Surveillance Monitoring for ART Toxicities Study in HIV Uninfected Children Born to HIV Infected Women (SMARTT)

ClinicalTrials.gov Identifier:
NCT01310023
First received: March 4, 2011
Last updated: April 10, 2014
Last verified: April 2014
  Purpose

SMARTT will estimate the incidence of conditions and diagnoses potentially related to in utero exposure to antiretroviral therapy and/or exposure in the first two months of life among children born of HIV-infected mothers.


Condition
Antiretroviral Toxicity

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Surveillance Monitoring for ART Toxicities Study in HIV Uninfected Children Born to HIV Infected Women

Resource links provided by NLM:


Further study details as provided by Harvard School of Public Health:

Primary Outcome Measures:
  • Lactic acidosis [ Time Frame: Birth, 1, 3, 5, 7, 9, 11, 13, 15, and 17 years of age. ] [ Designated as safety issue: No ]
    Assessed through the measurement of blood lactate levels using a point-of-care lactate measuring device. Venous lactate and pyruvate levels will be measured for children for whom the point-of-care lactate measurement is abnormal.

  • Neurologic abnormalities [ Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child. ] [ Designated as safety issue: No ]
    Assessed via head circumference measurement and medical record review for documented clinical diagnoses of seizures, microcephaly, or other neurologic diagnosis.

  • Neurodevelopmental abnormalities [ Time Frame: 1, 3, 5, 9, and 13 years of age, assessments vary based on age of child. ] [ Designated as safety issue: No ]
    Assessed via the following neurodevelopmental tests: Bayley Screener, Bayley III, WPPSI-III, BASC-2, WASI, WISC-IV, BRIEF, WIAT II.

  • Abnormal growth and metabolic function [ Time Frame: Annually birth through age 5; semiannual thereafter, assessments vary based on age of child. ] [ Designated as safety issue: No ]
    Assessed through the measurement of height, weight, tricep skinfold thickness, mid-upperarm circumference measurements, insulin and glucose, and fasting lipids.

  • Cardiac abnormalities [ Time Frame: Ages 3-5. ] [ Designated as safety issue: No ]
    Assessed through the administration of echocardiograms and serum biomarkers (ProBNP).

  • Hearing dysfunction [ Time Frame: At age 5 and for children of all ages meeting a hearing/language trigger. ] [ Designated as safety issue: No ]
    Assessed via audiologic evaluation conducted by an audiologist.

  • Language dysfunction [ Time Frame: 1, 2, 3, 5, and 9 years of age, assessments vary based on age. ] [ Designated as safety issue: No ]
    Assessed via the following language tests: MCDI, Ages and Stages Communication Scale, PPVT IV, Goldman Fristoe 2, Rice Wexler, TELD-3, TOLD-3, Woodcock, CELF IV.

  • Drug Use and Sexual Activity [ Time Frame: 11, 13, 15, and 17 years of age. ] [ Designated as safety issue: No ]
    The assessment of sexual behavior and substance use will be conducted using an Audio Computer Assisted Survey Instrument (ACASI). ACASI uses computer and voice recordings so that the participant hears (through headphones) and sees (on the screen) each question and response list. The use of ACASI is proven to minimize response bias due to the presence of an interviewer.

  • Abnormal organ function [ Time Frame: Birth and age one, semiannual thereafter. ] [ Designated as safety issue: No ]
    Assessed through the measurement of lipase, CPK, ALT, creatinine, glucose, LDH, BUN, WBC, PMN, lymphocytes, platelets, or hemoglobin ( ≥ Grade 3 adverse event).

  • Death due to unknown medical condition [ Time Frame: Annual. ] [ Designated as safety issue: No ]
    Assessed through autopsy review.


Secondary Outcome Measures:
  • Maternal substance use during pregnancy [ Time Frame: Entry visit. ] [ Designated as safety issue: No ]
    Obtained via interview, toxicology report, and meconium testing.


Biospecimen Retention:   Samples With DNA

Serum, cell pellets, meconium, saliva


Estimated Enrollment: 3400
Study Start Date: March 2007
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)
Groups/Cohorts
Static Cohort
HIV-uninfected children < 12 years of age at the time of enrollment, born of HIV-infected mothers
Dynamic Cohort
HIV-uninfected children born of HIV-infected mothers enrolled from prior to birth through ≤ 72 hours of age
Reference Cohort
HIV-uninfected children born to a mother HIV uninfected at the time of the child's birth enrolled at 1, 3, 5, or 9 years of age(± 3 months) at the time of the study visit

Detailed Description:

Many antiretroviral therapy (ART) medications given to a pregnant woman cross the placenta and can be detected in the amniotic fluid and cord blood resulting in substantial fetal exposure. Therefore, there is concern about toxicity of the drugs in the fetus and infant. It is noteworthy that none of the currently approved ART medications for the prevention of maternal to fetal transmission of HIV are in Food and Drug Administration (FDA) Pregnancy Category A (no fetal risk ascertained in adequately controlled human studies). Thus, there is continued need to examine the toxicity of ART in HIV transmission prevention for the short-term toxicity of newer agents and combinations as well as the unanswered questions of longer term toxicity and subtle adverse effects.

The study will use a registry approach to conduct active surveillance among children < 12 years of age at enrollment. Occurrences of abnormalities from ART exposure in utero and/or in the first two months of life will be sought in multiple domains, including metabolic, growth, cardiac, neurologic, neurodevelopmental, behavior, language, and hearing. Clinical and laboratory data will be examined for abnormalities through a hierarchy of evaluations: adverse events (AE) will be identified → selected AEs will trigger predefined additional evaluations → significant observations will be defined as cases → a pattern of significant study-wide cases will be defined as signals. The incidence of these events of interest will be monitored over time and by ART regimen, and compared with historical data that may be suggestive of a signal. Some signals may be testable using existing and/or previously collected data, while other signals may indicate the need for additional hypothesis-driven studies outside of SMARTT.

The objectives of SMARTT are:

  1. To estimate the occurrence of potential ART-related toxicities through an ongoing surveillance system among HIV-uninfected children born to mothers with HIV infection with and without exposure to ART in utero and/or in the first two months of life and compare the occurrences of these outcomes with other sources of data as well as by ART exposures; and
  2. To actively encourage hypothesis-driven studies to confirm that the signals are due to ART exposure in utero and/or in the first two months of life. Note that the full design and execution of these studies may be beyond the scope of the SMARTT study but will be facilitated by SMARTT.

The specific aims of SMARTT are:

  1. To create a Static Surveillance Cohort to extend domain-specific data collection in children either 1) previously enrolled in any of the approved studies for enrollment into SMARTT; 2) previously enrolled in another pediatric HIV/AIDS cohort study with SMARTT Protocol Chair approval, or 3) not previously enrolled in an approved study but with equivalent data available in the medical record;
  2. To create a Dynamic Surveillance Cohort to examine domain-specific data of children newly exposed to ART in utero and/or in the first two months of life;
  3. To identify a set of "triggers" for each domain that define a "signal" of possible ART toxicity and compare the occurrence of these signals with previously collected data and by ART exposure; and
  4. To encourage and facilitate the development of hypothesis-driven studies to evaluate whether a "signal" is the result of ART exposure in utero and/or in the first two months of life.
  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Children aged 0 - < 12 years born of HIV-infected mothers recruited from a clinical setting.

Criteria

Inclusion Criteria:

Static Surveillance Cohort:

  • HIV-exposed but -uninfected infants and children; lack of infection must be documented by medical or research record review. Children exposed and unexposed to ART while in utero and/or in the first two months of life will be enrolled.
  • Previously enrolled in any of the studies included on the list of approved studies for enrollment into SMARTT or another study with SMARTT Protocol Chair approval if the study has data on ART exposure by pregnancy trimester, ART exposure during the first 2 months of life, and pregnancy complication data or availability of ART exposure by pregnancy trimester (including start and stop dates), ART exposure during the first 2 months of life, and pregnancy complication data in the mother and/or child's medical record.
  • Age birth to < 12 years at entry.
  • Willingness of parent/legal guardian to provide written permission for child to participate in study.

Dynamic Surveillance Cohort:

  • HIV-exposed living fetus greater than or equal to 23 weeks gestation or a live infant born after 22 weeks gestation. Infants exposed and unexposed to ART will be enrolled.
  • Any infant born of an HIV-infected mother may be enrolled pending determination of the infant's HIV infection status. However, infants found to be HIV-positive will be discontinued from the study and will be referred for care outside this study. HIV infection status will be determined using the Diagnosis of Lack of Infection in HIV-Exposed Children.
  • ART exposure data by trimester of pregnancy must be available if ART exposed.
  • Entry prior to birth through < 72 hours of age.
  • Willingness of parent/legal guardian to provide written permission for child to participate in study.
  • Willingness of biological mother to enroll at initial enrollment of her child.

Reference Cohort:

  • Participants from clinical settings that are similar to participants enrolled in the PHACS SMARTT Static Cohort.
  • Antiretroviral therapy unexposed children born to a mother HIV uninfected at the time of the child's birth.
  • Ages 1, 3, 5, or 9 years (± 3 months) at the time of the study visit.
  • Willingness of parent/legal guardian to provide written permission for child to participate in study.

Exclusion Criteria:

Static and Dynamic Cohorts:

None

Reference Cohort:

  • Monolingual Spanish-speaking child or parent/caregiver.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01310023

Contacts
Contact: Julie K Alperen, DrPH 617-432-6762 jalperen@sdac.harvard.edu
Contact: Krystal V Cantos, BA 617-432-0146 kcantos@sdac.harvard.edu

Locations
United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35294
Principal Investigator: Marilyn Crain, MD         
United States, California
University of California San Diego Recruiting
La Jolla, California, United States, 92093
Principal Investigator: Stephen Spector, MD         
University of Southern California Recruiting
Los Angeles, California, United States, 90033
Principal Investigator: Toinette Frederick, PhD         
United States, Colorado
University of Colorado Denver Health Sciences Center Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Elizabeth McFarland, MD         
United States, Florida
Children's Diagnostic & Treatment Center Recruiting
Fort Lauderdale, Florida, United States, 33316
Principal Investigator: Ana Puga, MD         
University of Florida Health Science Center Recruiting
Jacksonville, Florida, United States, 32209
Principal Investigator: Mobeen Rathore, MD         
University of Miami Recruiting
Miami, Florida, United States, 33136
Principal Investigator: Gwendolyn Scott, MD         
United States, Illinois
University of Illinois, Chicago Recruiting
Chicago, Illinois, United States, 60612
Principal Investigator: Kenneth Rich, MD         
Ann and Robert H. Lurie Children's Hospital Recruiting
Chicago, Illinois, United States, 60614
Principal Investigator: Ram Yogev, MD         
United States, Louisiana
Tulane University Health Sciences Center Recruiting
New Orleans, Louisiana, United States, 70112
Principal Investigator: Russell Van Dyke, MD         
United States, Maryland
University of Maryland Terminated
Baltimore, Maryland, United States, 21201
United States, New Jersey
Rutgers - New Jersey Medical School Recruiting
Newark, New Jersey, United States, 07101-1709
Principal Investigator: Arry Dieudonne, MD         
United States, New York
Bronx Lebanon Hospital Center Recruiting
Bronx, New York, United States, 10457
Principal Investigator: Murli Purswani, MD         
Jacobi Medical Center Terminated
Bronx, New York, United States, 10461
SUNY Downstate Medical Center Recruiting
Brooklyn, New York, United States, 11203-2098
Principal Investigator: Hermann Mendez, MD         
New York University School of Medicine Recruiting
New York, New York, United States, 10016
Principal Investigator: William Borkowsky, MD         
SUNY Stony Brook Terminated
Stony Brook, New York, United States, 11794
United States, Pennsylvania
Children's Hospital of Philadelphia Terminated
Philadelphia, Pennsylvania, United States, 19104-4318
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105-2764
Principal Investigator: Katherine Knapp, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030-3498
Principal Investigator: Wililam Shearer, MD, PhD         
Puerto Rico
San Juan Research Hospital Recruiting
San Juan, Puerto Rico, 00936-8344
Principal Investigator: Midnela Acevedo Flores, MD         
University of Puerto Rico Medical Center Recruiting
San Juan, Puerto Rico, 00935
Principal Investigator: Zoe Rodriguez, MD         
Sponsors and Collaborators
Harvard School of Public Health
Tulane University School of Medicine
NIH Office of AIDS Research (OAR)
Investigators
Principal Investigator: George R. Seage, ScD, MPH Harvard School of Public Health
Principal Investigator: Russell Van Dyke, M.D. Tulane University School of Medicine
  More Information

Publications:

Responsible Party: George Seage, Professor of Epidemiology, Harvard School of Public Health
ClinicalTrials.gov Identifier: NCT01310023     History of Changes
Obsolete Identifiers: NCT00647803
Other Study ID Numbers: HD052102 - PH100, PH100
Study First Received: March 4, 2011
Last Updated: April 10, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by Harvard School of Public Health:
Conditions and diagnoses potentially related to perinatal exposure to antiretroviral medications

ClinicalTrials.gov processed this record on August 27, 2014