Statistical Analysis Plan (SAP): The Navigate Study

February 28, 2017

Statistical Analysis Plan (SAP):

The Navigate Study

Version 2.0

Principal Investigator:

Kelly Michelson, MD MPH

Ann & Robert H. Lurie Children’s Hospital of Chicago kmichelson@luriechildrens.org

Study Statistical Team:

Jody D. Ciolino, PhD

Statistician, Northwestern University jody.ciolino@northwestern.edu Karen Rychlik, MS

Statistician, Data Manager

Ann & Robert H. Lurie Children’s Hospital of Chicago KRychlik@luriechildrens.org

Approved By:

3/2/2017

Kelly Michelson, MD MPH Date

02/28/2017

Karen Rychlik, MS Date

02/28/2017

Jody D. Ciolino, PhD Date

1

February 28, 2017

2

I. Introduction

Parents of children admitted to the Pediatric Intensive Care Unit (PICU) often face challenging decisions.

Research demonstrates deficiencies in communication in the PICU which could impact decision making. This study team has developed a navigator-based intervention called PICU Supports. PICU Supports aims to provide the following types of support to parents of patients in the PICU: emotional;

facilitation of communication (between Healthcare Team Members [HTMs] and parents/families as well as among HTMs); decision making; transition out of the PICU (i.e., discharge transitions to a non-PICU hospital bed, a long-term care facility, or home); and information. Support is accomplished by navigator engagement with parents and HTMs and the guided use of navigator-supported ancillary tools provided to parents and HTMs as needed. During each patient’s PICU stay, the navigator activities and use of ancillary tools are directed by the individual family’s needs. Thus, PICU Supports uses a predefined framework of activities and tools to provide individualized support directed by the needs of the parent(s) and the patient situation. This research will test PICU Supports in the clinical setting. This will be accomplished by conducting a pilot study of PICU Supports at Ann & Robert H. Lurie Children's Hospital of Chicago (Lurie Children’s Hospital; LCH), followed by a randomized controlled trial (RCT) comparing the intervention, PICU Supports, to a control, parental receipt of an educational brochure.

The RCT will be conducted at Lurie Children's Hospital and at University of Chicago Medicine Comer Children’s Hospital (Comer Children’s Hospital; CCH).

II. Study Objectives and Endpoints

The primary goal of this study is test the use and efficacy of PICU Supports in the clinical setting. The study will strive to accomplish the following objectives:

a. Objectives and Hypotheses

i. Aim 1: Determine the feasibility, perceived acceptability, and effectiveness of PICU Supports.

1. H1a: Implementation of PICU Supports is feasible.

2. H1b: Parents perceive PICU supports as acceptable and effective.

3. H1c: HTMs perceive PICU supports as acceptable and effective.

ii. Aim 2: Test the impact of PICU Supports during and after PICU discharge on parent outcomes: satisfaction with decision making (DM), decision regret, anxiety,

depression, post-traumatic stress, health-related quality of life, and complicated bereavement.

1. H2a: PICU Supports improves parental satisfaction with DM.

2. H2b: PICU Supports decreases short-term parental decision regret.

3. H2c: PICU Supports decreases short-term parental anxiety, depression, symptoms of post-traumatic stress, improves health-related quality of life, and decreases severity of complicated bereavement.

iii. Aim 3: Test the impact of PICU Supports on parent and HTM assessments of communication and team collaboration.

1. H3a: PICU Supports improves parental assessments of communication between HTMs and parents and parental assessments of team

collaboration.

2. H3b: PICU Supports improves HTM assessments of team collaboration.

b. Primary and Secondary Outcomes

i. Primary Outcome(s): Aim 2 serves as the primary aim; major primary and secondary outcomes will be analyzed to address this aim and will be the focus of this SAP.

1. H2a: The percentage of “excellent” scores in the DM domain of the pFS-ICU between three and five weeks from discharge will serve as the primary outcome for this RCT. We anticipate the majority of these surveys to fall within the true three-five week window; however, we plan to allow for inclusion of surveys for this time point as long as they are returned prior to 12 weeks.

2. H2b: Decision regret score (ranging from 0-100, larger score suggests higher regret) serves as an important secondary outcome to address this

hypothesis. We will treat this outcome as a continuous variable.

3. H2c: Each of the following additional outcomes will serve as secondary outcomes to evaluate success of PICU Supports on short-term parental anxiety, depression, symptoms of post-traumatic stress, improving health- related quality of life, and decreasing severity of complicated bereavement (bereaved families only). We plan to use each assessments’ scoring manual as appropriate in order to obtain each endpoint for each participant.

a. PROMIS Anxiety Short Form 8a: we will use the T-score for analyses which is generally centered at 50 points with standard deviation of 10 points.

b. PROMIS Depression Short Form 8a: we will use the T-score for analyses which is generally centered at 50 points with standard deviation of 10 points.

This instrument will also be scored according to PROMIS conventions as above.

c. Impact of Event Scale-Revised (IES-R): the total score will range from 0 to 88 points with each of the subscales below ranging from 0 to 4 points.

i. Intrusion subscale ii. Avoidance subscale iii. Hyper-arousal subscale

d. PROMIS Global Health Short Form: we will use the T-score, centered at 50 points with standard deviation of 10 points.

e. Inventory of Complicated Grief (ICG) for bereaved parents only: the total score will range from 0 to 76 points, with each item scored on a five point scale (0 to 4). Higher scores indicate more complicated grief symptoms and scored greater than 30 may indicate

complicated grief.

ii. Additional Secondary Outcomes: The following outcomes will measure perceived impact on communication and they all pertain to Aim 3:

a. H3a: There are two outcomes to address parental satisfaction with communication:

i. Communication Assessment Tool (CAT): administered after family conferences with scores ranging from 0 to 5 points.

ii. Collaboration and Satisfaction about Care Decisions (CSACD)

1. Collaboration score: scores range from 7 to 49 points.

2. Satisfaction score: scores range from 2 to 14 points.

b. H3b: CSACD tool will be used to assess HTM perceptions of

communication both before and after the pilot/RCT. There may be some “paired” responses, but there may be some individual responses that cannot be linked pre-/post-study by participant.

c. Process Outcomes

Analyses outlined in this SAP will focus on the outcome(s) related to Aims 2 and 3 as mentioned above, but all relevant outcomes to examine perceived acceptability, feasibility, and effectiveness of the intervention alone correspond to Aim 1. The outcomes associated with this aim will primarily be proportions and/or percentages, and analyses will consist of simple descriptive statistics. Where indicated, continuous measures will be presented with mean/median/range of values. Quantiles and or confidence intervals may be provided as appropriate, but no formal statistical tests will be performed as part of this aim.

i. H1a:

1. Enrollment rate

2. Rate of return of study documents: Please refer to the study protocol (September 9, 2014 version) and appendices for the survey documents:

3. Fidelity rates (for intervention arm only):

a. Navigator meeting rate (actual meets/possible meets and actual meets/attempted meets) Day 1 and overall

b. Percentage of families total in which Navigator met with family on Day 1

c. Post discharge follow-up percentage

d. Healthcare team meeting rate (Day 1 and overall)

ii. H1b: The following questions on Parent Surveys 4 and 5 will be used to address this aim:

1. Usefulness of brochure (for Control families) 2. For intervention families:

a. How well PICU Supports helped with communication b. Quality of communication between parents and HTM c. Quality of communication within HTM

d. Timeliness of communication between parents and HTM e. Conversations with HTM about values

f. Hospital experience

g. Family-centeredness of care

h. The usefulness of the intervention will further be assessed with the following questions (scored 1-4: useless-extremely useful; 5=did not use):

i. Navigator’s weekday visits ii. Communication log iii. Regular family meetings

iv. PICU Handbook v. List of questions vi. Calendar/diary

vii. Any information/education materials

i. Note that formal statistical analyses involving the open-ended questions are not planned; however, select comments may be anonymously reported and/or examined.

iii. H1c: We will rely primarily on qualitative data (beyond the scope of this SAP) to address this hypothesis. Note that formal statistical analyses involving the open- ended questions are not planned; however, select comments may be anonymously reported and/or examined.

d. Safety Outcomes

Upon discussion with Data and Safety Monitoring Board (DSMB) chair, it was decided that the question at discharge and follow-up which asks: “How well did the PICU Supports help with communication in the PICU?” will serve as the safety assessment. If the percentage of negative responses to this item is deemed unacceptable by the DSMB, the DSMB may make recommendation to suspend enrollment or terminate the study.

e. Demographics, Confounders, Covariates

General demographic and clinical/dispositional information for patients and parent

participants will be summarized via simple descriptive statistics overall and by arm. For the purposes of these analyses, however, the following variables will be explored as potential covariates/confounders:

i. PIM2 score

ii. Length of stay (dichotomized into: <12 days vs. ≥12 days)

iii. Clinical site: Ann & Robert H. Lurie Children’s Hospital of Chicago or University of Chicago Medicine Comer Children’s Hospital

In addition, the following subgroups will be explored in greater detail:

iv. Patients who died

v. Patients surviving, but about whom an important life changing decision was required (i.e., trach, GT, initiation of chronic ventilation, introduction PC, implementing a new order to limit care)

vi. Patients staying in PICU for at least 12 days (versus those not) vii. Families in which the child has never been admitted in the PICU

viii. Patients at Lurie Children’s Hospital versus those at Comer Children’s Hospital

III. Study Methods

Following screening and consent of parents/families, patients will be randomized to either active intervention (PICU Supports) or an informational brochure via a randomized block design (1:1) to ensure equal allocation. The study statisticians uploaded the pre-generated randomization list was uploaded to REDCap prior to implementation. The randomization algorithm employed a random block design with blocks of size <XXXX> (masked to study investigators with the exception of the statisticians) to ensure equal allocation throughout the course of the study. Data were collected on relevant study participants at the following study time points:

a. Upon PICU admission b. During PICU stay

i. Primary outcome will be assessed weekly for four weeks, then monthly thereafter ii. Secondary outcomes regarding communication assessment will be assessed after

family meetings c. At PICU discharge

d. Between three and five weeks after PICU discharge e. Between three and five months after PICU discharge

The following illustrates collection time points for relevant family outcomes:

Outcome

Baseline During PICU Stay

At PICU Discharge~

3-5 Weeks Post- Discharge

3-5 Months Post- Discharge^%

Demographics x

Social Support x

Religious/Spirituality x

Resilience x

Previous Experience in PICU x

Anxiety Score (SF8a) x x x x

Depression Score (SF8a) x x x x

Global Health Score x x x x

Primary Outcome: pFS-ICU X* x x x

CSACD X* x x x

CAT X**

DRS x x x

IES-R x x x

ICG^# x x

Intervention

Acceptability/Effectiveness^ x x x

~Bereaved parents will not be approached for these outcomes at discharge

*Weekly for four weeks, then monthly

**After family meetings

^This will not be assessed in control families

#This will only be assessed for bereaved families

%This outcome time point will not be analyzed/addressed in this SAP; however, post hoc additional analyses may examine this time point as well.

In addition to family/patient data, HTM data will be collected at the following time points:

f. Prior to implementation of the study g. After study completion

Process measures by the navigator will be assessed:

h. Daily during PICU stay for intervention families i. After each family meeting for intervention families IV. Analysis Considerations

a. General Considerations

i. Timing of Analyses: interim analyses and data monitoring

Analyses will occur only upon final database freeze and export. There are no planned formal interim analyses; however, descriptive statistics (in aggregate, not broken down by arm) will be examined throughout in order to monitor study progress, identify data anomalies, data entry errors, and/or any safety/procedural concerns. Monthly data exports by the study statistician(s) will be used for this purpose. Further, DSMB meetings will occur roughly every six months. Unless specified by the DSMB, there will be no summarizations of data broken down by arm.

ii. Analysis Population

All analyses will assume the intent-to-treat (ITT) principle, whereby participants will be analyzed according to the group to which they were randomized, regardless of adherence to the study protocol or any potential cross contamination across arms.

Sensitivity analyses may be employed on a subset of the population; however, at the time of the SAP development there were no planned sensitivity analyses specified.

iii. Assumptions, Missing Data, and Handling Data Anomalies

Analyses will proceed under parametric, normal theory assumptions. Primary and secondary outcomes based on assessment scores will be analyzed as continuous measures. Residual diagnostics will be examined along with appropriate relevant assumptions. In cases where assumptions may be in question (e.g., normality) or in cases of small sample size, nonparametric methods may be applied. There are no plans to remove extreme observations or outlying values from analyses.

Given the nature of the data collection and the fact that primary outcome occurs between three and five weeks after discharge from the PICU, we anticipate missing data. Primary analyses outlined in this SAP will be based on complete cases;

however, exploratory sensitivity analyses may explore multiple imputation methods or further advanced methodologies. The details of these analyses will not be outlined in this SAP.

b. Planned Analyses

Since potentially more than one parent per patient may provide outcome data, we plan to account for intra-family correlation in general through the use of linear mixed modeling approaches (LMM) in which a random family effect will induce correlation between parents of the same family. Thus, unless otherwise specified, all analyses will employ LMM with random family effect and fixed arm and/or covariate effect(s).

The primary analysis time point will be the three-five week post discharge study follow-up time point. There may be future secondary analyses employing longitudinal mixed modeling or specific focus on additional analysis time points, but the primary results dissemination materials will be directed toward the three-five week follow-up time point. The analyses specified herein pertain to those from Aim 2 and some parts of Aim 3 above. The additional outcomes listed previously, but not included below will be summarized via descriptive statistics and/or secondary ancillary studies may employ more detailed analyses of these endpoints. At the time of formal analyses and dissemination for those endpoints, a separate analysis plan will accompany those analyses.

i. Primary Outcome

Primary outcome (percent satisfaction with DM on pFS-ICU between three and five weeks after discharge) will be analyzed under the following model assumption:

Y_ij=β₀+β₁(arm)+b_i+e_ij

i= 1,…,number of patients; j=1,2 (parent number); Yij = outcome; b_i N

(

^0,σb2

)

^;eij

~N(0, σ²¿;b_i⊥e_ij .

In addition, secondary analyses on the same outcome will assume:

Y_ij=β₀+β₁(arm)+β₂(PIM2)+β₃I(LOS ≥12)+β₄I(Comer)+b_i+e_ij

In each case, the hypothesis test of interest is H₀:β₁=0vs. H₁:β₁≠0 _{. We will} examine arm as the primary independent variable of interest in both unadjusted and adjusted analyses at the 5% level of significance. There will be no corrections made for multiple hypothesis testing for this outcome.

ii. Secondary Outcomes

Analyses for each of the following outcomes will proceed as outlined above (i.e., LMMs both adjusted and unadjusted for the two covariates of interest):

1. pFS-ICU: Satisfaction with Care score, Satisfaction with DM score, Total score 2. PROMIS Anxiety score

3. PROMIS Depression score

4. PROMIS Global Health: physical and mental domains 5. DRS

6. IES-R: Intrusion, Avoidance, Hyperarousal, Total scores 7. CSACD: Collaboration and Satisfaction scores cores 8. ICG for bereaved parents

Due to the large number of hypothesis tests for these secondary outcome analyses, we plan to employ Hochberg’s procedure for multiple hypothesis tests.

According to this process, we will order all secondary p-values from smallest to largest. We will reject all m hypotheses if p(m)<0.05/m. Otherwise, we will reject all (m-1) hypotheses if p(m-1)<0.05/(m-1), etc.

iii. Exploratory Outcomes and Analyses

1. We will repeat primary and secondary outcome analyses within each of the following pre-specified subgroups: patients who died; those surviving but requiring a life changing decision as mentioned above; patients with LOS≥12

days; those with LOS<12 days; parents whose child was never in PICU;

patients at Lurie Children’s Hospital; patients at Comer Children’s Hospital.

In all cases, we will assume: Y_ij=β₀+β₁(arm)+b_i+e_{ij as above.}

2. In addition, within the active intervention arm only, we will examine “dose- response” relationships by inclusion of an additional fixed effect “dose”

variable. This variable will be calculated as actual meets with the

Navigator/days in the PICU. We chose days in the PICU as the denominator (as opposed to days in the study, etc.) as this will most closely mirror real-life scenarios in which a navigator may or may not intervene upon a family the entire length of PICU stay. If this variable is significantly associated with primary outcome in a similar LMM at the 5% level, we may conclude that there is in fact a linear dose-response relationship between intervention and primary outcome of interest.

3. Additional analyses may explore higher order and/or interaction terms for fixed effects; however, these analyses will be post hoc and may carry less merit.

4. As previously mentioned, longitudinal modelling will not be the planned primary analyses, but these methods may be employed and reported upon in later dissemination materials.

c. Sample Size and Power Considerations

Without prior information regarding the primary outcome in this population and its standard deviation, sample size calculations had originally assumed a standard deviation of 17

percentage points, and enrollment called for 506 patients/families. It was anticipated that this would allow for adequate power for subgroup analyses; however, due to small

percentages of patients falling into pre-specified subgroups it was deemed impractical to enroll enough participants to achieve adequate power for these analyses.

Sample size considerations were updated based on a presumed more accurate standard deviation of approximately 30%-33% and feasible recruitment numbers within the study timeline. Since analyses within subgroups was deemed impractical, we chose to update our sample size considerations based on primary outcome analyses only (not within subgroups).

We anticipate enrollment of approximately 400 parents and a very large percentage of dropouts (i.e., 40%). Thus, we expect approximately 240 parent study participants with analyzable data. An independent two-sample t-test with equal allocation would give us 80%

power to detect a 10%-12% difference across arms at the 5% level of significance (effect size=0.3-0.4; on the order of small to moderate) if we have 240 independent observations.

We recognize that the independent two-sample t-test is not the planned means of analysis, but this should give us a reasonable estimate as we plan to analyze individual parent data via a LMM as there theoretically may be two analyzable outcomes per patient.

In addition, if we were to examine what we deem the larger subgroup (those with prolonged PICU stay), we anticipate 30% of the patients falling this group (roughly equally across arms), with the ability to detect a large effect size (Cohen’s d=0.7) across arms within this group.

V. Planned Data Summarizations and Reporting Conventions

Results will be reported according to CONSORT Guidelines. Planned results table templates are provided below. Note that final summarizations may stray slightly from those specified here according to practical/logistical considerations and journal requirements.

Table 1. Baseline Demographic and Clinical Characteristics

Variable Overall

Mean(std) / Frequency(%)

Intervention Mean(std) / Frequency(%)

Control Mean(std) / Frequency(%) Patient Characteristics

Parent Characteristics

Table 2. Primary and Secondary Outcome Results

Outcome Unadjusted Effect (95% CI) Adjusted Effect (95% CI) Primary

Secondary 1 Secondary 2 Etc.

Table 3. Subgroup Analysis Results

Subgroups Outcome1 (95% CI) Outcome2 (95% CI) Etc. Etc.

Patient who died Decision

Prolonged (≥12 days) LOS LOS < 12 days

Patient never in PICU Lurie Children’s Hospital Comer Children’s Hospital

VI. Additional Technical Details

a. Software: All analyses will be performed in SAS statistical software (version 9.4, Copyright 2012; The SAS Institute Inc.; Cary, NC). Some graphics and additional analyses may be performed using R (version 3.2.2, Copyright 2015; The R Foundation).

b. Data Storage: There are two study databases (one for each clinical site) stored in the Research Electronic Data Capture (REDCap) system housed at Northwestern University.

Planned database lock for primary and secondary outcome analyses as examined in this SAP will be March 7, 2017.

c. Modifications: Modifications to this document will be indicated via version control and date.

Any unspecified, post hoc analyses not specified by this SAP will be indicated as such in any dissemination materials.