TEMPO: A Feasibility Study of a Therapist-led Program for Parents of Extremely Pre-term Infants
Phase: NA
Conditions: Parent-Child Relations, Parents, Extreme Prematurity
Sponsor: University of North Carolina, Chapel Hill

STUDY PROTOCOL 
 
Therapist Education and Massage for Parent Infant-Outcomes 
(TEMPO) 
 
 
NCT number NCT04121897 
Document Date 10/17/2019 
 

 
 
Complete Title: TEMPO: A feasibility study of a physical therapist-led program for parents of extremely preterm infants  
Short Title: TEMPO 
Sponsor: NIH: National Center for Complimentary and Integrative Health 
Protocol Date: 5/10/19 
Amendment 1 Date: 10/17/19 
Amendment 2 Date:  
Amendment 3 Date: 
Amendment 4 Date:  
 
 
 
 
 
 
 
Sponsor: National Center for Complementary and Integrative Health 
6707 Democracy Boulevard II 
Suite 401 
Bethesda, MD 20892 (Courier Service – 20817) 
Office: 301-594-9346 
 
Study Principal Investigator: Dana McCarty, PT, DPT 
3024 Bondurant Hall, CB#7135 
Chapel Hill, NC 27599-7135 
dana_mccarty@med.unc.edu 
Office: (919) 843-8696 
 
 
 
 
 
PROTOCOL TITLE:  
TEMPO: A feasibility study of a physical therapist-led program for parents of extremely preterm 
infants  

 
 
 2 
Short Title:  
TEMPO  
Lead Investigator: 
Dana McCarty, PT, DPT 
 University of North Carolina at Chapel Hill 
Protocol Version: 2 
Version Date: 10/17/19 
 
I confirm that I have read this protocol and understand it.    
Principal Investigator Name:  
 
 
Dana McCarty  
Principal Investigator Signature:  
 
 
 
 
Date:   
 
 
 
10/17/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary of Changes from Previous Version (Version 1.0, 10 May 2019) 

 
 
 3 
 
Affected Section(s) 
Summary of Revisions Made 
Protocol Synopsis, 2.1, 
6.1 
Modified Aim 1, P5 to add “and weekly and bi-weekly reporting of 
physical therapy interventions (goal ≥ 50%)”. 
Protocol Synopsis, 3.1 
All IRB-approved study team members can approach potential 
participants.  
1.2, 1.3, 3.1, 4.3, 7 
Removed text messaging from study procedures 
1.3, 3.1, 4.2, 4.3, 4.4, 5, 
6.2 
Removed Spielberg State Trait Anxiety Inventory (STAI) from evaluation 
tools for parent measures 
1.3, 3.1, 4.2, 4.3, 4.4, 5, 
6.2 
Added the Acceptability of Intervention Measure (AIM), Feasibility of 
Intervention Measure (FIM), and/or Patient-Reported Outcomes 
Measurement Information System (PROMIS) Adult Profile Short Form – 
Anxiety to evaluation tools for parent measures.  
2.1 
Clarified primary objectives 
4.2, 4.3, 9 
Added methods for parents to record frequency of administered 
interventions  
5 
Modified salivary cortisol procedures – only Principal Investigator will 
collect buccal swab 
6.1 
Defined acceptability and feasibility for statistical considerations 
Entire Document 
Corrected formatting and typographical errors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
Table of Contents ..................................................................................................................... 4 
Abbreviations and Definitions of Terms ................................................................................... 5 

 
 
 4 
Protocol Synopsis ..................................................................................................................... 6 
1 
BACKGROUND  AND RATIONALE....................................................................................................................... 8 
2 
STUDY OBJECTIVES .......................................................................................................................................... 10 
3 
INVESTIGATIONAL PLAN .................................................................................................................................. 11 
4 
STUDY PROCEDURES ....................................................................................................................................... 13 
5 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................................................. 15 
6 
STATISTICAL CONSIDERATIONS ....................................................................................................................... 17 
7 
STUDY INTERVENTION (DEVICE OR OTHER INTERVENTION) .......................................................................... 19 
8 
SAFETY MANAGEMENT ................................................................................................................................... 20 
9     DATA COLLECTION AND MANAGEMENT ........................................................................................................ 23 
10 RECRUITMENT STRATEGY ............................................................................................................................... 25 
11 CONSENT PROCESS.......................................................................................................................................... 25 
12 PUBLICATION ................................................................................................................................................... 25 
13 REFERENCES .................................................................................................................................................... 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 

 
 
 5 
Abbreviation 
Definition 
TEMPO 
Therapist Education and Massage for Parent-Infant Outcomes 
PT 
Physical Therapist 
EP 
Extremely Preterm 
PTI 
Physical Therapy Interventions 
NCCC 
Neonatal Critical Care Center 
CRF 
Case Report Form 
AE/SAE 
Adverse Event/Severe Adverse Event 
NCCIH 
National Center for Complimentary and Integrative Health 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
 

 
 
 6 
Study Title 
TEMPO: A feasibility study of a physical therapist-led program for parents 
of extremely preterm infants 
Funder 
National Center for Complimentary and Integrative Health 
Clinical Phase 
Feasibility 
Study Rationale 
The TEMPO program is a structured, therapist-led PT program developed 
by the applicant based on her clinical experience.  TEMPO trains and 
supports parents to deliver PTIs such as massage and developmental play 
during hospitalization and in the home setting.  The goal of this project is 
to assess the feasibility and acceptability of TEMPO for parents of EP 
infants born in the Neonatal Critical Care Center (NCCC) at UNC Children’s 
Hospital. 
Study Objective(s) 
Aim 1. Evaluate feasibility by using the sample to estimate the following 
population parameters:  
P1 In the target population, the % of eligible dyads who would consent to 
enroll (goal ≥ 55%)  
P2 In the target population, the % of enrolled dyads who would consent 
to randomization (goal ≥ 70%)  
P3 In the target population, the % of enrolled dyads who would complete 
all protocol components (goal ≥ 70%)  
P4 In the target population, the % of enrolled dyads who would 
participate for the full 12 months (goal ≥ _70%)  
P5 In the target population, the % of enrolled dyads who would provide 
complete data and interviews (goal ≥ 70%) and weekly and bi-weekly 
reporting of physical therapy interventions (goal ≥ 50%) 
P6 In the target population, the % of enrolled dyads who would perform 
physical therapy interventions at least 2-to-3x/week (goal ≥ 70%)  
 
Aim 2. Use results from Aim 1 to refine the TEMPO intervention. 
Aim 3. Use the sample data to estimate of population parameters needed 
for planning a future study; specifically, estimates of means, standard 
deviations, and serial correlations of the distributions of the following 
variables: infant salivary cortisol, parent salivary cortisol, the parent 
questionnaire scores, and infant CTS and BSID scores. 
Study Design 
Prospective single group, non-randomized study 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria: Infants with gestational age <28 weeks gestation, 
within the first 3 weeks of life, and their biologic mother or father.  
Parent must be able to speak and understand English.  
Exclusion Criteria: Infants who do not have a biological parent available 
to consent within the first 3 weeks of life.  Infants with 
genetic/chromosomal abnormality, congenital neurological or 
musculoskeletal disorder, or abnormal bone density that would affect the 
ability to do massage and/or exercise and the safety of the infant.  
Parents who are unwilling to engage in all components of TEMPO. 

 
 
 7 
Number Of Subjects  
30 infant-parent dyads  
Study Duration 
Each parent-infant dyad’s participation will last approximately 15 
months. 
The entire study is expected to last approximately 27-28 months. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
• 
Screening: Once a PT referral is received for an infant born at <28 
weeks gestation, the PI will be notified by the receiving therapist 
and an IRB-approved study team member will approach the 
biologic mother and/or father of the infant to discuss the study.   
• 
Intervention: The components of TEMPO are evidence-based and 
include infant massage, PTIs including developmental support 
and play activities to promote infant behavioral-motor 
development, principles of family-centered care, and multiple 
modes of educational delivery to enhance parent retention of 
knowledge and confidence in continuing PTIs after discharge. 
• 
Follow-Up: Follow-Up after hospital discharge will include clinic 
visits at 2 and 12 months corrected age.  
Safety Evaluations 
The physical therapist, with the assistance of the bedside nurse, will 
monitor vital signs continuously (heart rate, oxygen saturation, and 
respiratory rate) during all massage and physical therapy interventions. If 
the infant demonstrates any of negative responses during massage or 
PTIs, then the PT will adjust the treatment session accordingly to focus on 
developmental support that the infant can tolerate, while continuing to 
educate the parent about their infant’s cues and behavior. 
Statistical And Analytic 
Plan 
Because the goal of this study is to assess feasibility and acceptability of 
the TEMPO program, we are not collecting the validated outcome 
measures (eg. Surveys, interview data, and infant motor assessment 
scores) to estimate the effectiveness of TEMPO; rather our goals are to:  
(1) assess the feasibility of completing each measure and  
(2) estimate the means and standard deviations as the basis for sample 
size calculations for future clinical trials.   
DATA AND SAFETY 
MONITORING PLAN 
• 
Independent monitor will review progress reports (patient 
recruitment, retention/attrition, and AEs) quarterly 
• 
Annual Report sent to Independent Monitor  
• 
Copy of Annual Report and Independent Monitor’s 
recommendations sent to NCCIH annually 
• 
The PI will carefully review study documentation on a weekly basis to 
ensure data collection from study subjects is complete.  
• 
Participant confidentiality is strictly held in trust by the investigators, 
study staff, and the sponsor(s) and their agents. 
 
 
1 
BACKGROUND AND RATIONALE 

 
 
 8 
1.1 
Introduction 
 
The Therapist Education and Massage for Parent-Infant Outcomes program (TEMPO) is a structured, therapist-led PT 
program developed by the applicant based on her clinical experience.  TEMPO trains and supports parents to deliver PTIs 
such as massage and developmental play during hospitalization and in the home setting.  The goal of this project is to 
assess the feasibility and acceptability of TEMPO for parents of EP infants born in the Neonatal Critical Care Center 
(NCCC) at UNC Children’s Hospital. 
 
There are several innovative aspects to this research.  First, the TEMPO program enhances standard care by structuring 
the nature and frequency of therapist-parent interactions to increase the parent’s comfort level with administering 
massage and developmental activities with their EP infant.  In standard care, parent education during hospitalization is 
provided spontaneously if the parent is available, does not include infant massage, does not use supplementary written 
materials or resources, and does not include check-ins with a therapist post-discharge.  Second, this project will recruit 
parents of infants <28 weeks gestation, a population that has not been studied in previous research on massage.  Third, 
the TEMPO program emphasizes the critical role therapists can have not only in educating and supporting parents of EP 
infants, but in developing and rigorously testing complementary/integrative health approaches in unique patient 
populations. Finally, once TEMPO is further developed it can be adapted to evaluate other complementary/integrative 
health approaches for the EP population and other high-risk infant populations (e.g., neonatal drug withdrawal, infants 
with hypoxic ischemic encephalopathy). 
 
 
1.2 
Name and Description of Investigational Product or Intervention  
The Therapist Education and Massage for Parent-Infant Outcomes program is evidence-based and includes infant 
massage,1,8,9 PTIs including developmental support and play activities to promote infant behavioral-motor 
development,5,6 principles of family-centered care,5 and multiple modes of educational delivery6 to enhance parent 
retention of knowledge, parent-infant bonding, and confidence in continuing PTIs after discharge.  TEMPO includes 
these components: 
• 
Early Parent Education Session  
• 
Weekly Parent Education Sessions  
• 
Infant Massage Parent Education Sessions  
• 
Discharge Parent Education Session  
• 
Parent Education Post-Discharge  
• 
Bi-weekly emails 
• 
2 Month Follow-up Massage Review Session 
 
1.3 
Non-Clinical and Clinical Study Findings 
Potential Benefits related to TEMPO intervention:  
 
Parent becoming more comfortable touching, holding, and playing with your infant from a very young age 
during hospitalization 
 
Parent feeling confident in your ability to read your infant’s body language and needs as they change during 
hospitalization 
 
Increased opportunities for infant-parent bonding 

 
 
 9 
 
Learning how to perform infant massage with your infant which has many benefits for parent (eg. reducing 
stress and depression) and for infant (eg. gaining weight and staying calm)  
 
Parent may develop a strong relationship with the therapy team in the NCCC and will receive weekly updates 
about your infant’s motor progress 
 
Parent will continue to receive therapist tips about infant development after discharge home 
 
Parent will receive a one-on-one infant massage review session after discharge home 
 
Parent will have the opportunity to reflect on sense of parent competence during the first year of infant’s life 
 
Risks related to TEMPO intervention:   
• 
Infant autonomic instability/stress, discomfort, or skin reaction as a result of Vaseline or Aquaphor during the 
massage session 
• 
Inconvenience or stress to parents from weekly meetings with therapist and/or completion of questionnaires 
• 
Psychological distress of parents when learning about preterm development or if the infant does not have a 
positive response to massage 
• 
Breach of confidentiality if emails are seen by other persons than the parent, or if data from the medical record 
is breached 
 
 
1.4 
Relevant Literature and Data 
Physical therapists (PTs) play a major, but often unrecognized role, in supporting extremely preterm (EP) infants and 
their parents through non-pharmacologic and developmentally-supportive care during and after long-term hospital 
stays.  While there is strong evidence to support that physical therapy interventions (PTIs) improve, or even cure, a 
number of pediatric conditions (e.g. torticollis), there is little data demonstrating how PTIs done in the NICU setting 
influence outcomes in EP infants or whether there is benefit to parents continuing PTIs after hospital discharge.  In 
addition, the clinical experience of the applicant suggests that parents can be taught how to do PTIs with their infant and 
doing so may be an important contributor to increasing parent confidence in taking care of their infant.  This is especially 
important because parents of EP infants experience a challenging transition to parenthood and often experience 
increased levels of stress, depression, and fear of incompetence in caring for their child compared to parents of non-EP 
infants.1 Over the long-term, these issues can negatively impact parent-infant bonding2 and parent quality of life.3  In 
addition, decreased parental bonding and attention can effect motor outcomes of the infant.4   
The extra-uterine environment presents significant challenges for infants born extremely preterm (EP). In the NCCU, 
physical therapists provide ongoing assessment of infant development and deliver interventions designed to mitigate 
the behavioral-motor effects of preterm birth.5 This presents a unique opportunity for PTs to foster parental 
involvement in their infant’s care by teaching parents how to respond to their infant’s behavioral cues and to facilitate 
their infant’s motor development through techniques such as massage.6  Massage has been shown to be safe,1 is 
associated with many benefits for EP infants,7 and has been shown to be beneficial in decreasing parent depression1 and 
anxiety.8,9  However, the applicant’s clinical experience is that despite being taught how to administer massage by the PT 
during admission, parents do not regularly continue this practice.  Because of the potential benefits to parents in terms 
of decreased stress, anxiety and an increased sense of parent-infant bonding, there is a critical need to find more 
feasible ways to teach and support parents to deliver massage and other PTIs throughout the infant’s hospitalization and 
post-discharge. TEMPO has been developed to address this need.   
 
Established Validity for Scales and Evaluation Tools 
 

 
 
 10 
Parent Measures  
• 
Acceptability of Intervention Measure (AIM): A 12 item implementation outcome assessment designed to measure if 
the intervention is perceived as agreeable, palatable, or satisfactory.11 
• 
Feasibility of Intervention Measure (FIM): A 9 item implementation outcome assessment designed ot measure the 
extent to which a new treatment can be successfully used or carried out.11 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Profile Short Form - Anxiety:  The 
PROMIS Anxiety short form is a valid and reliable measurement tool used to assess self-reported fear, anxious 
misery, hyperarousal, and somatic symptoms related to arousal.12 
• 
Centers for Epidemiologic Studies Depression Scale (CESD): A valid, reliable self-assessment tool for evaluating 
depressive symptoms in adult populations, including among mothers during and after parturition.13 The CESD 20-
item scale will be used.  
• 
Edinburgh Postnatal Depression Scale (EPDS): A 10-item self-report questionnaire validated to detect change in 
depressive symptoms in mothers both during and after the postnatal period.14 EPDS ratings in parents have been 
correlated with scores of infant temperament as measured by the Carey Temperament Scale, and shown to improve 
with massage.13  
• 
Parenting Sense of Competence Scale (PSOC): A 17-item scale to assess satisfaction of parenting and parental self-
efficacy in a variety of populations,15 with higher scores indicating a greater sense of parental self-efficacy.  
• 
Postnatal Attachment Questionnaire (PAQ): A postnatal questionnaire with 4 components: pleasure in proximity, 
tolerance, need-gratification and protection, and knowledge acquisition designed to query the parents’ feelings 
about their infants under 1 year of age.16 This questionnaire is associated with the Attachment Q-set (ASQ), an 
observational assessment of infant-parent bonding.16 
• 
Salivary Cortisol: Salivary cortisol is a biomarker for stress.17 Salivary cortisol concentrations (ng/dl) may be used to 
understand the mechanism by which TEMPO impacts physiological stress states. 
Infant Measures  
• 
Salivary Cortisol: Salivary cortisol is a biomarker for stress.17 Salivary cortisol concentrations (ng/dl) may be used to 
understand the mechanism by which TEMPO impacts physiological stress states. 
• 
Carey Temperament Scales (CTS): This questionnaire assesses nine temperamental characteristics of infants. 
Caregivers are presented with a statement describing a certain behavior and asked to rate how often their child 
behaves in that way on a scale from 1 (almost never) to 6 (almost always), with higher scores indicating more 
difficult temperament.13  
• 
Bayley Scales of Infant Motor Development-III (BSID-III): A standardized assessment to evaluate cognitive 
development, expressive and receptive language, and fine and gross motor development in children between the 
ages of 1 month and 42 months.18 This assessment will be completed at the 12 month corrected at follow-up visit. 
 
2 
STUDY OBJECTIVES  
The goals of this project are to test feasibility and acceptability of the TEMPO program and study protocol.   
2.1 
Primary Objective 
To conduct a pilot study to demonstrate TEMPO’s feasibility as assessed by:  
P1 In the target population, the % of eligible dyads who would consent to enroll (goal ≥ 55%)  
P2 In the target population, the % of enrolled dyads who would consent to randomization (goal ≥ 70%)  
P3 In the target population, the % of enrolled dyads who would complete all protocol components (goal ≥ 70%)  
P4 In the target population, the % of enrolled dyads who would participate for the full 12 months (goal ≥ _70%)  
P5 In the target population, the % of enrolled dyads who would provide complete data collection and interviews (goal ≥ 

 
 
 11 
70%) and weekly and bi-weekly reporting of physical therapy interventions (goal ≥ 50%) 
P6 In the target population, the % of enrolled dyads who would perform physical therapy interventions at least 2-
3x/week (goal ≥ 70%)  
 
Secondary Objectives 
Based on the quantitative and qualitative data from Aim 1, refine TEMPO to facilitate parent-administered physical 
therapy and massage during neonatal intensive care hospitalization and after discharge. 
Additionally, we will use the sample data to estimate of population parameters needed for planning a future study; 
specifically, estimates of means, standard deviations, and serial correlations of the distributions of the following 
variables: infant salivary cortisol, parent salivary cortisol, the parent questionnaire scores, and infant CTS and BSID 
scores. 
 
3 
INVESTIGATIONAL PLAN  
3.1 
Study Design 
Type of design: This is a prospective single group, non-randomized study designed to determine the feasibility and 
acceptability of TEMPO. The TEMPO program as part of this study would be offered in addition to standard of care 
physical therapy intervention in the NCCC. Standard of care physical therapy in the NCCC involves 1-2 PT sessions 
weekly, spontaneous (unplanned) parent education as the parent is available in the hospital, and follow up outpatient 
clinic visits with a PT. 
Screening/Baseline:  
The recruitment process with the parents will be initiated once the physical therapy referral has been made by the 
treating physician. The neonatology provider team will receive an introduction to the study from the PI (McCarty) and 
chief neonatologist/grant mentor (O’Shea) prior to study initiation. All infants who meet eligibility criteria for the study 
also receive standard physical therapy orders in the Newborn Critical Care Center (NCCC). A physical therapist attends 
weekly developmental rounds in the NCCC and participates in the physical therapy referral process by screening patients 
who are under a certain age and weight. The physical therapy referral is received when the infant is clinically stable and 
thus should avoid the initial parent distress and need for orientation after the birth and admission to the NCCC.  Once a 
PT referral is received for an infant born at <28 weeks gestation, the PI will be notified by the receiving therapist and an 
IRB-approved member of the study team will approach the biologic mother and/or father of the infant to discuss the 
study.  In order to ensure that parents have sufficient time to consider participation, the study team member will 
contact the family at the bedside or by phone call once the physical therapy referral has been initiated to introduce the 
TEMPO study. The study team member will offer to leave the consent document with the parent(s).  An IRB-approved 
member of the study team will always be available to answer any questions related to the informed consent, and if they 
express interested in participating, then informed consent will be obtained.     
 
Intervention/Treatment and Follow up: Please see Table 1 and Figure 1 below for information regarding the timing and 
sequence of intervention and follow up.  Additional detail regarding the study intervention can be found in sections 4 
and 7. 
Table 1: Study Events 

 
 
 12 
Event 
Baseline 
During 
Hospital 
Admission 
Hospital 
Discharge 
Post 
discharge 
First 
F/U 
visit 
F/U at 
12 
mos 
visit 
Parent measures: (AIM, FIM, 
PROMIS, CESD, EPDS, PSOC) 
x 
  
x 
  
x 
x 
PAQ 
  
  
  
  
  
x 
Parent Interview 
  
  
  
  
x 
x 
Parent Education Sessions 
x 
x  
x 
  
  
  
Salivary cortisol pre and post 
massage 
  
x 
  
  
  
  
Weekly Parent Education 
including massage 
 
x 
 
 
 
 
Email  
 
 
 
bi-weekly 
Massage Review 
  
  
  
  
x 
  
Infant measures 
  
  
  
  
x 
x 
 
 
 
3.2 
Study Duration, Enrollment and Number of Subjects 
Study Duration:  
 
Enrollment and Number of Subjects: The study will be conducted in the Neonatal Critical Care Center at UNC Children’s 
Hospital where approximately 100 EP infants (<28 weeks gestation) are born each year. Of these infants, approximately 
75% will survive, and approximately 57 of these infants will meet eligibility criteria. Our goal is to enroll 55% of eligible 
infants-parent dyads, and therefore our proposed sample size is 30 dyads, but will enroll up to 40 dyads over the period 
of 12 months. 

 
 
 13 
3.3 
Study Population 
Inclusion Criteria: Infants with gestational age <28 weeks gestation, within the first 3 weeks of life, and their biologic 
mother or father.  Must be able to speak and understand English.  
Exclusion Criteria: Infants who do not have a biological parent available to consent within the first 3 weeks of life.  
Infants with genetic/chromosomal abnormality, congenital neurological or musculoskeletal disorder, or abnormal bone 
density related to a congenital condition that would affect the ability to do massage and/or exercise and the safety of 
the infant.  Parents who are unwilling to engage in all components of TEMPO. 
4 
STUDY PROCEDURES  
4.1 
Screening/Baseline Visit procedures 
At the baseline visit, the therapist will provide parent education (as described in section 7, Early Parent Education), and 
the parent will complete baseline surveys (as described in section 1.4) on the study iPad. While both parents may elect 
to receive training in the intervention, they will be asked to designate one parent who is the most likely to perform the 
intervention after discharge and this same parent should complete all the parent interviews and questionnaires.  Please 
see Table 1: Study Events and Figure 1: Study Scheme in the Appendix for a complete timeline. 
4.2 
Intervention/Treatment procedures (by visits) 
The TEMPO program involves components during and after hospitalization. 
During infant hospitalization 
• 
Visit 1: Early Parent Education Session: Initiated within 3 weeks of infant birth. The PT will educate the parent 
about the importance of infant positioning, the impact of prematurity on the motor and sensory systems, and 
how to read and respond to infant behavioral-motor cues5 using a written pamphlet with pictures to 
supplement the verbal education lasting about 30 minutes.  
o At this visit, the therapist will have the parent fill out the following questionnaires for baseline 
measurement: AIM, FIM, PROMIS, CESD, EPDS, PSOC 
o The therapist will also ask the parent to complete a contact information form and a demographic form. 
• 
Visits 2-8: Weekly Parent Education Sessions <34 weeks: Following the initial parent education session, the PT 
will hold weekly parent education sessions, ideally at the time of therapy. When the infant is this young (<34 
weeks gestation), PT intervention and education will focus on infant behavioral-motor cues, reading/response to 
infant cues, positioning strategies/concerns, and developmentally appropriate stimulation of the infant. If the 
parent is not available for all therapy sessions, then the parent will receive a weekly update about their infant’s 
progress face-to-face and/or via video chat.  
o Parents will be asked to record the frequency of physical therapy interventions on a bedside card. 
• 
Visits 9-10: Infant Massage Parent Education Sessions: Parent-administered infant massage will be 
incorporated into the therapy plan of care as soon as the infant’s medical provider determines that the infant is 
physiologically stable and can tolerate massage. This time is generally once the infant is approximately 34 weeks 
gestational age, approximately 1500 grams, and is demonstrating temperature stability out of the isolette for 
short periods. At a minimum, the therapist will teach massage for the back or lower extremities over 2 parent 
education sessions. The therapist will demonstrate massage strokes on a doll using verbal cues to guide the 
parent while the parent administers massage on the infant. An instructional massage pamphlet will be provided. 
Once the therapist has determined parent safety with massage administration, parents will be encouraged to 
practice infant massage when they visit the baby and to note when they do this by marking a card at the 
bedside.   

 
 
 14 
o Pre and Post both massage sessions, the PI or study coordinator will collect salivary cortisol via buccal 
swab as a measure of physiologic stress. 
• 
Visits 11+: Weekly Parent Education Sessions >34 weeks: Weekly parent education once the infant is >34 weeks 
will begin to incorporate hands-on developmental play activities, introduction to visual engagement, and 
postural control practice in variety of positions that the infant tolerates. Additionally, the PT and parent may 
choose to review massage at these visits. If the parent is not available for all therapy sessions, then the parent 
will receive a weekly update about their infant’s progress face-to-face and/or via video chat.  
o Parents will be asked to record the frequency of physical therapy interventions on a bedside card. 
• 
Final Visit during hospitalization: Within the week of hospital discharge, the PT will schedule a face-to-face 
parent education session lasting about 30 minutes to review age-appropriate developmental play activities for 
home and review infant massage. A supplemental handout and therapist email and pager information will be 
provided.  
o At this visit, the therapist will have the parent fill out the following questionnaires for ongoing 
measurement: AIM, FIM, PROMIS, CESD, EPDS, PSOC (Aim 1).  
 
4.3 
Follow- up procedures (by visits) 
The TEMPO program has additional components that extend beyond the hospital period. Parent and infant outcome 
measures will be collected at the first follow-up and 12 month corrected age follow-up clinic visits. Please see Table 1: 
Study Events and Figure 1: Study Scheme in the Appendix for a complete timeline. 
After hospitalization:  
• 
Visit 1: Parent Education Post-Discharge: The PT will call the parent within 2 weeks of discharge to follow up about 
discharge education and massage. During this phone call, the PT will review the home program and massage 
techniques. The PT will also answer any parent questions.  Therapist email and pager information will be provided.  
• 
Visits 2-12 (approximate): Bi-weekly emails:  The PT will send bi-weekly emails with developmental play activity and 
massage reminders and tips from hospital discharge through the first follow up appointment.   
o These emails will include a link for parents to report frequency of PT intervention and massage at home. 
• 
Visit 13 (approximate): First Visit Follow-up Massage Review Session: At the infant’s first follow-up appointment 
with the multidisciplinary neonatology team, the PT will provide a gross motor screening assessment and education. 
In addition, as part of the TEMPO program, a PT will facilitate a parent-administered infant massage session to 
provide an opportunity for parent to receive feedback on technique from the PT. This session will address any safety 
concerns, infant changes, and parent questions. 
o At this visit, the therapist will have the parent fill out the following questionnaires for ongoing 
measurement: AIM, FIM, PROMIS, CESD, EPDS, PSOC 
o At this visit, the PI or study coordinator will interview the parent about acceptability of the TEMPO 
program. 
• 
Visits 14+ (approximate): Bi-weekly emails:  The PT will continue to send bi-weekly emails with developmental play 
activity and massage reminders until the 12 month follow up appointment.   
o These emails will include a link for parents to report frequency of PT intervention and massage at home. 
• 
12 Month Follow-up Appointment: At the standard of care 12 month corrected age follow-up appointment with the 
multidisciplinary neonatology team, the PT will administer a standardized assessment of gross and fine motor skills 
(Bayley Scales of Infant Development-III). 
o At this visit, the therapist will have the parent fill out the following questionnaires for ongoing 
measurement: AIM, FIM, PROMIS, CESD, EPDS, PSOC (Aim 1) 

 
 
 15 
o Additionally, the parent will complete the PAQ questionnaire. (Aim 1) 
o At this visit, the PI or study coordinator will interview the parent about acceptability of the TEMPO 
program. (Aim 1, Aim 2) 
 
4.4 
Subject Completion/ Withdrawal procedures 
The study staff will inform the subject when his/her participation has come to an end and will document the discussion 
in the study record. If the infant is transferred to an outside hospital prior to discharge home, then the parents will be 
asked to complete the parent measures (PROMIS, CESD, EPDS, PSOC) at that time instead of hospital discharge. If the 
parent chooses to withdraw their infant for any reason, the parent does not have to complete the above measures. 
An infant may no longer participate in the study under any of the following circumstances: 
 
• 
The medical condition of the infant deteriorates and the medical team no longer recommends PT or massage 
• 
The infant experiences a severe AE or SAE related to the intervention 
• 
The Parent is no longer interested in participating 
 
In the event that an infant has an AE related to massage medium (Aquaphor), then massage will be performed without 
the medium once the skin has healed. 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS  
Variables that will be abstracted from medical charts: 
o Infant: 
o Name 
o Date of birth 
o Gestational age at birth 
o Birth weight 
o Race/ethnicity 
o Salivary Cortisol (post-salivary swab 
test) 
o Parent: 
o Name 
o Age 
o Race/ethnicity 
o Highest education completed (if 
available) 
o Salivary Cortisol (post salivary swab 
test)
Parent Measures  
• 
Acceptability of Intervention Measure (AIM): A 12 item implementation outcome assessment designed to measure if 
the intervention is perceived as agreeable, palatable, or satisfactory. 
• 
Feasibility of Intervention Measure (FIM): A 9 item implementation outcome assessment designed ot measure the 
extent to which a new treatment can be successfully used or carried out. 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Profile Short Form - Anxiety:  The 
PROMIS Anxiety short form is a valid and reliable measurement tool used to assess self-reported fear, anxious 
misery, hyperarousal, and somatic symptoms related to arousal. 
• 
Centers for Epidemiologic Studies Depression Scale (CESD): The CESD 20-item scale will be used.  
• 
Edinburgh Postnatal Depression Scale (EPDS): A 10-item self-report questionnaire validated to detect change in 
depressive symptoms in mothers both during and after the postnatal period.  
• 
Parenting Sense of Competence Scale (PSOC): This measure will be used to assess change in the parent’s sense of 
competence in caring for their infant throughout the study period.  

 
 
 16 
• 
Postnatal Attachment Questionnaire (PAQ): This questionnaire is associated with the Attachment Q-set (ASQ), an 
observational assessment of infant-parent bonding, and will serve as a measure of the parent emotional component 
of infant-parent bonding in the follow-up stage of the study period.   
• 
Salivary Cortisol: Salivary cortisol is a biomarker for stress. Salivary cortisol concentrations (ng/dl) may be used to 
understand the mechanism by which TEMPO impacts physiological stress states. The PI or research coordinator will 
swab the parent’s buccal mucosa immediately pre- and post-massage at the first massage education session.  
• 
Parent Interview: The parent who performed the study intervention will be interviewed at the first follow-up visit 
and the 12-month follow-up visit to obtain their insights on the feasibility, acceptability and perceived benefit of 
TEMPO. The PI or study coordinator elicit their feedback on program materials, intervention components, and 
factors that influenced whether they were able to continue the protocol at various time points post-discharge.  For 
example:  what they liked or disliked about the program, how often they did massage and for how long, did they find 
the massage easy to do on an ongoing basis, do they have suggestions to improve feasibility? We will also ask about 
willingness to have participated in this study if it were a randomized trial. This information will be critical to develop 
the planned trial (Aim 1 and 2). For example, should a parent not be willing to be randomized, the trial may need to 
randomize at some level other than individual infants/parents (e.g., hospital or a waitlist control condition). 
 
 
Infant Measures  
• 
Salivary Cortisol: Salivary cortisol will be collected by PI via buccal swab immediately pre- and post-massage at the 
first massage education session. 
• 
Carey Temperament Scales (CTS): This questionnaire assesses Infant temperament to better understand if infant 
temperament may be influenced by massage and is associated with parent-infant bonding.  
• 
Bayley Scales of Infant Motor Development-III (BSID-III): A standardized assessment provided by a developmental 
specialist (physical or occupational therapist in our study) to evaluate cognitive development, expressive and 
receptive language, and fine and gross motor development in children between the ages of 1 month and 42 months. 
 
5.1 
Safety Evaluations 
The infant will be monitored for safety throughout all PT sessions. With the assistance of the bedside nurse, vital signs 
will be monitored continuously (heart rate, oxygen saturation, and respiratory rate) during all massage and physical 
therapy interventions. The massage or PTIs will be stopped if the infant’s heart rate exceeds 200 beats per minute, if the 
infant’s oxygen saturation drops <90%, or respiratory rate exceeds 90 breaths per minute without spontaneous recovery 
or response to strategies employed by the PT or nurse to resolve. Additionally, the PT will monitor infant behavioral-
motor cues for signs of overstimulation or stress during massage and PTIs in order to promote a positive experience for 
the infant and parent. If the infant demonstrates any of these negative responses during massage or PTIs, then the PT 
will adjust the treatment session accordingly to focus on developmental support that the infant can tolerate, while 
continuing to educate the parent about their infant’s cues and behavior. 
 
Prior to the parent education for massage session, the PT will test a small area of the infant’s skin (likely on the lower leg 
or back) to assess any negative skin reaction to Aquaphor, the medium used for massage. If after 24 hours of 
monitoring, the infant does not develop skin irritation, then the PT will proceed with an introductory massage session. If 
the infant has a skin reaction to Aquaphor, then the PT will determine an alternative medium for massage in 
consultation with the medical team and the skin care nurse. Infant massage will first be administered by the PT to 
determine the infant’s tolerance prior to the parent education for massage session. 
 

 
 
 17 
The study team will generate Study Reports for the Independent Monitor and will provide information on the following 
study parameters:  screened and enrolled parent-infant dyads, unanticipated, serious adverse events, missed study visits 
and dyads that are lost to follow-up.   
 
6 
STATISTICAL CONSIDERATIONS    
6.1 
Primary Objectives 
No hypothesis tests will be performed in this study. The primary goal of this project is to test feasibility and acceptability 
of the TEMPO program and study protocol (Aim 1).  As such, the analysis plan will not focus on inferential statistics but 
on measures of feasibility identified in the NCCIH’s Framework for Developing and Testing Mind and Body Interventions10 
(https://nccih.nih.gov/grants/mindbody/framework):   
• 
Recruitment:  Percentage of eligible infant-parent dyads who enroll in the study (Goal >55%) 
• 
Willingness to be randomized:  Percentage of enrolled parents who, in interviews, report they would agree to be 
randomized (Goal >70%) 
• 
TEMPO delivered per protocol:  Percentage of enrolled parents who complete all TEMPO components per protocol 
(Goal >70%) and weekly and bi-weekly reporting of physical therapy interventions (goal ≥ 50%). 
• 
Retention: Percentage of enrolled parents who are retained in the study at 12 months (Goal >70%), reasons for 
attrition for those who do not complete the protocol 
• 
Complete data collection:  Percentage of enrolled parents who complete data collection, including interviews 
(Goal >70%) 
• 
Adherence:  Percentage of enrolled parents who complete at least 2-3x/week during hospitalization and 2-
3x/week in-home PTIs as noted on the parent log or survey (Goal >70%) 
• 
Acceptability and Feasibility of TEMPO:  Percentage of parents who rate acceptability and feasibility as 4/5 or 5/5 
using the Acceptability of Intervention Measure and the Feasibility of Intervention Measure (Goal >70%) 
• 
Acceptability of the Protocol: A structured interview guide will be followed by the PI or research coordinator. 
Interviews will be audio recorded and transcribed by a confidential online service. All audio files will be stored and 
transmitted using TLS 1.2 encryption for a high level of security. Interviews will be coded by the PI for content and 
qualitative analysis to derive themes. (Aim 1 and 2) 
 
 
6.2 
Secondary Objectives 
Additionally, we plan to estimate the means and standard deviations as the basis for sample size calculations using the 
following measures for future clinical trials.   
Parent Measures  
• 
PROMIS Adult Short Form - Anxiety 
• 
Centers for Epidemiologic Studies Depression Scale (CESD) 
• 
Edinburgh Postnatal Depression Scale (EPDS)  
• 
Parenting Sense of Competence Scale (PSOC)  
• 
Postnatal Attachment Questionnaire (PAQ)  
• 
Salivary Cortisol 
• 
Parent Interview 
Infant Measures  
• 
Salivary Cortisol 

 
 
 18 
• 
Carey Temperament Scales (CTS) 
• 
Bayley Scales of Infant Motor Development-III (BSID-III)  
 
6.3 
Statistical Methods 
In addition to the analysis plan above, we will calculate the mean and standard deviation of each potential outcome 
measure to estimate the sample size required for a randomized trial.  All statistical estimates of population parameters 
will be tabulated along with corresponding confidence intervals (CIs) (Aim 1). We will combine that information with 
what we learn from parent interviews as the basis for selecting primary and secondary outcomes for future randomized 
trials to evaluate TEMPO (Aim 2). 
 
Although validated outcome measures will be collected in this pilot study in order to refine the TEMPO protocol for 
future study, these variables will not be incorporated in the statistical analyses of outcomes. Collection of the validated 
measures will also be used to select a sample size for a full study (Aim 3). We anticipate this data will be used to develop 
estimates of correlations among repeated measures, means and standard deviations. Point-estimates of the means, 
standard deviations, and correlations will be tabulated along with corresponding confidence intervals (Aim 3). 
 
 
6.4 
Interim Analysis 
Apart from safety monitoring, no interim analyses will be performed. 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including compliance 
with protocol enrollment criteria) 
Every 2 weeks 
PI 
Quarterly  
Independent Monitor 
Status of all enrolled subjects, as of 
date of reporting  
Monthly 
PI 
Quarterly 
Independent Monitor 
Data entry quality control checks on 
20% of charts 
Quarterly 
PI 
Adherence data regarding study 
visits and intervention 
Monthly 
PI 
Quarterly 
Independent Monitor 
AEs  
Monthly, within 24 hours 
PI 
Quarterly, within 24 hours 
 
Independent Monitor 
Annually 
NCCIH 
SAEs (unexpected and related) 
Per occurrence 
PI, Independent  Monitor  
NIH/NCCIH 

 
 
 19 
 
 
7 
STUDY INTERVENTION  
• 
Early Parent Education Session: Initiated within 3 weeks of infant birth. The PT will educate the parent about 
the importance of infant positioning, the impact of prematurity on the motor and sensory systems, and how to 
read and respond to infant behavioral-motor cues5 using a written pamphlet with pictures to supplement the 
verbal education lasting about 30 minutes.  
• 
Weekly Parent Education Sessions <34 weeks: Following the initial parent education session, the PT will hold 
weekly parent education sessions, ideally at the time of therapy. When the infant is this young (<34 weeks 
gestation), PT intervention and education will focus on infant behavioral-motor cues, reading/response to infant 
cues, positioning strategies/concerns, and developmentally appropriate stimulation of the infant. If the parent is 
not available for all therapy sessions, then the parent will receive a weekly update about their infant’s progress 
face-to-face and/or via video chat.  
• 
Infant Massage Parent Education Sessions: Parent-administered infant massage will be incorporated into the 
therapy plan of care as soon as the infant’s medical provider determines that the infant is physiologically stable 
and can tolerate massage. At a minimum, the therapist will teach massage for the back or lower extremities over 
2 parent education sessions – one early session in the isolette (if necessary) and one later session out of the 
isolette. The therapist will demonstrate massage strokes on a doll using verbal cues to guide the parent while 
the parent administers massage on the infant. An instructional massage pamphlet will be provided. The massage 
intervention is comprised of moderately firm effleurage strokes on the extremities for periods of 10-20 minutes 
followed by gentle passive muscle elongation. Use of upper or lower body swaddle, pacifier, and room 
darkening may be necessary to achieve positive infant responses during massage. 
• 
Visits 11+: Weekly Parent Education Sessions >34 weeks: Weekly parent education once the infant is >34 weeks 
will begin to incorporate hands-on developmental play activities, introduction to visual engagement, and 
postural control practice in variety of positions that the infant tolerates. Additionally, the PT and parent may 
choose to review massage at these visits. If the parent is not available for all therapy sessions, then the parent 
will receive a weekly update about their infant’s progress face-to-face and/or via video chat.  
• 
Discharge Parent Education Session: Within the week of hospital discharge, the PT will schedule a face-to-face 
parent education session lasting about 30 minutes to review age-appropriate developmental play activities for 
home and review infant massage. A supplemental handout and therapist email and pager information will be 
provided.  
o Additional Physical Therapy Intervention Description: Age appropriate physical therapy interventions 
and developmental play activities will be taught to parents during the hospital stay at weekly visits and 
at the discharge parent education session. These activities may include but are not limited to: Prone 
positioning to develop head, neck, and shoulder strength, supine play activities like patty-cake and leg 
bicycles to promote flexion of the trunk and extremities against gravity, visual tracking activities to 
promote symmetrical movement of the neck/head, and supported sitting activities in the parent’s lap to 
promote postural control. 
• 
Parent Education Post-Discharge: The PT will call the parent within 2 weeks of discharge to follow up about 
discharge education and massage. During this phone call, the PT will review the home program and massage 
Unanticipated Problems 
Monthly 
PI 
Per Policy 
IRB, NCCIH 

 
 
 20 
techniques. The PT will also answer any parent questions.  Therapist email and pager information will be 
provided.  
• 
2 Month Follow-up Massage Review Session: At the standard of care 2-month follow-up appointment with the 
multidisciplinary neonatology team, the PT will provide a gross motor screening assessment and education. In 
addition, as part of the TEMPO program, a PT will facilitate a parent-administered infant massage session to 
provide an opportunity for parent to receive feedback on technique from the PT. This session will address any 
safety concerns, infant changes, and parent questions. 
• 
Bi-weekly emails:  The PT will continue to send bi-weekly emails with developmental play activity and massage 
reminders until the 12 month follow-up appointment.   
• 
12 Month Follow-up Appointment: At the standard of care 12 month follow-up appointment with the 
multidisciplinary neonatology team, the PT will administer a standardized assessment of gross and fine motor 
skills (Bayley Scales of Infant Development 3). 
 
8 
SAFETY MANAGEMENT 
This study will be stopped prior to its completion if: (1) the intervention is associated with AEs that call into question the 
safety of the intervention in infants <28 weeks gestational age; (2) significantly lower study recruitment or retention 
than expected that will impact the ability to evaluate feasibility of TEMPO. 
Definitions  
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the clinical study or with 
use of the experimental agent being studied. An adverse finding can include a sign, symptom, abnormal assessment 
(laboratory test value, vital signs, electrocardiogram finding, etc.), or any combination of these regardless of relationship 
to participation in the study. 
Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to subjects or 
others to include, in general, any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in 
the protocol-related documents, such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
Serious Adverse Event (SAE)  
A serious adverse event (SAE) is one that meets one or more of the following criteria: 

 
 
 21 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect   
An important medical event that may not result in death, be life threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Time Period and Frequency for Event Assessment and Follow-Up 
An independent monitor has been identified to review enrollment, UPs, and AEs. The study team will send the 
independent monitor a report on enrollment every 4 months, with the expectation that the independent monitor will 
provide input on enrollment within 30 days. UPs and AEs will be reported to the independent monitor within 24 hours 
with the expectation that the independent monitor will provide input on UPs and/or AEs within 5 days.  
 
Characteristics of an Adverse Event 
 
Relationship to Study Intervention 
The potential event relationship to the study intervention and/or participation is assessed by the site investigator. A 
comprehensive scale in common use to categorize an event is: 
• 
Definitely Related:  The adverse event is clearly related to the investigational agent/procedure – i.e. an event 
that follows a reasonable temporal sequence from administration of the study intervention, follows a known 
or expected response pattern to the suspected intervention, that is confirmed by improvement on stopping 
and reappearance of the event on repeated exposure and that could not be reasonably explained by the 
known characteristics of the subject’s clinical state. 
• 
Possibly Related:  An adverse event that follows a reasonable temporal sequence from administration of the 
study intervention follows a known or expected response pattern to the suspected intervention, but that 
could readily have been produced by a number of other factors. 
• 
Not Related:  The adverse event is clearly not related to the investigational agent/procedure - i.e. another 
cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the 
onset of the event and the study intervention and/or a causal relationship is considered biologically 
implausible. 
 
Expectedness of SAEs 
Massage has been studied extensively in infant born at less than 32 weeks gestation, and reported AEs in the literature 
are rare. Massage has not been studied as extensively in the extremely preterm infant population (<28 weeks gestation), 
so we will monitor infant heart rate and respiratory rate continuously during massage intervention, and temperature 
before and after intervention, as outlined in section 5.1 “Safety Evaluations” section. These risks are addressed in the 
informed consent document. The study PI, infant’s medical team, and the independent monitor will review any AE to 

 
 
 22 
determine if it is expected or unexpected based on characteristics of the event and risk information previously described 
in the literature. 
Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on infant’s routine care 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on infant’s routine care 
3. Severe: significant symptoms requiring invasive intervention; infant requires additional medical attention, 
significant impact on infant’s routine care 
Reporting Procedures 
Information previously unknown to the UNC IRB that suggests new or increased risk to subjects or others is promptly 
reportable to OHRE within 7 calendar days of the investigator becoming aware of the information. 
Reporting for Multi-Center Trials 
 
This is a single site study. 
Unanticipated Problem Reporting  
All UPs will be recorded using an “unanticipated problem report form” which will include the following information: 
• 
Appropriate identifying information for the research protocol, such as the title, PI’s name, and the IRB project 
number; 
• 
A detailed description of the UP;  
• 
An explanation of the basis for determining that the adverse event, incident, experience, or outcome represents 
an unanticipated problem;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are proposed in 
response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported as follows:   
• 
Unanticipated problems that are serious adverse events will be reported to the IRB, Independent Monitor, and 
NCCIH within 24 hours of the PI becoming aware of the event.  
 
Adverse Event Reporting  
 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the Independent 
Monitor, IRB, and NCCIH in accordance with requirements.   

 
 
 23 
• 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NCCIH Program 
Officer, and Independent Safety Monitor(s) within 3 days of the investigator becoming aware of the event.  
Other serious and unexpected AEs related to the intervention will be reported within 7 days. 
• 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the Independent 
Safety Monitor(s), IRB, and other oversight organizations in accordance with their requirements. and will be 
reported to NCCIH on an annual basis.    
• 
All other AEs documented during the course of the trial will be reported to NCCIH on an annual basis by way of 
inclusion in the annual report and in the annual AE summary which will be provided to NCCIH and to the 
Independent Monitors.  The Independent Safety Monitor(s) Report will state that all AEs have been reviewed. 
Halting Rules 
 
 
An infant may no longer participate in the study under any of the following circumstances: 
 
• 
The medical condition of the infant deteriorates and the medical team no longer recommends PT or massage 
• 
The infant experiences a severe AE or SAE related to the intervention 
• 
The Parent is no longer interested in participating 
 
In the event that an infant has an AE related to massage medium (Aquaphor), then massage will be performed without 
the medium or with a medium approved by the medical team once the skin has healed. 
 
 
 
9 
DATA COLLECTION AND MANAGEMENT  
 
Data Monitoring 
 
Study progress and safety will be reviewed on a monthly basis or more frequently as needed. Progress reports, including 
patient recruitment, retention/attrition, and AEs will be provided to the Independent Monitor quarterly.  An Annual 
Report will be compiled and will include a list and summary of AEs.  In addition, the Annual Report will address (1) 
whether AE rates are consistent with pre-study assumptions; (2) reason for dropouts from the study; (3) whether all 
participants met eligibility criteria; (4) whether continuation of the study is justified on the basis that additional data are 
needed to accomplish the stated aims of the study; and (5) conditions whereby the study might be terminated 
prematurely.  The Annual Report will be sent to the Independent Monitor and a copy of the Annual Report with the 
independent monitor’s recommendations and comments will be forwarded the NCCIH Program Officer within one 
month following.   
The PI will carefully review study documentation on a weekly basis to ensure data collection from study subjects is 
complete. This includes vitals (heart rate, oxygen saturation, and respiratory rates) during PTIs and salivary cortisol 
concentrations (ng/dl) documented in the medical chart, weekly parent reports of bedside PTIs, bi-weekly parent 
reports of home PTIs, and completeness of any questionnaires given to parents at various points in the TEMPO protocol. 
The PI will review this documentation for completeness. 
 
Data on adherence to the TEMPO protocol will be reported by the parents on a form at the infant’s bedside. This data 
will be collected weekly by research staff and reviewed monthly by the PI.  The PI will determine adherence of parents 
to the TEMPO protocol by reviewing reported TEMPO intervention targets on the form at the infant’s bedside. At each 
weekly parent education session, the therapist will review the TEMPO interventions and recommended frequency. If the 
parents are unable to meet the frequency, then barriers to this will be recorded by the therapist and shared with the PI. 

 
 
 24 
No data exists on the frequency of the use of massage and physical therapy interventions at the bedside and at home, 
but we anticipate that 70% of parents will perform massage and/or physical therapy interventions 2-3x/week at the 
bedside and at home.  If adherence falls below the suggested rate, the PI will convene study personnel to discuss 
methods for improving adherence. 
The data will be collected and managed by the PI and the study coordinator. They should ensure that parent surveys are 
recorded accurately, completely, and in a timely manner. All surveys will be completed digitally on an iPad to ensure 
accurate interpretation of data. 
Data Management and Confidentiality 
Data collection and accurate documentation are the responsibility of the study staff under the supervision of the PI.  All 
source documents and laboratory reports must be reviewed by the PI and/or study coordinator, who will ensure that 
they are accurate and complete.  Unanticipated problems and adverse events must be reviewed by the PI within 24 
hours of being made aware of the event.  
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and their agents. 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. The 
investigators will maintain adequate case histories of study participants, including accurate case report forms (CRFs), 
and source documentation.   
Data collection and accurate documentation are the responsibility of the study staff under the supervision of the 
investigator. All source documents will be reviewed by the study team and data entry staff, who will ensure that they 
are accurate and complete. Unanticipated problems must be reviewed by the investigator or designee.   
A web-based data management system will be built in REDCap for use in for this study. This data management system 
provides all of the capabilities required for research data management, including: data transfer, data entry, data 
validation, database updating, database closure, data retrieval, data inventory, security and confidentiality, and 
archiving. This database is virtually encrypted.  The database will be secured with password protection. Information that 
is entered into the database will be coded using study identification numbers.  Any electronic communication with 
outside collaborators (e.g. Independent Monitor) will involve only unidentifiable information. The database incorporates 
an electronic audit trail to show change(s) to data after original entry including the date/time and user making the 
change. 
 
Direct data entry, where data initially are entered on the screen without having completed a paper form first, will be 
used when possible; otherwise, paper forms will be utilized and the data will be entered into the REDCap database by a 
research assistant.  
REDCap is housed on a secure, climate-controlled server. UNC has in place an IT Security Plan as required by NIH 
contracts and grants.  As part of the plan, the principle of least access privilege for study files is implemented.  Included 
in the plan are a risk assessment, a system continuity plan, and a disaster recovery plan.  Support for REDCap services is 
provided by the NC TraCS Institute, the Clinical and Translational Science Award center at UNC-CH.   
Data confidentiality and security measures will be applied at all levels of TEMPO data acquisition, transfer and storage. 
REDCap meets exacting data management standards of confidentiality, as well as HIPAA requirements. Beyond the 
password-controlled access to REDCap, data are encrypted by the system and can only be decrypted for display on-
screen by authorized study personnel. Personal identifiers are collected on separate forms as an additional safeguard 
against linking of identifiers and medical information.  
Enrollment and other data management reports will be available from the REDCap database.  Monthly reports on study 
enrollment, intervention, unexpected events, and adverse events will be provided to the principal investigator and 

 
 
 25 
quarterly reports will be provided to the independent monitor. Annual progress reports will be submitted to NIH and to 
the University of North Carolina IRB. 
Study records will be maintained for at least three years from the date that the grant federal financial report (FFR) is 
submitted to the NIH.   
 
10 
RECRUITMENT STRATEGY 
The recruitment process with the parents will be initiated once the physical therapy referral has been made by the 
treating physician. The neonatology provider team will receive an introduction to the study from the PI (McCarty) and 
chief neonatologist/grant mentor (O’Shea) prior to study initiation. All infants who meet eligibility criteria for the study 
also receive standard physical therapy orders in the Newborn Critical Care Center (NCCC). A physical therapist attends 
weekly developmental rounds in the NCCC and participates in the physical therapy referral process by screening patients 
who are under a certain age and weight. The physical therapy referral is received when the infant is clinically stable and 
thus should avoid the initial parent distress and need for orientation after the birth and admission to the NCCC.  In order 
to ensure that parents have sufficient time to consider participation, the study coordinator will contact the family at the 
bedside or by phone call once the physical therapy referral has been initiated to introduce the TEMPO study. The study 
coordinator will offer to leave the consent document with the parent(s).  Once parents feel they have had adequate 
time to review the informed consent, the informed consent process will proceed.     
 
11 
CONSENT PROCESS 
The informed consent process is initiated prior to the parent agreeing to participate in the study and continues 
throughout study participation.  Extensive discussion of risks and possible benefits of study participation will be provided 
to parents. A consent form describing in detail the study procedures and risks will be given to the parent.  Consent forms 
will be IRB-approved, and the subject is required to read and review the document or have the document read to him or 
her.  The investigator or study coordinator will explain the research study to the subject and answer any questions that 
may arise.  The parent will sign the informed consent document prior to any study-related assessments or procedures.  
Parents will have the opportunity to discuss the study with others or think about it prior to agreeing to participate.  They 
may withdraw consent at any time throughout the course of the study.  A copy of the signed informed consent 
document will be given to the parents for their records.  The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if they decline to participate in 
this study. 
The consent process will be documented in the clinical and research record. 
 
12 
PLANS FOR PUBLICATION 
At the conclusion of the study period, the data will be analyzed and reviewed by the PI and study team. A manuscript 
will be drafted and submitted to a multidisciplinary neonatal-perinatal medicine journal in order to reach a variety of 
audiences. 
 
 
 

 
 
 26 
13 
REFERENCES 
1. Holditch-Davis D, White-Traut RC, Levy JA, O'Shea TM, Geraldo V, David RJ. Maternally administered 
interventions for preterm infants in the NICU: effects on maternal psychological distress and mother-infant 
relationship. Infant Behav Dev. 2014;37(4):695-710. 
2. Ionio C, Colombo C, Brazzoduro V, et al. Mothers and Fathers in NICU: The Impact of Preterm Birth on Parental 
Distress. Eur J Psychol. 2016;12(4):604-621. 
3. Moura MRS, Araújo CGA, Prado MM, et al. Factors associated with the quality of life of mothers of preterm 
infants with very low birth weight: a 3-year follow-up study. Quality of Life Research. 2016;26(5):1349-1360. 
4. Greene MM, Rossman B, Meier P, Patra K. Elevated maternal anxiety in the NICU predicts worse fine motor 
outcome in VLBW infants. Early Hum Dev. 2018;116:33-39. 
5. Sweeney JK, Heriza CB, Blanchard Y, Dusing SC. Neonatal physical therapy. Part II: Practice frameworks and 
evidence-based practice guidelines. Pediatr Phys Ther. 2010;22(1):2-16. 
6. Dusing SC, Murray T, Stern M. Parent preferences for motor development education in the neonatal intensive 
care unit. Pediatr Phys Ther. 2008;20(4):363-368. 
7. Juneau AL, Aita M, Heon M. Review and Critical Analysis of Massage Studies for Term and Preterm Infants. 
Neonatal Netw. 2015;34(3):165-177. 
8. Feijo L, Hernandez-Reif M, Field T, Burns W, Valley-Gray S, Simco E. Mothers' depressed mood and anxiety levels 
are reduced after massaging their preterm infants. Infant Behav Dev. 2006;29(3):476-480. 
9. Afand N, Keshavarz M, Fatemi NS, Montazeri A. Effects of infant massage on state anxiety in mothers of preterm 
infants prior to hospital discharge. J Clin Nurs. 2017;26(13-14):1887-1892. 
10. Health NNCfCaI. Pilot Studies: Common Uses and Misuses. 2017; 
https://nccih.nih.gov/grants/whatnccihfunds/pilot_studies. Accessed November 21, 2018. 
11. Welch MG, Halperin MS, Austin J, et al. Depression and anxiety symptoms of mothers of preterm infants are 
decreased at 4 months corrected age with Family Nurture Intervention in the NICU. Arch Womens Ment Health. 
2016;19(1):51-61. 
12. Hanington L, Ramchandani P, Stein A. Parental depression and child temperament: assessing child to parent 
effects in a longitudinal population study. Infant Behav Dev. 2010;33(1):88-95. 
13. Garfield CF, Lee YS, Kim HN, et al. Supporting Parents of Premature Infants Transitioning from the NICU to 
Home: A Pilot Randomized Control Trial of a Smartphone Application. Internet Interv. 2016;4(Pt 2):131-137. 
14. Feldstein S HA, Morrison BM, Huang KY. Relation of the Postnatal Attachment Questionnaire to the Attachment 
Q-set. Journal of Reproductive and Infanat Psychology. 2004;22(2):111-121. 
15. Bae YJ, Reinelt J, Netto J, et al. Salivary cortisone, as a biomarker for psychosocial stress, is associated with state 
anxiety and heart rate. Psychoneuroendocrinology. 2018;101:35-41. 
16. de Oliveira Tobinaga WC, de Lima Marinho C, Abelenda VL, de Sa PM, Lopes AJ. Short-Term Effects of 
Hydrokinesiotherapy in Hospitalized Preterm Newborns. Rehabil Res Pract. 2016;2016:9285056. 
17. Lester BM, Salisbury AL, Hawes K, et al. 18-Month Follow-Up of Infants Cared for in a Single-Family Room 
Neonatal Intensive Care Unit. J Pediatr. 2016;177:84-89.