Clinical trial NCT02340169
Conditions: Plaque Psoriasis
Sponsor: Sun Pharmaceutical Industries, Inc.
Start date: 2015-01-23; Completion date: 2021-11-22
Enrollment: 129 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to evaluate the potential of Topicort® (desoximetasone) Topical Spray, 0.25% to suppress hypothalmic pituitary adrenal axis function. The secondary objectives are to evaluate the efficacy parameters, pharmacokinetics and adverse event profile.

Detailed description:
An open label, post marketing safety study to assess the potential of a TOPICORT® (desoximetasone) Topical Spray, 0.25% to suppress HPA axis function following twice daily dosing for 28 days.

Arms: arm 1: Topicort® (desoximetasone) Topical Spray, 0.25%, twice a day for 28 days
Interventions: intervention 1: Topicort® (desoximetasone) Topical Spray, 0.25%
Intervention descriptions: intervention 1: Topicort® (desoximetasone) Topical Spray, 0.25% applied to affected areas twice a day for 28 days

Protocol documents:
Prot_SAP_000.pdf: 
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dsxs-1303-protocol


STATISTICAL ANALYSIS PLAN 
 
IND # 101789/ NDA # 204141                                Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
 
 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc.  
6. STATISTICAL ANALYSIS METHODS 
If not otherwise specified, statistical significance is defined as p < 0.05 and is two-tailed. Data 
will be summarized with respect to demographic and baseline characteristics, efficacy variables 
and safety variables. 
 
For categorical variables, the number and percent of each category within a parameter will be 
calculated for non-missing data. For continuous variables, statistics will include number of 
observations, mean, standard deviation, median, minimum and maximum values.  
 
All statistical analyses will be conducted using SAS®, Version 9.4 or higher. Datasets will be prepared 
using headings from Clinical Data Interchange Consortium (CDISC) Study Data Tabulation Model 
(SDTM) implementation for human clinical trials and ADaM (Analysis Dataset Model).  
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc. 
6.1 Baseline Characteristics 
6.1.1 Demographics 
Demographic information collected at baseline includes the following: 
•
Age (years)
•
Gender (Male/Female)
•
Ethnicity (Hispanic/non Hispanic)
•
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander,
Asian, American Indian or Alaska Native, Other)
•
Weight
•
Height
Summary tables by cohort and by PK subgroup within a cohort will be presented. Continuous 
variables will be summarized using descriptive statistics (n, median, minimum, maximum, 
mean, standard deviation). Categorical variables will be summarized using frequencies and 
percentages.  
Baseline comparability of the treatments will be presented using Cochran-Mantel-Haenszel 
(CMH) test for the categorical variables, and Analysis of Variance for the continuous variables.  
All data will be listed by cohort, PK subgroup within a cohort, and patient. 
6.2 Statistical Analyses 
Patients are required to apply a total of 56 doses for the study. Patients will dose twice daily for 
28 days. Patients in the PK Sampling Group will dose in the office at End of Treatment Visit. All 
patients who are enrolled and used at least 75%-125% of scheduled doses (i.e., between 42 - 70 
doses) of the study drug and have data from a post-treatment cortisol response test will be 
included in the analysis.  
6.2.1 Primary Analysis 
Potential HPA axis suppression 
The following criteria indicate a normal cortisol response (all criteria must be met): 
1. Their basal (pre-Cortrosyn™ injection) cortisol concentration is > 5 mcg/100 mL
2. Their 30 minute post injection cortisol level is at least 7 mcg/100 mL greater than
the basal level (≥ basal value + 7)
3. The post stimulation level is > 18 mcg/100 mL
Patients found to have abnormal adrenal function after the baseline Cortisol Response Test will 
not be enrolled in the study.  
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc. 
The test at the End of Study visit should not be performed if the patient dosed within 8 hours. 
HPA axis suppression will be defined as a 30 minute post-CortrosynTM injection level cortisol 
level of ≤ 18 mcg/100 mL. 
Any patient with abnormal test results, as defined above, will be considered to be exhibiting 
signs of HPA axis suppression. As the study treatment period will be over, any patients with 
abnormal results will be advised not to initiate any new steroid therapy, topical or otherwise, and 
to return to the site in 28 days at which time they will be assessed for HPA axis suppression. 
Any patient presenting with symptoms of HPA axis suppression, such as nausea, headache, 
myalgia, fatigue or loose stool, will be referred to an endocrinologist. As an additional safety 
precaution, wristbands identifying the patient as someone suffering from adrenal suppression 
secondary to steroid withdrawal will be provided to alert medical personnel should any 
emergencies arise before adrenal function returns to normal. 
If the results of the cortisol response test still show signs of HPA axis suppression 28 days after 
discontinuing therapy they will be asked to return in 28 days (56 days after discontinuing steroid 
therapy) for another follow-up test. If the patient is still showing signs of HPA axis suppression 
56 days after discontinuing steroid therapy and presents with related symptoms they will be 
referred to an endocrinologist. 
If HPA axis suppression persists for 56 days after discontinuing steroid therapy, but the patient 
has no symptoms they will be asked to return in 28 days (84 days after discontinuing steroid 
therapy) for another follow-up test. If HPA axis suppression persists for 84 days after 
discontinuing steroid therapy patients will be referred to an endocrinologist regardless of 
symptoms. 
Descriptive Summary 
The primary analysis will be proportion of evaluable patients across all age cohorts with HPA 
axis suppression, as observed from results of a cortisol response (ACTH stimulation) test at Day 
30 (Post Treatment). Evaluable subjects are those that have both a baseline and end-of-study 
Cortisol Response Test results and have not been identified as having enrolled in the study 
previously. Patients found to have abnormal adrenal function after the baseline Cortisol 
Response Test will not be included in the evaluable patients for analysis. 
6.2.2 Secondary Analyses 
•
Proportion of evaluable patients in each cohort with HPA axis suppression after the end
of treatment.
•
Pharmacokinetic parameters for desoximetasone at the end of treatment.
•
Change from baseline/descriptive statistical analyses for the Physician Global
Assessment (PGA) score at the end of treatment.
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc. 
•
Change from baseline/descriptive statistical analyses for clinical signs and symptoms
(erythema, scaling, plaque elevation) of psoriasis at the end of treatment.
6.2.2.1 HPA Axis Suppression Analysis by Cohort 
Similar to the primary analysis above, descriptive summary (frequency and proportion) of 
evaluable patients in each cohort with HPA axis suppression after the end of treatment will be 
presented. 
6.2.2.2 Pharmacokinetic Analysis – PK Sampling Group Only 
Concentrations of desoximetasone in plasma will be measured by the central laboratory using a 
fully validated analytical method. Pharmacokinetic and statistical analyses will be performed by 
Novum Pharmaceutical Research Services. The Statistical Analysis System (SAS®, Version 9.4 or 
higher) will be used for all pharmacokinetic and statistical calculations. 
For Cohort 1, steady-state pre-dose (trough) plasma desoximetasone concentrations (Cpre(Dx)) x = 
1, 8, 15, 22, 29) will be measured from morning pre-dose blood draws at Visits 2-6 (Days 1, 8, 
15, 22 and 29). At Visit 6 (Day 29), in addition to the pre-dose draw, patients will have blood 
collections following a dose applied in the clinic. The blood collection schedule will be as 
follows: 0 (pre-dose), 15 min, 30 min, 40 min, 50 min, 60 min, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 
12 hr (Cpost(D29),12hr) following the morning dose. Linear and semi-logarithmic graphs of each 
patient’s plasma concentration-time profile for desoximetasone will be constructed using the 
actual times of sample collections. 
For Cohort 2, steady-state pre-dose (trough) plasma desoximetasone concentrations (Cpre(Dx), x 
= 1, 8, 15, 22, 29) will be measured from morning pre-dose blood draws at Visits 2-6 (Days 1, 
8, 15, 22 and 29). At Visit 6 (Day 29), in addition to the pre-dose draw, patients will have 
blood collections following a dose applied in the clinic. The blood collection schedule will be 
as follows: 0 (pre-dose) 1 hr and 3 hr following the morning dose. Linear and semi-logarithmic 
graphs of each patient’s plasma concentration-time profile for desoximetasone will be 
constructed using the actual times of sample collections. 
If sufficient data are available and pending review of the individual pre-dose profiles, the 
approach to steady-state concentrations may be evaluated from the measurable morning pre-dose 
concentrations (Cpre(Dx)) on Days 8, 15, 22 and 29, using Helmert contrasts comparing Day 22 
and Day 29, Day 15 and the average of Days 22 and 29, and Day 8 and the average of Days 15, 
22 and 29. The individual pre-dose profiles will be first reviewed visually to determine if the 
steady-state analysis is warranted and can be reliably assessed. 
Graphical presentations of mean results will use the scheduled times of sample collections. A 
complete listing of the scheduled and actual times of sample collections for each patient and the 
concentration reported for each collected sample will be provided. 
No concentration estimates will be provided for missing sample values. Any sample with a 
missing value will be treated as if the sample had not been scheduled for collection. 
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc.  
For the derivation of PK parameters for Cohort 1 on Day 29, plasma concentrations recorded as 
below the lower limit of quantitation (LLOQ) of 25 pg/mL (i.e., BLQ) will be handled per 
Sections 5.2.1.1, 5.2.1.2 and 5.2.3.1 of Novum's SOP 6102C (Handling Below Lower Limit of 
Quantitation Data in Pharmacokinetic Studies) and assigned a value of zero (i.e., 0) if they occur 
at the beginning or end of the 12-hour concentration-time profile and assigned a missing value if 
they occur in the middle of the PK profile for each patient. All BLQ values for Cpre(Dx) in 
Cohorts 1 and 2 will be assigned a value of zero.  
Data from patients with missing concentration values (missed blood draws, lost samples, samples 
unable to be quantified) may be used if pharmacokinetic parameters can be estimated using 
remaining data points, otherwise data from these patients will be excluded from the final 
descriptive statistics. 
For Cohorts 1 and 2 on Day 29, the peak exposure at steady-state (Cmax-ss) will be the observed 
maximum plasma concentration and the steady-state time to peak exposure (Tmax-ss) will be the 
collection time at which Cmax-ss is first observed. 
Steady-state area under the plasma concentration-time curve over the 12-hour dosing interval 
from time of dosing (t = 0 hr) to the time of last sample at 12 hours post-dose (AUCss) will be 
calculated by the linear trapezoidal method for Cohort 1 on Day 29. An AUC profile must have 
at least three consecutive measurable concentrations (i.e., > LLOQ), including Cmax-ss, to be 
considered evaluable. No AUCss and Cmax-ss values will be reported for those PK profiles with 
fewer than three consecutive measurable concentrations. For those PK profiles with 0-
concentration values at the end of the profile, AUCss will include the triangle area portion from 
tz (time of last measurable concentration) to time of the first 0-concentration value at the end of 
the profile. If the 12-hour concentration is missing then AUCss will be calculated up to tz but this 
value will not be included in the descriptive statistics for AUCss. AUCss will not be calculated 
for Cohort 2. 
The apparent first-order terminal disposition rate constant (Kel) will be estimated, when possible, 
from the negative of the slope of the regression line for the terminal ln-linear concentration-time 
values for Cohort 1 on Day 29. The values to be included in the regression lines will be selected 
by examination of each patient's semi-logarithmic concentration-time plot. The first-order 
terminal disposition half-life (T½) will be estimated as ln(2)/Kel. 
Descriptive statistics for all PK parameters (n, mean, SD, % coefficient of variation (%CV), 
minimum, median, maximum, geometric mean, geometric %CV) and for each time point (n, 
mean, SD, % coefficient of variation (%CV), minimum, median, maximum) will be reported by 
cohort. All BLQ concentration values will be replaced with 0 for the purpose of descriptive 
statistics for each time point.  
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc. 
6.2.2.3 Physician Global Assessment (PGA) Score 
At all Visits a visual inspection to confirm a diagnosis of chronic plaque psoriasis will be done. 
PGA scores will be assessed at each visit on a 5-point scale (Appendix B): 0=clear, 1=almost 
clear, 2=mild, 3=moderate, 4=severe, 5=very severe. 
Frequency and percentage will be presented for PGA scores by cohort and study day. 
Descriptive summary (n, mean, standard deviation, minimum, median and maximum) will be 
presented for PGA scores by cohort and study day as well as change from baseline to end of 
treatment. Baseline is defined as the PGA score at Day 1 (Visit 1). 
PGA scores will be listed by cohort, patient and study day. 
6.2.2.4 Clinical Signs and Symptoms of Psoriasis 
At all Visits a visual inspection to confirm a diagnosis of chronic plaque psoriasis will be done.  
Clinical signs and symptoms (erythema, scaling, plaque elevation) will be assessed at each visit 
on a 5-point scale: 0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe, 5=very severe.  
Frequency and percentage will be presented for clinical signs and symptoms by cohort and study 
day.  
Descriptive summaries (n, mean, standard deviation, minimum, median and maximum) will be 
presented for clinical signs and symptoms by cohort and study day as well as change from 
baseline to end of treatment. Baseline is defined as the clinical signs and symptoms at Day 1 
(Visit 1). 
Clinical signs and symptoms will be listed by cohort, patient and study day. 
6.3 Safety Analysis 
Safety analysis will be conducted on all patients who applied at least one dose of study drug. 
6.3.1 Adverse Events 
All the adverse events (AEs) reported throughout the study will be coded and classified 
according to the MedDRA (Medical Dictionary for Regulatory Activities) coding dictionary 
(Version 16.0 or higher). Each adverse event is to be evaluated for date of start and end, 
seriousness, severity, causal relationship with the study drugs, action taken and outcome. 
All AEs will be listed by cohort and patient. 
A summary table of the number and percent of patients with AEs by system organ class, 
preferred term, and cohort will be presented. Each patient will be counted only once within each 
preferred term. 
dsxs-1303-statistical-methods


STATISTICAL ANALYSIS PLAN 
IND # 101789/ NDA # 204141
Protocol No. DSXS-1303
TOPICORT® (desoximetasone) Topical Spray, 0.25% Pediatric HPA Axis study 
02/06/2020 
 Taro Pharmaceuticals U.S.A., Inc. 
A frequency summary table of the number of AEs by system organ class, preferred term, 
severity, and cohort will be presented. Severity will be classified as “Mild”, “Moderate”, or 
“Severe”.  
Similarly, a frequency summary table of the number of AEs by system organ class, preferred 
term, and relationship to a study drug, and cohort will be presented. Relationship to a study drug 
will be classified as “Not Related” or “Related” where “Related includes “Possible”, “Probable”, 
or “Definite”. 
6.3.2 % BSA Assessment 
The Subject’s body weight (kg) and height (cm) will be measured while the Subject is lightly 
clothed (e.g., no coat or shoes) to calculate the subject’s BSA. %BSA will be assessed at every 
visit using instructions in Appendix A. To be eligible for inclusion, the patient must have an 
affected BSA of ≥10%. 
Descriptive summary (n, mean, standard deviation, median, minimum, maximum) will be 
presented for %BSA by cohort and study day.  
% BSA data will be listed by cohort, patient and study day. 
6.3.3 Concomitant Medications 
At Visit 1 subjects and parents/legal guardians will be questioned about current and concomitant 
medication use over the previous 12 weeks. At all Interim and End of Study Visits subjects and 
parents/legal guardians will be questioned about ongoing or new concomitant medication use. 
All prior and concomitant medications taken since screening until the end of the study will be 
listed by cohort and patient.  
6.4 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
6.5 Methods for Handling Missing Data 
For demographic and baseline characteristics, each variable will be analyzed using all available 
data. Patients with missing data will be excluded only from analyses for which data are not 
available. 
6.6 Interim Analyses 
Two planned interim analyses will be conducted to evaluate safety following the end of the 
treatment periods for Cohorts 1 and 2. Before Cohorts 2 and 3 are initiated, all data from Cohort 
1 will be analyzed and the protocol will be amended and submitted for IRB approval. 
dsxs-1303-statistical-methods