	32 100%
Birthweight (grams) [Median (Full Range) ]
Median (Full Range) [grams]	1295

Outcome Measures

1. Primary Outcome

Title	Clearance (CL)
Description	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
Time Frame	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

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [L/h/kg]	0.278

2. Primary Outcome

Title	Volume of Distribution (V)
Time Frame	up to 3 days of study drug administration and 10 days of safety monitoring

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [L/kg]	3.34

3. Primary Outcome

Title	Half-life (T1/2)
Time Frame	up to 3 days of study drug administration and 10 days of safety monitoring

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [h]	7.07

4. Primary Outcome

Title	Maximum Steady State Concentration (Cmaxss)
Time Frame	up to 3 dasy of study drug administration and 10 days of safety monitoring

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [mg/L]	11.1

5. Primary Outcome

Title	Steady State Concentration at 50% of the Dosing Interval (C50ss)
Time Frame	up to 3 days of study drug administration and 10 days of safety monitoring

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [mg/L]	6.33

6. Primary Outcome

Title	Minimum Steady State Concentration (Cminss)
Time Frame	up to 3 days of study drug administration and 10 days of safety monitoring

Outcome Measure Data

Analysis Population Description

32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.

Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
Measure Participants	28
Median (Full Range) [mg/L]	4.15

Adverse Events

Time Frame	Up to 3 days of study drug administration and 10 days of safety monitoring
Arm/Group Title	Acyclovir Study Design
Arm/Group Description	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).
All Cause Mortality
	Acyclovir Study Design
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Acyclovir Study Design
	Affected / at Risk (%)	# Events
Total	4/32 (12.5%)
General disorders
Death	2/32 (6.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroblastoma	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Neonatal asphyxia	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Acyclovir Study Design
	Affected / at Risk (%)	# Events
Total	21/32 (65.6%)
Blood and lymphatic system disorders
Haemolytic anemia	1/32 (3.1%)	1
Cardiac disorders
Cardiomegaly	1/32 (3.1%)	1
Congenital, familial and genetic disorders
Atrial septal defect	1/32 (3.1%)	1
Congenital cardiovascular anomaly	7/32 (21.9%)	7
Nonketotic hyperglycinaemia	1/32 (3.1%)	1
Patent ductus arteriosus	3/32 (9.4%)	3
Ventricular septal defect	1/32 (3.1%)	1
Endocrine disorders
Adrenal insufficiency	3/32 (9.4%)	3
Hepatobiliary disorders
Hyperbilirubinaemia	1/32 (3.1%)	1
Hyperbilirubinaemia neonatal	1/32 (3.1%)	1
Infections and infestations
Sepsis	1/32 (3.1%)	1
Investigations
Blood creatinine abnormal	1/32 (3.1%)	1
Blood creatinine increased	1/32 (3.1%)	1
Electrocardiogram QT prolonged	1/32 (3.1%)	1
Metabolism and nutrition disorders
Electrolyte imbalance	1/32 (3.1%)	1
Hyperglycaemia	1/32 (3.1%)	1
Hyperkalaemia	1/32 (3.1%)	1
Hypoalbuminaemia	1/32 (3.1%)	1
Hypocalcaemia	1/32 (3.1%)	1
Neonatal hyponatraemia	1/32 (3.1%)	1
Nervous system disorders
Intraventricular haemorrhage neonatal	1/32 (3.1%)	1
Renal and urinary disorders
Renal failure	2/32 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
Apnoea	1/32 (3.1%)	1
Chronic respiratory disease	1/32 (3.1%)	1
Infantile apnoeic attack	2/32 (6.3%)	2
Pleural effusion	1/32 (3.1%)	1
Respiratory distress	1/32 (3.1%)	1
Skin and subcutaneous tissue disorders
Dermatitis diaper	1/32 (3.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.