Conditions: Plaque Psoriasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
To evaluate the potential of DFD-01 (betamethasone dipropionate) Spray, 0.05% to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

Detailed description:
To evaluate the potential of DFD-01 (betamethasone dipropionate) Spray, 0.05% to suppress the hypothalamic-pituitary-adrenal (HPA) axis when applied twice daily for 15 days or when applied twice daily for 29 days, in adolescent subjects with moderate to severe plaque psoriasis under maximal use conditions.

Arms:
arm 1: DFD01 spray, twice daily, 15 days arm 2: DFD01 spray, twice daily, 29 days

Interventions: intervention 1: DFD01 Spray
Intervention descriptions: intervention 1: DFD-01 (betamethasone dipropionate) Spray, 0.05%

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Version 2 (Amendment 01) 
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CLINICAL STUDY PROTOCOL 
 
A Randomized, Parallel Group, Open-Label, Multicenter Study to Assess the Potential for 
Adrenal Suppression and Systemic Drug Absorption Following Multiple Dosing with DFD-01 
(betamethasone dipropionate) Spray, 0.05% in Adolescent Subjects with Moderate to Severe 
Plaque Psoriasis  
 
Protocol Number:  
DFD01-CD-013     
 
Version:  2 
 
 
Phase: 
3b      
 
 
 
Date:  13 March 2017 
 
Sponsor: 
Promius Pharma, LLC 
 
107 College Rd East 
 
Princeton, NJ   08540 
 
Sponsor Contact: 
Felicia Rackowski, RN, BSN 
 
Associate Director, Clinical Operations 
Promius Pharma, LLC 
 
Phone:  609-282-1425  
 
 
E-mail: frackowski@promiuspharma.com 
 
Medical Monitor: 
Srinivas Sidgiddi, MD 
 
Director – Clinical Development, Dermatology 
Promius Pharma, LLC 
Phone:  908-458-5362 
 
E-mail: srinivassidgiddi@drreddys.com 
 
CRO Contact: 
Debra Dow, Pharm D 
 
Vice President, Scientific Affairs 
 
Symbio, LLC 
 
21 Perry Street 
 
Port Jefferson, NY 11777 
 
Phone: 707-795-3599 
 
E-mail: ddow@symbioresearch.com 
 
Serious Adverse Events: Shahida Hasan, MD, MS 
 
Fax:   609 228-5408 
 
 
  
 
Email:  DFD01-CD-013@promiuspharma.com  
 
 
 
Previous Version/Date: Version 1/ June 1, 2015




 
 
 
 
 
 
 
 
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SYNOPSIS 
Title:    A Randomized, Parallel Group, Open Label, Multicenter Study to Assess the Potential 
for Adrenal Suppression and Systemic Drug Absorption Following Multiple Dosing with DFD-
01 (betamethasone dipropionate) Spray 0.05%  in Adolescent Subjects with Moderate to 
Severe Plaque Psoriasis 
 
Sponsor:   
Promius Pharma, LLC 
 
107 College Road East 
 
Princeton, NJ 08540 
Study Centers:     8 
Number of Subjects:  50 
 
Study Period: 
 15 or 29 Days 
Clinical Phase: Phase 3b 
 
Objectives: 
The objectives of this study are: 
• To evaluate the potential of DFD-01 (betamethasone dipropionate) Spray, 0.05% to 
suppress the hypothalamic-pituitary-adrenal (HPA) axis when applied twice daily for 15 
days or when applied twice daily for 29 days, in adolescent subjects with moderate to 
severe plaque psoriasis under maximal use conditions with the final-to-be-marketed 
formulation.  
• To assess the plasma concentrations of betamethasone dipropionate and its metabolites 
after multiple uses of DFD-01 (betamethasone dipropionate) Spray, 0.05%) under 
maximal use conditions with the final-to-be-marketed formulation.   
Methods:   
This is a 15 or 29-day, randomized, multicenter, multi-dose, open label study.  Subjects, who are 
at least 12 years old and not more than 16.9 years old with moderate to severe plaque psoriasis, 
will be randomized to treatment with either DFD-01 spray 15-day treatment or DFD-01 spray 
29-day treatment in a 1:1 ratio. These investigational products will be applied twice daily to all 
affected areas on the body excluding face, scalp, groin, axillae and other intertriginous areas. 
Subjects must have ≥ 10% body surface area (BSA) treated to achieve maximal use exposure.  
 
Subject visits will take place at Screening, Baseline (Day 1), Day 8, Day 15, Day 29 (as 
appropriate) and Day 43 or 57 (if needed to confirm recovery).  Clinical determinations of 
disease severity will be conducted using the Investigator Global Assessment (IGA) for overall 
severity at each visit. Subjects will be tested for HPA axis function using the ACTH stimulation 
test (a cosyntropin i.v. or i.m. injection) at the Screening Visit (at least 14 days and no more 
than 28 days prior to Baseline) and at the End of Treatment Visit (i.e., Day 15 for the 15-day 
treatment arm or Day 29 for the 29-day treatment arm).  If HPA axis is suppressed at the End of 
Treatment Visit, another test will be administered approximately 28 days later (at Day 43 or 57, 
as appropriate) to confirm recovery.  The ACTH stimulation test will be repeated approximately 
every 28 days until recovery is confirmed (or until the cause of suppression is diagnosed).  Pre-
stimulation and post-stimulation cortisol levels will be measured in serum and saliva.   


 
 
 
 
 
 
 
 
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At the time of the screening ACTH stimulation test, a PK blood sample will be taken to obtain a 
baseline value (PK screening sample). At the End of Treatment Visit, subjects will apply the last 
dose of study product at the clinic up to 60 minutes after a pre-treatment PK blood sample is 
taken (0 hour – End of Treatment Visit). PK blood samples will then be collected at 1, 3 and 6 
hours (± 5 minutes) after application of the study product.   
 
Local cutaneous safety evaluations (including atrophy, telangiectasia, pruritus, pain and 
burning/stinging) will be performed at Visits 2, 3, 4, and 5 (if appropriate). Other safety 
assessments include vital signs (blood pressure, pulse), urine pregnancy tests, and collection of 
adverse event data.   
 
Number of Subjects: 
A total of approximately 50 subjects will be randomized across approximately 8 sites in the 
United States. No more than 65 subjects will be randomized. 
 
Diagnosis and Criteria for Inclusion / Exclusion: 
Inclusion: 
1. Subject and legal guardian understand the study procedures and agree to participate by 
giving written assent and written informed consent, respectively. Legal guardian must be 
willing to authorize use and disclosure of protected health information collected for the 
study. 
2. Subjects must be at least 12 years of age and no more than 16.9 years of age at the time of 
randomization. 
3. Subjects must weigh at least 55 pounds at the Screening Visit. 
4. Subjects must present with a clinical diagnosis of stable (at least 3 months) plaque 
psoriasis. 
5. Subjects with psoriasis involving  ≥ 10% BSA, not including the face, scalp, groin, 
axillae and other intertriginous areas.   
6. Subjects must have an IGA grade of at least 3 (moderate) at the Baseline Visit. 
7. All females must complete a urine pregnancy test (test must have a sensitivity of at least 
25 mIU/mL for human chorionic gonadotropin) at the Baseline Visit (Visit 2), and the test 
result must be negative to be eligible for randomization.   
8. Female subjects who are sexually active must agree to use contraception during the 
study.  Reliable methods of contraception are: 
 
- 
hormonal methods or intrauterine device in use ≥ 90 days prior to study product 
administration; or 
 
-    barrier methods plus spermicide in use at least 14 days prior to study product 
administration. 
 
- 
partner has had a vasectomy at least 3 months previous to study product 
administration. 


 
 
 
 
 
 
 
 
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Note:  Sexually inactive female subjects should be counseled to remain sexually inactive for 
the duration of the study and should be made to understand the possible risks involved in 
getting pregnant during the study. An abstinent female subject must agree that if she 
becomes sexually active during the study she will use an acceptable form of contraception. 
9. Subjects must be in good general health as determined by the investigator and supported 
by the medical history and normal or not clinically significant abnormal vital signs 
(blood pressure and pulse). 
10. Subjects whose results from the screening ACTH stimulation test are considered normal 
(blood cortisol level >18 ug/dL at 30 minutes post stimulation) and show no other signs 
of abnormal HPA axis function or adrenal response.   
Exclusion: 
1. Current diagnosis of unstable forms of psoriasis including guttate, erythrodermic, 
exfoliative or pustular psoriasis. 
2. History of organ transplant requiring immunosuppression, HIV, or other 
immunocompromised state. 
3. Have received treatment for any type of cancer within 5 years of the Baseline Visit. 
4. Use within 60 days prior to the Baseline Visit of: 1) immunosuppressive drugs (e.g., 
tacrolimus, pimecrolimus), 2) systemic antipsoriatic treatment (e.g., methotrexate, 
cyclosporine, hydroxyurea), or 3) biologic treatment for psoriasis (e.g., infliximab, 
adalimumab, etanercept, ustekinumab, secukinumab, or alefacept). 
5. Use within 30 days prior to the Baseline Visit of: 1) topical antipsoriatic drugs (salicylic 
acid, anthralin, coal tar, calcipotriene), 2) PUVA therapy, 3) systemic anti-inflammatory 
agents (e.g., mycophenolate mofetil, sulfasalazine, 6-thioguanine), or 4) UVB therapy. 
6. Use within 30 days prior to the Screening Visit of any product containing corticosteroids. 
Inhaled, intraocular, intranasal, etc. steroids are not allowed. 
7. Use within 14 days prior to the Baseline Visit of topical retinoids. 
8. Subjects with known hypersensitivity to betamethasone dipropionate or any component of 
DFD-01.  
9. Subjects who have an abnormal sleep schedule or work overnight. 
10. Subjects who have participated in a study of an investigational product or device 60 days 
prior to the Baseline Visit. 
11. Subjects unable to comply with study requirements.  
12. Female subjects who are pregnant (or planning to become pregnant) or breast-feeding. 
13. Subjects with a known history of acute adrenal crisis, Addison’s disease or decreased 
adrenal output, low pituitary function or pituitary tumors. 
14. Subjects who have a history of an adverse reaction to cosyntropin injection or similar test 
reagents. 


 
 
 
 
 
 
 
 
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15. Subjects with any history of illegal drug or alcohol use.  
 
Investigational Product, Dose and Mode of Administration: 
DFD-01 (betamethasone dipropionate) Spray, 0.05% 
 
The investigational product will be applied topically to all affected areas (i.e., those areas that 
were affected at Baseline, even if resolved, and new lesions that develop at any time during the 
treatment period) twice daily, approximately 12 hours apart.  The target dose is at least 3 to 5 g 
per day (10 to 15 pumps, twice daily). Product is not to be applied to face, scalp, groin, axillae, 
or other intertriginous areas.  
 
 Duration of Treatment and Study: 
Subjects will treat affected areas for either 15 days or 29 days. Since the screening ACTH test 
must occur 14 to 28 days before the Baseline Visit, the total study duration is 29 to 43 or 43 to 
57 days plus any wash-out period.  Some subjects may need to return for a follow-up visit at 
Day 43 or 57. 
 
 
Criteria for Evaluation: 
Safety criteria: 
The proportion of subjects with abnormal serum cortisol response for ACTH stimulation test at 
the end of treatment (cortisol serum level ≤18 ug/dL at 30 minutes post stimulation) is the 
primary safety variable. 
 
Efficacy Criteria: 
IGA will be collected and summary statistics provided. 
 
 


 
 
 
 
 
 
 
 
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Study Schedule ( 29-day treatment arm) 
 
 
Visit 1 
Visit 2 
Visit 3 Visit 4 
Visit 5 
Visit 6 
Screena 
Day 1 
(Baseline) Day 8b Day 
15b 
Day 29b (End 
of Treatment) 
Day 57c 
Informed Consent 
X 
 
 
 
 
 
Collect Demographic Data 
X 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
X 
 
 
 
 
Med History / Prior & Con Meds 
X 
X 
 
 
 
 
Vital Signs (BP, Pulse) 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
Xd 
X 
X 
X 
Xd 
Xd 
Determine BSA  
X 
X 
 
 
X 
 
IGA 
X 
X 
X 
X 
X 
 
ACTH stimulation testg (blood and 
saliva samples) 
Xe 
 
 
 
Xh 
Xi 
Local Cutaneous Safety Evaluation  
 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
Weigh and Dispense Medication (as 
needed) 
 
X 
X 
X 
 
 
Supervised treatment 
 
X 
 
 
Xk 
 
Take Blood Samples for PKj 
X 
 
 
 
X 
 
Dispense/Review/Collect Study Diary 
 
X 
X 
X 
X 
 
Diagram affected areas to be treated 
 
X 
X 
X 
 
 
Review Subject Instructions 
 
X 
X 
X 
X 
 
Collect and Weigh Used Containers 
 
 
X 
X 
X 
 
Evaluate Compliance 
 
 
X 
X 
X 
 
Review Concomitant Medications 
 
 X 
X 
X 
X 
X 
Adverse Event Assessment 
 
Xf 
X 
X 
X 
X 
End of Study  
 
 
 
 
X 
X 
      a No more than 60 days before Visit 2 
h ACTH stimulation test should be performed within 1 hour of time 
      b Allowed visit window ± 3 day 
  of when Screening test was performed 
      c If needed due to abnormal ACTH test result at 
i ACTH stimulation test will be repeated until recovery (or is 
      End of Treatment Visit 
  explained) 
      d Pregnancy test just prior to ACTH stimulation test  
j Blood will be drawn at the time of the screening pre-stimulation 
      e At least 14 days, and no more than 28 days, prior to  
  ACTH test and at 0, 1, 3, 6 hours (+/-5 minutes) after application at 
      Day 1  
  End of Treatment Visit 
      f Related to study procedures only 
k Weigh bottle before and after application 
      g ACTH stimulation test to be performed between 7:00 
         and 9:30AM 
 
 
 
 
 


 
 
 
 
 
 
 
 
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Study Schedule (15-day treatment arm) 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screena 
Day 1 
(Baseline) Day 8b 
Day 15b 
(End of 
Treatment) 
Day 43c 
Informed Consent 
X 
 
 
 
 
Collect Demographic Data 
X 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
X 
 
 
 
Med History / Prior & Con  Meds 
X 
X 
 
 
 
Vital Signs (BP, Pulse) 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
Xd 
X 
X 
Xd 
Xd 
Determine BSA  
X 
X 
 
X 
 
IGA 
X 
X 
X 
X 
 
ACTH stimulation testg (blood and saliva 
samples) 
Xe 
 
 
Xh 
Xi 
Local Safety Evaluation  
 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
Weigh and Dispense Medication (as needed) 
 
X 
X 
 
 
Supervised treatment 
 
X 
 
Xk 
 
Take Blood Samples for PKj 
X 
 
 
X 
 
Dispense/Review/Collect Study Diary 
 
X 
X 
X 
 
Diagram affected areas to be treated 
 
X 
X 
 
 
Review Subject Instructions 
 
X 
X 
X 
 
Collect and Weigh Used Containers 
 
 
X 
X 
 
Evaluate Compliance 
 
 
X 
X 
 
Review Concomitant Medications 
 
 X 
X 
X 
X 
Adverse Event Assessment 
 
Xf 
X 
X 
X 
End of Study  
 
 
 
X 
X 
      a No more than 60 days before Visit 2 
h ACTH stimulation test should be performed within 1 hour of time 
      b Allowed visit window ± 3 day 
  of when Screening test was performed 
      c If needed due to abnormal ACTH test result at 
i ACTH stimulation test will be repeated until recovery (or is 
      End of Treatment Visit 
 explained) 
      d Pregnancy test just prior to ACTH stimulation test  
j Blood will be drawn at the time of the screening pre-stimulation 
      e At least 14 days, and no more than 28 days, prior to  
 ACTH test and at 0, 1, 3, 6 hours (+/-5 minutes) after application at 
      Day 1 
  End of Treatment Visit 
      f Related to study procedures only 
k Weigh bottle before and after application 
      g ACTH stimulation test to be performed between 7:00 
        and 9:30AM 
 
 
 
 


 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
COMPLIANCE STATEMENT ..................................................................................................... 2 
SIGNATURES ............................................................................................................................... 2 
SYNOPSIS ..................................................................................................................................... 3 
List of Abbreviations ................................................................................................................... 11 
List of Definitions ........................................................................................................................ 12 
1 
INTRODUCTION ............................................................................................................... 13 
2 
ETHICAL CONSIDERATIONS ......................................................................................... 14 
2.1 
Institutional Review Board Review .............................................................................. 14 
2.2 
Ethical Conduct of Study .............................................................................................. 14 
2.3 
Informed Consent .......................................................................................................... 14 
2.4 
Selection of Investigators .............................................................................................. 15 
3 
STUDY OBJECTIVES ........................................................................................................ 15 
4 
STUDY DESIGN................................................................................................................. 15 
5 
SELECTION OF STUDY POPULATION ......................................................................... 16 
5.1 
Number of Subjects ....................................................................................................... 16 
5.2 
Inclusion Criteria ........................................................................................................... 16 
5.3 
Exclusion Criteria .......................................................................................................... 17 
6 
SUBJECT TREATMENT ................................................................................................... 19 
6.1 
Investigational Products ................................................................................................ 19 
6.1.1 
Description ............................................................................................................. 19 
6.1.2 
Labels and Packing ................................................................................................ 19 
6.1.3 
Accountability ........................................................................................................ 20 
6.1.4 
Dispensing and Return ........................................................................................... 20 
6.1.5 
Storage ................................................................................................................... 21 
6.2 
Treatment Regimen ....................................................................................................... 21 
6.3 
Treatment and Protocol Compliance ............................................................................. 21 
6.4 
Method of Assigning Subjects to Treatment Groups .................................................... 22 
6.5 
Blinding ......................................................................................................................... 22 
6.5.1 
Method of Blinding ................................................................................................ 22 
6.5.2 
Unblinding ............................................................................................................. 22 
6.6 
Prior and Concomitant Therapy .................................................................................... 22 
7 
STUDY PROCEDURES AND EVALUATIONS .............................................................. 24 
7.1 
Informed Consent Process ............................................................................................. 24 
7.2 
Screening ....................................................................................................................... 24 
7.3 
Demographic and Baseline Characteristics ................................................................... 24 
7.4 
Efficacy Assessments .................................................................................................... 24 
7.4.1 
Investigator’s Global Assessment (IGA) ............................................................... 24 
7.4.2 
BSA ........................................................................................................................ 25 
7.5 
Safety Assessments ....................................................................................................... 25 
7.5.1 
ACTH Stimulation Test ......................................................................................... 25 
7.5.2 
Other Safety Assessments ...................................................................................... 26 
7.5.3 
Drug Concentration Measurements/PK Blood Sampling ...................................... 27 
7.6 
Early Withdrawal of Subjects ....................................................................................... 27 
7.7 
Modification of Protocol ............................................................................................... 28 
7.8 
Early Termination of Study ........................................................................................... 28 


 
 
 
 
 
 
 
 
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7.9 
Study Schedule .............................................................................................................. 28 
7.9.1 
Visit 1 - Screening Visit (60 days or less from Baseline Visit 2) .......................... 29 
7.9.2 
Visit 2 - Day 1 - Baseline Visit .............................................................................. 29 
7.9.3 
Visit 3 - Day 8 ± 3 days ......................................................................................... 30 
7.9.4 
Visit 4 - Day 15 ± 3 days (29-day treatment group only; not applicable for 15-day 
treatment group) ................................................................................................................... 31 
7.9.5 
Visit 4 (Day 15 ± 3 days) for 15-day treatment group or Visit 5 (Day 29 ± 3 days)  
for 29-day treatment group (End of Treatment Visit 7:00 am to 9:30 am).......................... 32 
7.9.6 
Visit 5 (Day 43) or 6 (57)  (if required) ................................................................. 32 
8 
ADVERSE EVENTS ........................................................................................................... 33 
8.1 
Adverse Event Reporting Period ................................................................................... 34 
8.2 
Recording Adverse Events ............................................................................................ 34 
8.3 
Assessment of Adverse Events ..................................................................................... 35 
8.3.1 
Severity .................................................................................................................. 35 
8.3.2 
Relationship to Study Product (Causality) ............................................................. 35 
8.3.3 
Seriousness ............................................................................................................. 35 
8.4 
Reporting Serious Adverse Events ................................................................................ 36 
8.5 
Discontinuation Due to an Adverse Event .................................................................... 36 
8.6 
Exposure in utero (Pregnancy) ...................................................................................... 36 
9 
DATA HANDLING AND RECORD KEEPING ............................................................... 37 
9.1 
Confidentiality ............................................................................................................... 37 
9.2 
Source Documents......................................................................................................... 37 
9.3 
Screening/Enrollment Log ............................................................................................ 37 
9.4 
Case Report Forms ........................................................................................................ 37 
9.5 
Data Capture .................................................................................................................. 38 
9.6 
Archiving of Study Documentation .............................................................................. 38 
10 MONITORING AND DATA QUALITY ASSURANCE .................................................. 38 
11 STATISTICAL CONSIDERATIONS................................................................................. 39 
11.1 
Sample Size ............................................................................................................... 39 
11.2 
Analysis Data Set....................................................................................................... 39 
11.3 
Demographic and Baseline Data ............................................................................... 39 
11.4 
Efficacy Summary ..................................................................................................... 39 
11.5 
Safety Summaries ...................................................................................................... 39 
11.5.1 Extent of Exposure ................................................................................................. 40 
11.5.2 Local Safety Evaluation ......................................................................................... 40 
11.5.3 ACTH Stimulation Test ......................................................................................... 40 
11.5.4 Pharmacokinetics ................................................................................................... 40 
11.5.5 Adverse Events ...................................................................................................... 40 
11.5.6 Vital signs .............................................................................................................. 41 
11.5.7 Safety Laboratory Values ...................................................................................... 41 
11.5.8 Subset Analyses ..................................................................................................... 41 
12 REFERENCES .................................................................................................................... 42 
 
APPENDIX 1:   Declaration of Helsinki (2013) ......................................................................... 43 
APPENDIX 2:   Subject Instructions ........................................................................................... 48 
 
 


 
 
 
 
 
 
 
 
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List of Abbreviations  
 
Abbreviations 
Description 
ACTH 
Adrenocorticotropic hormone 
AE 
adverse event 
BP 
blood pressure 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CRO 
contract research organization 
FDA 
Food and Drug Administration 
GCP 
 
ICH 
Good Clinical Practice 
 
International Conference on Harmonization 
 
IGA 
Investigator’s Global Assessment 
i.m. 
intramuscular 
IRB 
institutional review board 
i.v. 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
PHI 
 
PK 
 
protected health information 
 
pharmacokinetics 
SAE 
serious adverse event 
UPT 
urine pregnancy test 
 
 
 
 
 


 
 
 
 
 
 
 
 
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List of Definitions 
 
 
Term 
Definition 
 
 
Screening Visit  
(Visit 1) 
 
 
 
 
 
The day a subject is screened according to the protocol 
inclusion/exclusion criteria, legal guardian having provided 
informed consent, and tentatively qualifies for randomization 
pending all screening activities or protocol required wash-out 
period.  
 
Screened Subject 
A subject who’s legal guardian has signed informed consent and 
has completed part or all of the Screening Visit.  
 
Baseline Visit  
(Visit 2/Day 1) 
The day of randomization and the first study product 
application. The first study product application is done at the 
site by the subject during the visit. 
 
 
Subject Number 
 
 
 
 
 
 
Randomized Subject 
 
 
A unique number assigned to a screened subject once informed 
consent is obtained.  The number consists of the 3-digit unique 
site number followed by a 3-digit sequential number for each 
subject in chronological order (e.g., 406001, 406002, where the 
site number is 406 and the first and second screened subjects at 
site 406 are 001 and 002, respectively).  
 
A subject is considered to be randomized once they have been 
assigned a study product per the randomization schedule. 
 
Randomization 
Number 
The number from the randomization schedule associated with the 
study product that is assigned to the subject at the time of study 
product dispensing. 
Study product(s) 
Investigational product(s) 
 
 
 


 
 
 
 
 
 
 
 
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1 INTRODUCTION 
Promius Pharma, LLC has developed a new spray formulation of betamethasone dipropionate, 
DFD-01 - Betamethasone Dipropionate Spray, 0.05% (potency expressed as betamethasone), for 
the topical treatment of psoriasis. Betamethasone dipropionate is a synthetic, fluorinated 
corticosteroid. 
 
Psoriasis is a multisystem disease with predominantly skin and joint manifestations. The major 
manifestation of psoriasis is inflammation of the skin characterized by disfiguring, scaling, and 
erythematous plaques that may be painful or pruritic.  Psoriasis is a chronic disease that waxes 
and wanes during a patient’s lifetime, is often modified by treatment initiation and cessation and 
has few spontaneous remissions (Menter, 2008).  
 
Psoriasis affects 7.5 million or 2.2% of the USA population at an estimated cost of 11.25 billion 
dollars annually (National Psoriasis Foundation). The most common form of psoriasis is chronic 
plaque disease. This presents as well-defined red scaly plaques typically distributed over the 
scalp, lower back, and extensor aspects of the limbs. Clinical variants include guttate psoriasis, 
sebopsoriasis, and pustular forms of psoriasis. A minority of patients with psoriasis (7%) also 
develop a seronegative inflammatory arthritis. Microscopically, lesional skin shows increased 
proliferation and abnormal differentiation of keratinocytes, infiltration by activated T-helper 
lymphocytes and neutrophils, and activation of the cutaneous vasculature (Mendonca, 2003). 
 
Approximately 80% of patients affected with psoriasis have mild to moderate disease. The 
majority of these patients can be treated with topical agents, which generally provide both good 
efficacy and safety. Topical agents are also used adjunctively for resistant lesions in patients 
with more extensive psoriasis who are being concurrently treated with either ultraviolet light or 
systemic medications. Treatment should be tailored to meet individual patient’s needs. These 
needs vary depending on body location, characteristics of the psoriasis being treated including 
lesion thickness, degree of erythema, and amount of scaling, as well as patient preference.  The 
choice of vehicle can alter the use and penetration of the medication (Menter, 2009).  
There are many approved topical products containing betamethasone dipropionate on the market 
in the USA indicated for the treatment of corticosteroid responsive dermatoses such as psoriasis 
and atopic dermatitis.  The first product was approved in 1975.  Adverse events associated with 
the use of topical betamethasone dipropionate include erythema, folliculitis, pruritus, and 
vesiculation each occurring in less than 1% of patients. 
In addition, the following additional local adverse reactions have been reported with topical 
corticosteroids, and they may occur more frequently with the use of occlusive dressings and 
higher potency corticosteroids.  These reactions are listed in an approximately decreasing order 
of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform 
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary 
infection, skin atrophy, striae, and miliaria. 
DFD-01 contains 0.05% betamethasone dipropionate (potency expressed as betamethasone) in a 
convenient, cosmetically elegant spray formulation.  The inactive ingredients are commonly 


 
 
 
 
 
 
 
 
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used excipients for topical products.  More information about DFD-01 can be found in the 
Investigator’s Brochure.   
 
The current clinical study is intended to evaluate the potential for HPA axis suppression of this 
new formulation of betamethasone dipropionate in adolescent subjects with moderate to severe 
psoriasis. Exogenous corticosteroids can suppress the HPA axis, resulting in decreased 
circulating adrenocorticotropic hormone (ACTH) levels, atrophy of glucocorticoid-secreting 
cells in the adrenal cortex, and secondary adrenal insufficiency.  HPA axis suppression will be 
determined from the results of an ACTH stimulation test.   
 
The ACTH stimulation test measures how well the adrenal glands respond to the hormone 
ACTH. ACTH is a hormone produced in the pituitary gland that stimulates the adrenal glands to 
release cortisol. A normal response is a serum cortisol level of more than 18 ug/dL 30 minutes 
after the ACTH is injected.  Cortisol can also be reliably measured in saliva (Gallagher, 2006) 
but the criteria for a normal response to ACTH has not been established.  Both serum and saliva 
cortisol will be measured in this study to provide data about the saliva level criterion for a 
normal response.  
 
The potential for HPA axis suppression of DFD-01 has been studied in adults with moderate to 
severe psoriasis (Study BDS1307).  After 15 and 29 days of treatment, 20.8% (5 out of 24) and 
0% (0 out of 24) of subjects had abnormal cortisol levels in the ACTH stimulation test, 
respectively. This study is to determine the potential for HPA axis suppression and extent of 
systemic drug exposure in the adolescent population with moderate to severe psoriasis.   
 
2 ETHICAL CONSIDERATIONS 
2.1 
Institutional Review Board Review 
The protocol, protocol amendments, subject recruiting materials, the informed consent form and 
any other materials provided to subjects must be approved by an Institutional Review Board 
operating in compliance with 21 CFR Part 56.  A copy of the approval letter must be received 
by the sponsor or CRO prior to shipment of drug supplies to the site. 
 
Records of the Institutional Review Board’s review and approval of all documents pertaining to 
the study must be kept on file by the investigator and are subject to sponsor and FDA inspection 
at any time.   
 
2.2 
Ethical Conduct of Study 
The investigator will ensure that this study is conducted in full conformity with the principles 
set forth in 21 CFR Part 50 – Protection of Human Subjects and in the Declaration of Helsinki 
(2013) (See Appendix 1). 
 
2.3 
Informed Consent 
Written informed consent of subject’s legal guardian must be obtained before a subject can 
participate in the study, prior to performing any study related procedures, and before withdrawal 


 
 
 
 
 
 
 
 
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of any therapies prohibited during the study.  Subjects must provide written assent. Informed 
consent and assent is a process that is initiated prior to the subject’s and legal guardian’s 
agreement to participate in the study and continues throughout the subject’s study participation. 
The process involves an extensive discussion with the subject and legal guardian about the study 
procedures and the risks and possible benefits of participation in the study.  
 
2.4 
Selection of Investigators 
Investigators for the study should be board certified dermatologists licensed in the state where 
the study is being conducted, with knowledge and understanding of Good Clinical Practice 
(GCP) and experience in treating psoriasis. In some cases, qualified physicians who are not 
board certified dermatologists may participate based on training and experience in the treatment 
of psoriasis.  Sub-investigators may be licensed physicians, physician assistants, or nurse 
practitioners with experience in psoriasis or dermatology and a good understanding of GCP.  
Investigators may delegate study tasks to other site personnel as long as they are qualified to 
perform the task and the delegation is documented. 
 
3 
STUDY OBJECTIVES 
The objectives of this study are  
• To evaluate the potential of DFD-01(betamethasone dipropionate) spray, 0.05% to 
suppress the hypothalamic-pituitary-adrenal (HPA) axis when applied twice daily for 15 
days or when applied twice daily for 29 days in adolescent subjects with moderate to 
severe plaque psoriasis under maximal use conditions.  
• To assess the plasma concentrations of betamethasone dipropionate and its metabolites 
after multiple uses of DFD-01 (betamethasone dipropionate) spray, 0.05% to DFD-01 
under maximal use conditions in adolescent subjects with moderate to severe plaque 
psoriasis.   
 
4 
STUDY DESIGN 
This is a 15 or 29-day, randomized, multicenter (approximately 8 sites), multi-dose, open label 
study. Approximately 50 adolescent subjects with moderate to severe plaque psoriasis will be 
randomized to treatment either with DFD-01 (betamethasone dipropionate) spray, 0.05% 
applied for 15 days or DFD-01(betamethasone dipropionate) spray, 0.05% applied for 29 days, 
in a 1:1 ratio.  The investigational product will be applied twice daily to all affected areas on the 
body excluding face, scalp, groin, axillae and other intertriginous areas.  Subject visits are 
scheduled at Screening, Baseline (Day 1) and Days 8, 15, 29 (as appropriate) and Day 43 or 57 
(if needed).  Clinical determinations of disease severity will be conducted using the Investigator 
Global Assessment (IGA) for overall severity at each visit.   
 
Subjects will be tested for HPA axis function using the ACTH stimulation test at least 14 days 
and no more than 28 days, prior to the Baseline Visit and at the End of Treatment Visit.  The 
screening ACTH stimulation test can be conducted on the day of the Screening Visit (if timing 
is appropriate) or on a separate day (e.g., when washout is needed).  If HPA axis is suppressed 
at the End of Treatment Visit, another test will be administered at Day 43 or 57 (as appropriate) 


 
 
 
 
 
 
 
 
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to confirm recovery.  The ACTH stimulation test will be repeated until the HPA axis is 
stabilized (or explained). Pre-stimulation and post-stimulation cortisol levels will be measured 
in serum and saliva.   
 
At the time of the screening ACTH stimulation test, a blood sample for pharmacokinetics (PK) 
will be taken to obtain a baseline value (PK screening sample).  At the End of Treatment Visit, 
subjects will apply the last dose of study product at the clinic up to 60 minutes after a pre-
treatment PK blood sample is taken (0 hour – End of Treatment Visit). PK blood samples will 
then be collected at 1, 3 and 6 hours (± 5 minutes) after application of the study product.   
 
Total blood sample volume taken at the Screening Visit will be approximately 16 mL and at the 
End of Treatment Visit approximately 34 mL.  These blood volumes are safe for subjects who 
weigh at least 55 pounds and would not exceed approximately 2.5% of total blood volume. 
 
Local cutaneous safety evaluations (including atrophy, telangiectasia, pruritus, pain and 
burning/stinging) will be performed at Visits 2, 3, 4 and 5 (if appropriate).  Other safety 
assessments include vital signs (blood pressure, pulse), urine pregnancy tests, and collection of 
adverse event data. 
 
5 
SELECTION OF STUDY POPULATION 
5.1 Number of Subjects 
Approximately 50 subjects will be randomized.  No more than 65 subjects will be randomized.  
There will be approximately 8 sites with each site randomizing 5 to 15 subjects.   
 
5.2 
Inclusion Criteria 
1. Subject and legal guardian understand the study procedures and agree to participate by 
giving assent and written informed consent, respectively. Legal guardian must be willing 
to authorize use and disclosure of protected health information collected for the study. 
2. Subjects must be at least 12 years of age and no more than 16.9 years of age at the time 
of randomization. 
3. Subjects must weigh at least 55 pounds at the Screening Visit. 
4. Subjects must present with a clinical diagnosis of stable (at least 3 months) plaque-
type psoriasis. 
5. Subjects with psoriasis involving  ≥ 10% BSA affected, not including the face, scalp, 
groin, axillae and other intertriginous areas.   
6. Subjects must have an IGA grade of at least 3 (moderate) at the Baseline Visit. 
7. All females must complete a urine pregnancy test (test must have a sensitivity of at 
least 25 mIU/mL for human chorionic gonadotropin) at the Baseline Visit (Visit 2), and 
the test result must be negative to be eligible for randomization. 
8. Female subjects who are sexually active must agree to use contraception during the 
study. Reliable methods of contraception are: 


 
 
 
 
 
 
 
 
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- 
hormonal methods or intrauterine device in use > 90 days prior to study product 
administration; or 
 
-    barrier methods plus spermicide in use at least 14 days prior to study product 
administration. 
 
- 
partner has had a vasectomy at least 3 months previous to study product 
administration. 
 
Note:  Sexually inactive female subjects should be counseled to remain sexually inactive for 
the duration of the study and should be made to understand the possible risks involved in 
getting pregnant during the study. An abstinent female subject must agree that if she 
becomes sexually active during the study she will use an acceptable form of contraception. 
9. Subjects must be in good general health as determined by the investigator and 
supported by the medical history and normal or not clinically significant abnormal 
vital signs (blood pressure and pulse). 
10. Subjects whose results from the screening ACTH stimulation test are considered 
normal (blood cortisol level >18 ug/dL at 30 minutes post stimulation) and show no 
other signs of abnormal HPA axis function or adrenal response. 
5.3 
Exclusion Criteria 
1. Current diagnosis of unstable forms of psoriasis including guttate, erythrodermic, 
exfoliative or pustular psoriasis.   
2. History of organ transplant requiring immunosuppression, HIV, or other 
immunocompromised state. 
3. Have received treatment for any type of cancer within 5 years of the Baseline Visit. 
4. Use within 60 days prior to the Baseline Visit of: 1) immunosuppressive drugs (e.g., 
tacrolimus, pimecrolimus), 2) systemic antipsoriatic treatment (e.g., methotrexate, 
cyclosporine, hydroxyurea), or 3) biologic treatment for psoriasis (e.g., infliximab, 
adalimumab, etanercept, ustekinumab, secukinumab, or alefacept). 
5. Use within 30 days prior to the Baseline Visit of: 1) topical antipsoriatic drugs (salicylic 
acid, anthralin, coal tar, calcipotriene), 2) PUVA therapy, 3)  systemic anti-inflammatory 
agents (e.g., mycophenolate mofetil, sulfasalazine, 6-thioguanine), or 4) UVB therapy.   
6. Use within 30 days prior to the Screening Visit of any product containing 
corticosteroids.  Inhaled, intraocular, intranasal, etc. steroids are not allowed. 
7. Use within 14 days prior to the Baseline Visit of topical retinoids. 
8. Subjects with known hypersensitivity to betamethasone dipropionate or any component 
of DFD-01. 
9. Subjects who have an abnormal sleep schedule or work overnight. 
10. Subjects who have participated in a study of an investigational product or device 60 days 
prior to the Baseline Visit. 
11. Subjects unable to comply with study requirements.  


 
 
 
 
 
 
 
 
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12. Female subjects who are pregnant (or planning to become pregnant) or breast-feeding. 
13. Subjects with a known history of acute adrenal crisis, Addison’s disease or decreased 
adrenal output, low pituitary function or pituitary tumors.  
14. Subjects who have a history of an adverse reaction to cosyntropin injection or similar 
test reagents.  
15. Subjects with any history of illegal drug or alcohol use.  
Subjects must not use the medications shown in Table 1 for the period specified before the 
Baseline Visit (Visit 2).   
Table 1: Wash-out Table 
Product 
Prior to ACTH 
stimulation test 
Prior to Baseline 
Visit 2 
Other investigational product or device 
Immunosuppressive drugs (tacrolimus or 
pimecrolimus) 
Systemic antipsoriatic agents (methotrexate, 
cyclosporine, hydroxyurea) 
Biologic treatment for psoriasis (infliximab, 
adalimumab, etanercept, ustekinumab, 
secukinumab, or alefacept). 
 
60 days 
Systemic anti-inflammatory agents 
(mycophenolate mofetil, sulfasalazine, 6-
thioguanine) 
PUVA therapy 
UVB therapy 
Topical antipsoriatic drugs (salicylic acid, 
anthralin, coal tar, calcipotriene) 
 
30 days 
Any product containing corticosteroids 
30 days 
 
Topical retinoids 
 
14 days 
 
 
 


 
 
 
 
 
 
 
 
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6 SUBJECT TREATMENT 
6.1 
Investigational Products 
6.1.1 Description 
The investigational product is: 
 
• DFD-01 (betamethasone dipropionate) spray, 0.05% 
 
      (120 mL spray bottle, Promius Pharma, LLC) 
 
 
DFD-01 Spray will be provided by Promius Pharma, LLC, Princeton, NJ 08540.    The spray 
formulation is a thin, white emulsion.     
 
Initially, 6 bottles (DFD-01 Spray 0.05%) will be sent to each site.  Additional bottles will be 
sent as needed.  The spray product should be shaken before use. 
 
6.1.2 Labels and Packing 
Bottles will be packed one to a box. Labels on the bottles will be in English and Spanish and 
include product name, protocol number, a unique bottle number, investigational use warning, 
storage conditions, brief instructions for use, and sponsor name and address.  Subjects will be 
asked to return bottles in the box. 
 
Bottle Label for DFD-01 Spray - Provided in English and Spanish Text  
DFD-01 
Protocol: DFD01-CD-013        Bottle ID: FXXXX         
Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C 
(59°-86°F). For Topical Use Only. Shake well before use. Apply twice daily as instructed. 
Rub in gently and completely.  
Caution:  New Drug – Limited by Federal (or United States) Law to Investigational Use 
 
Promius Pharma, LLC   
Princeton, NJ 08540 
 
 
 


 
 
 
 
 
 
 
 
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Labels on the box will be in English and Spanish and include product name, protocol number, a 
unique bottle number, investigational use warning, and storage conditions, brief instructions for 
use, and sponsor name and address. In addition, there will be a place to write the subject number 
and subject initials. The box-label will also have a tear-off panel that includes the protocol 
number and unique bottle number.  The tear-off panel is to be affixed to the source document 
(drug dispensing record).  
 
Box Label for DFD-01 Spray - Provided in English and Spanish Text 
DFD-01 
Protocol: DFD01-CD-013        Bottle ID: FXXXX       
Subject No.:                 Subject Initials:  ________       
 
Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted 
to 15°-30°C (59°-86°F). For Topical Use Only. Shake well before use. Apply 
twice daily as instructed. Rub in gently and completely.  
 
Caution:  New Drug – Limited by Federal (or United States) Law to 
Investigational Use. 
 
Promius Pharma, LLC, Princeton, NJ 08540 
DFD-01 
Protocol: DFD01-CD-013 
Bottle ID: FXXXX 
Subject No.: _____ 
Subject Initials: ____ 
 
Tear off portion to be affixed to 
source document and filed with 
dispensing confirmation in 
Subject’s chart. 
 
 
 
6.1.3 Accountability 
Documentation of receipt, study product inventory, and return shipments of the study product 
must be maintained at each study site. Upon receipt of the study product supplies, an inventory 
must be performed. It is important that site personnel count and verify that the shipment 
contains all the items noted in the shipment record and that they are in good condition. At study 
completion, all containers of study product, used and unused, must be returned to the sponsor or 
designee.  
 
In addition, a study product accountability log showing dispensing to and return by subjects 
must be maintained at each study site. Any dispensed bottles that are not returned to the clinic 
must be documented on the log. 
 
6.1.4 Dispensing and Return  
One bottle of study product will be dispensed to subjects at the Baseline Visit (Visit 2) by study 
staff. The weight of the bottles should be recorded before dispensing. Additional bottles will be 
dispensed as needed. Partially filled bottles can be redispensed back to the subject. The  study 
product to be dispensed for each subject will be identified by referring to the site randomization 
schedule.  The tear-off panel is to be affixed to the source document. Subject initials and subject 
number must be written on the box label. Study staff will then dispense and instruct subject and 
legal guardian on study product use.   
 


 
 
 
 
 
 
 
 
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Dispensing and return of study product must be documented on the Investigational Product Site 
Dispensing and Return Log. 
 
Subjects must return the used bottles even if empty throughout the trial.  At the end of the trial, 
all used and unused bottles must be returned to the clinic for eventual destruction by the sponsor 
or designee. Any dispensed bottles that are not returned to the clinic must be documented on the 
log. 
 
6.1.5 Storage 
Study products must be kept in a secure room temperature-controlled/monitored space at 20°-
25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F).  
 
6.2 
Treatment Regimen 
Subjects will use study product under the supervision and with help, if needed, of their legal 
guardian, twice daily with approximately 12 hours between applications for either 15 or 29 days 
starting on Day 1 during the study visit. Subjects will apply study product to all affected areas 
except the face, scalp, groin, axillae and other intertriginous areas.  The target dose is at least 3 
to 5 g per day (10 to 15 pumps of spray) , twice daily, applied at approximately 2 mg/cm2 on 
10% BSA – 1500 cm2).  Subjects with greater than 10% BSA will apply more, as appropriate.  
All baseline affected areas and newly affected areas should be treated until the end of the study 
even if cleared. The investigator shall diagram the affected areas (in the source document), 
update the diagram at each visit, and remind the subjects and legal guardians where study 
product is to be applied at each visit using the diagram. Study product should be sprayed 
directly onto affected areas and rubbed in gently and completely. Study product should be 
applied after bathing, if applicable. 
 
The first and last dates of treatment should be recorded in the CRF with the number of 
applications made on those days. 
 
The first and last application of study product will be applied by the subjects or their legal 
guardian at the site under supervision.  At the last visit, the bottle should be weighed before and 
after the application to determine the amount of study product applied for the last dose. 
 
6.3 
Treatment and Protocol Compliance 
Subjects and legal guardians will be provided an instruction sheet specific for the study product,  
along with a diagram of affected areas to be treated. Study staff should review the instruction 
sheet and diagram with the subjects and their legal guardian to ensure protocol compliance. If 
new affected areas appear between visits, the subject may start treating the new area between 
visits.  Treatment areas are to be updated on the diagram at each visit. 
 
At each visit, the investigator or designee will interview subjects and their legal guardian 
concerning treatment compliance and ask if any doses have been missed.  The investigator will 
also ask about compliance with protocol requirements. Protocol deviations will be recorded in 
the subject’s chart and Protocol Deviation Form. A Protocol Deviation Form is not needed for 


 
 
 
 
 
 
 
 
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missed visits, missed applications, out-of-window visits and missing data. These items will be 
apparent from the missing data on the CRF and will be identified programmatically during data 
analysis for purposes of reporting. The sponsor should be consulted before discontinuing 
subjects due to protocol deviations unless safety is a concern. 
 
Subjects/legal guardian will be provided a diary card for documenting the dates of applications.  
The subjects and legal guardian will review the diary card with the investigator or designee at 
each visit. The number of applications and the number of missed applications will be recorded 
on the CRF.  By definition, there are no missed applications after the last date of treatment even 
if recorded on the diary. 
 
In addition, bottles of study product will be weighed before dispensing and before and after the 
last application. These weights should be entered into the CRF. 
 
6.4 
Method of Assigning Subjects to Treatment Groups 
Approximately 50 subjects will be assigned randomly to one of the two treatment groups in a 
1:1 ratio (25 for DFD-01 spray 29-day and 25 for DFD-01 spray 15-day). A subject 
randomization schedule will be created stratified by site.  The site randomization schedule will 
be provided to each site for reference during randomization and drug dispensing.  The next 
available randomization number and associated treatment duration will be assigned to subjects 
eligible for randomization at the time of study product dispensing in sequential order (e.g. the 
first subject to be dispensed study product for the first time on any particular day will be 
assigned the next available randomization number and study duration). No randomization 
number is to be skipped.  The date and time of randomization, the randomization number and 
the assigned study product should be entered on the CRF. The randomization schedule will be 
generated and maintained by a third party vendor.   
 
The investigator shall ensure that study products are only used by subjects under the 
investigator's personal supervision or under the supervision of a sub-investigator responsible to 
the investigator and in accordance with the protocol.  
 
6.5 
Blinding 
6.5.1 Method of Blinding 
This is an open label study. 
 
6.5.2 Unblinding 
This is an open label study; therefore, there is no unblinding involved. 
 
6.6 
Prior and Concomitant Therapy 
Chronic medications being used at the time of the Screening and Baseline Visit, with the 
exception of those specified as prohibited, may be continued at the discretion of the 
Investigator.  History of medications, therapies and procedures are collected from the prior 2 
month period for determination of eligibility.  


 
 
 
 
 
 
 
 
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New medications or the change in a dose of a current medication, required for another medical 
condition, which in the opinion of the investigator will have no material impact on the study, are 
permitted.  The addition of such a new medication during the study will be documented as a 
concomitant medication and the associated medical need must be recorded as an adverse event.   
 
All medications (topical, oral, prescription, over-the-counter, and herbal medications) and 
medical therapies or procedures that are used during the study for other diseases/conditions must 
be recorded on the CRF. Medications taken before the Baseline Visit need not be recorded on 
the CRF but should be reviewed to determine eligibility. 
 
The following medications are prohibited during the study: 
• inhaled, intraocular, intranasal steroids, etc 
• systemic steroids 
• systemic antipsoriatics (methotrexate, cyclosporine, hydroxyurea) 
• PUVA therapy 
• UVB therapy 
• topical antipsoriatic drugs (salicylic acid, anthralin, coal tar, calcipotriene) 
• topical corticosteroids 
• immunosuppressive drugs (tacrolimus, pimecrolimus) 
• topical retinoids (tazarotene, tretinoin) 
• systemic anti-inflammatory drugs (mycophenolate mofetil, sulfasalazine, 6-thioguanine) 
• biologics (infliximab, adalimumab, etanercept, ustekinumab, secukinumab or alefacept)   
• oral retinoids (acitretin, isotretinoin) 
 
The use of illegal drugs or prescription drugs that have not been prescribed for the subject are 
not permitted during the study. 
 
Topical products other than the assigned treatment including moisturizers, creams, ointments, 
lotions, and powders applied on or near the affected areas that are being treated with study 
product should not be used during the study from Baseline Visit to End of Treatment Visit. 
Moisturizers can be used on the face, scalp, groin, axillae and other intertriginous areas. If a 
subject has been regularly using an anti-psoriasis, medicated shampoo product (e.g., tar 
shampoo, salicylic acid shampoo, zinc pyrithione) on the scalp for 3 months prior to 
randomization, he/she may continue on the same.  Subjects with scalp psoriasis may not start the 
use or change the use of an anti-psoriasis, medicated shampoo product for the scalp during the 
study. 
 
Use of the following should not occur during the study: 
• tanning booths, sun lamps, or nonprescription UV light sources 
• phototherapy 
• sunbathing 
• occlusive dressings on treated areas 
 


 
 
 
 
 
 
 
 
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If HPA axis suppression test is abnormal at the End of Treatment Visit, subjects should be 
advised to avoid products containing corticosteroids until recovery is determined. 
 
7 
STUDY PROCEDURES AND EVALUATIONS 
7.1 
Informed Consent Process 
Informed consent must be obtained from the subject’s legal guardian before a subject can 
participate in the study, prior to performing any study related procedures and before withdrawal 
of any therapies prohibited during the study.  The investigator must discuss the study fully with 
the subject and the legal guardian. Subjects must demonstrate their willingness to participate in 
the study and comply with the study procedures by giving written assent. The consent form 
must be signed and dated by the subject’s legal guardian. A copy of the consent form and assent 
form must be given to the legal guardian and subject, and the date of the consent process and 
who conducted the consent process must be documented in the source documents. 
 
7.2 
Screening 
The Screening Visit should occur no more than 60 days before the Baseline Visit. 
 
The screening ACTH stimulation test must be conducted at least 14 days and no more than 28 
days prior to the Baseline Visit. Subjects should tentatively qualify for study enrollment before 
the ACTH stimulation test is conducted. The ACTH stimulation test can be conducted on the 
day of the Screening Visit (if timing is appropriate) or on a separate day (e.g., when washout is 
needed). 
 
The subject’s medical history should be recorded in the source documents and reviewed for 
study eligibility.  However, only the concurrent medical conditions need to be entered on the 
CRF. 
 
A screen failure is a subject who received information about the study, including signing an 
assent/consent form, and possibly performing some study related procedures but was not 
randomized. The subject number, date of visit, date of consent, reason for screen failure, and 
study status (screen failure) will be captured on the CRF for every screen failure subject.   
 
7.3 
Demographic and Baseline Characteristics 
Demographic variables include age (computed from date of birth and Baseline Visit date), race, 
ethnicity, weight and sex.  Baseline characteristics are the baseline values for ACTH stimulation 
test, IGA and BSA affected (body surface area affected excluding the face, scalp, groin, axillae 
and other intertriginous areas).  BSA should be determined using the area of the subject’s hand 
print (palm plus extended fingers) as an estimate of 1% BSA (Finlay, 2005).  
 
7.4 
Efficacy Assessments 
7.4.1 Investigator’s Global Assessment (IGA) 
Clinical determinations of disease severity using IGA will be performed at each visit from 
screening through the end of treatment. The IGA scoring is shown in Table 2 below.  IGA score 


 
 
 
 
 
 
 
 
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is a static assessment of disease severity and should be based on overall severity of signs at the 
visit. The inclusion criteria for this study require a Baseline IGA of at least 3 (moderate). 
 
Table 2: Investigator’s Global Assessment (IGA) of Disease Severity 
Score  Grade  
Definition  
0 
None 
No plaque elevation above normal skin level  
may have residual non-erythematous discoloration 
no psoriatic scale  
no erythema 
1 
Minimal 
or 
Almost 
clear 
No more than: 
very slight elevation above normal skin level 
faint light pink coloration 
occasional very fine scale partially covering some of the lesions  
2 
Mild 
No more than: 
slight but definite elevation of plaque above normal skin level  
light red coloration 
fine scale with some lesions partially covered  
3 
Moderate 
No more than: 
definite elevation with rounded or sloped edges to plaque 
definite red coloration 
somewhat coarse scale with most lesions partially covered  
4 
Severe/ 
Very 
Severe 
At least one: 
marked elevation with hard, sharp edges to plaque 
dark red coloration 
coarse, thick scale with virtually all lesions mostly covered and a rough 
surface 
7.4.2 BSA 
BSA affected should be determined at the Screening, Baseline and End of Treatment Visits. 
BSA should be determined using the area of the subject’s hand print (palm plus extended 
fingers) as an estimate of 1% BSA (Finlay, 2005).  
 
7.5 Safety Assessments  
7.5.1 ACTH Stimulation Test 
Subjects will be tested for HPA axis function using the ACTH stimulation test (cosyntropin i.v. 
or i.m. injection) at a Screening Visit and at the End of Treatment Visit.  If HPA axis is 
suppressed at the end of treatment, another test will be administered 28 days later (at 
approximately Day 43 or 57, as appropriate) to confirm recovery.  The ACTH stimulation test 
will be repeated approximately every 28 days until recovery is confirmed or until the cause of 
suppression is diagnosed. The test should be conducted between the hours of 7:00 and 9:30 AM.   
The Screening Visit test must be normal to be eligible for the study (cortisol level > 18 ug/dL at 
30 minutes post stimulation). The End of Treatment test should be performed within 1 hour of 
the time when the Screening Visit test was performed. 
 
For female subjects, a urine pregnancy test will be conducted just prior to the ACTH 
stimulation test.  The test must have a sensitivity of at least 25 mIU/mL for human chorionic 
gonadotropin. The test must be negative to be eligible for the study. 


 
 
 
 
 
 
 
 
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Procedure 
The entire test must be completed between approximately 7:00 am and 9:30 am, including pre- 
and post-stimulation blood and saliva samples. A pre-dose, control blood sample of 4 to 5 mL 
will be collected in a serum separator tube and a pre-dose, control saliva sample of 0.2 mL to 
0.5 mL will be collected with a Salivette® collection system. Then 0.25 mg of cosyntropin, 
reconstituted according to package insert instructions, will be injected intravenously or 
intramuscularly. The chosen route should be recorded on the CRF. The reconstituted drug 
product should be inspected visually for particulate matter and discoloration prior to injection. 
Reconstituted cosyntropin should not be retained. A second blood sample of 4 to 5 mL and a 
second saliva sample of 0.2 mL to 0.5 mL will be collected 30 minutes after injection of 
cosyntropin.  Both blood sampling and cosyntropin administration (if administered 
intravenously) should take place in the same arm, if possible.  
 
Sample Preparation and Shipment 
All blood samples for estimation of serum cortisol levels should be centrifuged, serum separated 
and stored frozen (-20° C) until shipped according to the laboratory manual. Saliva samples 
should be stored frozen (-20° C) until shipped according to the laboratory manual. 
 
Sample Analysis 
The determination of the serum and saliva cortisol levels will be estimated by a validated 
method.  A normal response is defined as a serum cortisol level of more than 18 ug/dL at 30 
minutes post-stimulation. An abnormal response at end of treatment should be recorded as an 
adverse event of HPA axis suppression. 
 
7.5.2 Other Safety Assessments 
Other safety assessments include vital signs, local cutaneous safety evaluation of the treated 
skin, and adverse events (AEs).  Vital signs (blood pressure, pulse) will be collected at each 
visit.  Adverse events will be collected by spontaneous reports from subjects and legal guardian, 
either verbal or recorded in the subject diary, by directed questioning of subjects and legal 
guardian, and by observation (see Section 8 for details about AEs).  
 
At Visits 2 (Baseline) through the End of Treatment Visit, the investigator will assess local 
cutaneous safety by examining treated areas for clinically significant atrophy and telangiectasia 
that will be recorded on the CRF as present or absent. The investigator will also ask the subject 
if any burning/stinging, pain, or itching has occurred in the treated areas since the last visit (for 
Visit 2 in the last 2 weeks). Baseline assessments are made prior to first application.  
Subsequent to the Baseline Visit, for each symptom reported by subjects and/or each clinically 
significant sign, the presence of the sign or symptom must be recorded as “Yes” even if severity 
is not worse than Baseline. An adverse event should be recorded if the severity is worse than 
Baseline. 
  
For female subjects, urine pregnancy tests will be conducted at Screening, Baseline, and every 
subsequent visit. These tests will be conducted just prior to the ACTH stimulation test, as 


 
 
 
 
 
 
 
 
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appropriate.  The test must have a sensitivity of at least 25 mIU/mL for human chorionic 
gonadotropin. 
 
Adverse events, whether believed by the investigator to be related or unrelated to treatment, will 
be recorded on the CRF.  
 
7.5.3 Drug Concentration Measurements/PK Blood Sampling 
Sampling Schedule 
A screening PK blood sample will be taken at the time of the screening ACTH stimulation test 
to obtain a baseline value. 
At the End of Treatment Visit, subjects will apply the last dose of study product at the clinic up 
to 60 minutes after a pre-treatment PK blood sample is taken (0 hour – End of Treatment Visit). 
PK blood samples will then be collected at 1, 3 and 6 hours (± 5 minutes) after application of 
the study product. 
Each blood draw will be accomplished by a fresh, clean venipuncture or collection from 
previously implanted catheter. Blood (approximately 6 ml per PK time point) will be collected 
in NaF/Na2EDTA blood collection tubes. Approximately a total of 30 mL of blood per subject 
will be drawn for drug assays during the study (6 mL at the Screening Visit and 24 mL at the 
End of Treatment Visit). 
 
Sample Processing 
Within approximately 1 hour of collection, plasma should be separated and processed.  Samples 
should be stored and shipped according to the laboratory manual.  
 
Analytical Procedure 
Plasma betamethasone, betamethasone-17-propionate, and betamethasone -17,21-dipropionate 
will be measured by a validated, LC/MS/MS analytical method with a limit of quantitation of at 
most 5 pg/mL. Each assay run should include standards and quality control samples.  The 
reference standard should be obtained from an official source.  Failed batches will be 
documented in a run summary. 
A validation report describing the method accuracy, precision, linearity, and robustness must be 
available for the analytical procedure. Stability of analytes must be shown for the storage period 
before assay and during the assay procedures.   
 
7.6 
Early Withdrawal of Subjects 
1. Subjects should be withdrawn from the study if they or their legal guardian no longer wish 
to participate, are being uncooperative, or if the investigator feels that it is in the best interest 
of the subject to withdraw.  
2. Subjects with protocol deviations or for whom it is discovered should have been excluded 
should not be withdrawn unless there is a safety concern.  The protocol deviation should be 
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3. Subjects who experience an AE resulting in or requiring discontinuation of study product 
use should be encouraged, in conjunction with their legal guardian, to be followed until the 
AE is resolved or stabilized.   
4. If a female subject becomes pregnant during the study, study product will be discontinued 
immediately and she will be followed through the pregnancy and delivery. Details of the 
pregnancy, delivery and health of the infant should be recorded on the Pregnancy 
Surveillance Form and the sponsor notified immediately. 
5. At the time of study discontinuation, the investigator will record the reason for early 
withdrawal, date of last study product application, date of last visit or contact, collect 
adverse event data, and, if possible, perform all End of Treatment Visit specific evaluations. 
Every attempt should be made to contact subjects who are lost-to-follow-up via their legal 
guardian for a final safety assessment. At least three attempts must be documented in the 
subject’s chart including the use of at least 1 certified letter.  Any contact, either direct or 
indirect, should be made with the purpose to document the final status of the subject with 
regard to safety.   
6. Subjects who withdraw early will not be replaced. 
 
7.7 
Modification of Protocol 
No amendments to this protocol can be made without consultation with and agreement of the 
sponsor, the FDA, and IRB. Amendments must be made in writing. Modifications needed for 
the safety of subjects will be made immediately with notifications made as soon as possible. 
 
7.8 
Early Termination of Study 
If it is determined by the sponsor or investigators that the study presents an unreasonable and 
significant risk to subjects, the study will be terminated as soon as possible, and in no event later 
than 5 working days following the determination that the study should be discontinued. The IRB 
and FDA must be notified as soon as possible about early termination of the study due to safety 
concerns. 
 
7.9 
Study Schedule 
Study Schedule charts can be found on pages 7 and 8. There are at least 4 or 5 study visits; 
Screening (Visit 1), Baseline (Visit 2, Day 1), Day 8 (Visit 3), Day 15 (Visit 4 – End of 
Treatment Visit for the 15-day treatment group), and Day 29 (Visit 5 – End of Treatment Visit 
for the 29-day treatment group). A supplemental Visit 5 or 6 (Day 43 or 57) may be required to 
repeat the ACTH stimulation test if it was abnormal at the End of Treatment Visit.   
 
This is a short trial and it is imperative that subjects and their legal guardians understand the 
importance of attending each visit as scheduled. This should be discussed with the subject and 
legal guardian before randomization at Visit 2.  Randomized subjects and legal guardians must 
be counseled to keep all scheduled appointments and to return to the site within the permitted 
visit windows for each treatment visit (± 3 days for Visits).  If a subject misses a visit, they and 
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Visit (Visit 2) date.  It is especially important for the subject to complete the End of Treatment 
evaluation. 
 
7.9.1 Visit 1 - Screening Visit (60 days or less from Baseline Visit 2) 
1. Obtain written informed consent from legal guardian and written assent from subject prior to 
completing any study procedures.  Document informed consent and assent in the subject’s 
study record.  
2. List subject on Screening/Enrollment Log. Assign subject number consisting of the 3 digit 
site number followed by sequential 3 digit numbers starting with 001 (e.g. 400001, 400002, 
400003, etc.).   
3. Collect demographic data – date of birth, sex, race, weight, and ethnicity. 
4. Review and record medical history and concomitant medications, therapies and procedures.  
Medical history should be collected for the prior 1 year period and concomitant medications, 
therapies and procedures collected from the prior 2 month period. (record on source only) 
5. Screen subject according to the study inclusion/exclusion criteria to determine tentative 
eligibility.  
6. Initiate any protocol required washout. 
7. Assess severity of psoriasis using IGA (record on source only). 
8. Assess BSA excluding face, scalp, axillae, groin and other intertriginous areas. (record on 
source only) 
9. Collect vital signs (blood pressure, pulse).  (record on source only) 
10. Conduct urine pregnancy test (UPT) for all female subjects (record on source only).  Test 
must be negative to proceed. 
11. If tentatively eligible and UPT is negative, conduct ACTH stimulation test (approximately 
10 mL of blood is required).  This test should be conducted at least 14 days and no more 
than 28 days prior to Visit 2 (Baseline). The entire test, including pre- and post-stimulation 
blood and saliva samples, should be completed between approximately 7:00 am and 9:30 
am. Schedule for another day if needed. Also a screening PK blood sample will be drawn to 
obtain a baseline value.  Blood (approximately 6 ml) will be collected in NaF/Na2EDTA 
blood collection tubes for PK analysis. 
Note: Subjects with an abnormal ACTH stimulation test (cortisol level < 18 ug/dL at 30 
minutes post stimulation) should be referred to their primary care physician, as needed.  
 
7.9.2 Visit 2 - Day 1 - Baseline Visit  
1. Update the medical history and concomitant medications.  Any medical event (not related to 
a protocol intervention) that occurred since informed consent was signed should be recorded 
as medical history if still ongoing.  
2. Collect adverse events. Any new medical event, need for new medication, or change in 
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be considered an adverse event except for worsening of psoriasis.  
3. Confirm eligibility according to inclusion/exclusion criteria. 
4. Conduct urine pregnancy test on female subjects.  Record method of contraception, as 
applicable, on source only.   
5. Collect vital signs (blood pressure, pulse). 
6. Conduct clinical assessments: 
a. IGA (Table 2) 
b. Local cutaneous safety evaluation for clinically significant atrophy and telangiectasia in 
areas to be treated. The investigator should also ask the subject if any burning/stinging, 
pain, or itching has occurred in the areas to be treated in the last 14 days. 
c. Diagram affected areas to be treated (excluding face, scalp, axillae, groin and other 
intertriginous areas).   
d. Determine BSA excluding face, scalp, axillae, groin and other intertriginous areas.  
7. Randomize the subject by referring to the randomization schedule and dispense study 
product to the subject/legal guardian. The tear-off panel from the box is to be affixed to the 
source document.  Make a note on source document regarding treatment duration. 
8. Instruct subject and legal guardian on study product use. Review the appropriate Subject 
Instructions with subject (See Appendix 2). Using the diagram of affected areas, have the 
subject treat the affected areas under supervision after weighing the study product.  
9. Dispense and review use of diary.  Remind subject and legal guardian to record actual 
application dates and/or potential adverse events as well as any medication used in the diary 
and to bring diary to each visit. 
10. Schedule next visit. 
11. Complete CRF for all subjects including screen failures. Only enter concurrent medical 
conditions and concomitant medications on the CRF. 
 
7.9.3 Visit 3 - Day 8 ± 3 days 
1. Evaluate treatment and protocol compliance and record any deviations.  This includes a 
review of the diary card for number of applications and missed applications. 
2. Conduct clinical assessments: 
a. IGA (Table 2) 
b. Local cutaneous safety evaluation for clinically significant atrophy and telangiectasia in 
the treated areas. The investigator should also ask the subject and legal guardian if any 
burning/stinging, pain, or itching has occurred in the treated areas since the last visit. 
c. Update diagram of affected areas to be treated.  Subjects should continue to treat areas 
that have cleared and any new areas that develop during the treatment period. 
3. Collect vital signs (blood pressure, pulse). 


 
 
 
 
 
 
 
 
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4. Conduct urine pregnancy test for female subjects.  Test must be negative to proceed. 
5. Collect adverse event data.  This includes a review of the diary card for potential AEs.   
6. Update concomitant medications data. 
7. Redispense diary and review instructions and diagram of affected areas to be treated with 
subject.  
8. If subject requires more study product, weigh then dispense the assigned study product, as 
needed. Collect and record weight of empty or nearly empty bottles. Re-dispense partially 
filled bottles.  
9. Schedule next visit. Remind the subject to come to the next visit well hydrated. 
10. Complete CRF.  
 
7.9.4 Visit 4 - Day 15 ± 3 days (29-day treatment group only; not applicable for 15-day 
treatment group) 
1. Evaluate treatment and protocol compliance and record any deviations.  This includes a 
review of the diary card for number of applications and missed applications. 
2. Conduct clinical assessments: 
a. IGA (Table 2) 
b. Local cutaneous safety evaluation for clinically significant atrophy and telangiectasia in 
the treated areas. The investigator should also ask the subject and legal guardian if any 
burning/stinging, pain, or itching has occurred in the treated areas since the last visit. 
c. Update diagram of affected areas to be treated.  Subjects should continue to treat areas 
that have cleared. 
3. Collect vital signs (blood pressure, pulse). 
4. Collect adverse event data.  This includes a review of the diary card for potential AEs.   
5. Update concomitant medications data. 
6. Conduct a urine pregnancy test for female subjects.  The test must be negative for the 
subject to continue in the study. 
7. Redispense diary and review instructions and diagram of affected areas to be treated with 
subject.  
8. If subject requires more study product, weigh then dispense assigned study product, as 
needed. Collect and record weight of empty or nearly empty bottles. Re-dispense partially 
filled bottles.  
9. Schedule next visit.  Remind subject to come to the next visit well hydrated. 
10. Complete CRF.  
 


 
 
 
 
 
 
 
 
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7.9.5 Visit 4 (Day 15 ± 3 days) for 15-day treatment group or Visit 5 (Day 29 ± 3 days)  
for 29-day treatment group (End of Treatment Visit 7:00 am to 9:30 am) 
1. Evaluate treatment and protocol compliance and record any deviations.  This includes a 
review of the diary card for number of applications and missed applications. 
2. Conduct clinical assessments: 
a. IGA (Table 2) 
b. Local cutaneous safety evaluation for clinically significant atrophy and telangiectasia in 
the treated areas. The investigator should also ask the subject if any burning/stinging, 
pain, or itching has occurred in the treated areas since the last visit. 
c. Assess BSA excluding face, scalp, axillae, groin and other intertriginous areas. 
3. Collect vital signs (blood pressure, pulse). 
4. Collect adverse event data.  This includes a review of the diary card for potential AEs.   
5. Update concomitant medications data. 
6. Conduct urine pregnancy test for female subjects. Test must be negative to proceed with the 
ACTH stimulation test. 
7. Draw pre-treatment (0 hour) PK blood sample no more than 60 minutes before planned 
study product application and process sample. Blood (approximately 6 ml) will be collected 
in NaF/Na2EDTA blood collection tubes. 
8. Collect all study product bottles and record weight. 
9. Supervise last application of study product by subject. Record weight of bottle after 
application.  
10. Draw post-treatment PK blood samples at 1, 3 and 6 hours after study product application 
and process samples. Blood (approximately 6 ml each sample for a total of 18 mL) will be 
collected in NaF/Na2EDTA blood collection tubes. 
11. Conduct ACTH stimulation test after the last application (approximately 5 mL for each 
sample for a total of 10 mL). The entire test, including pre- and post-stimulation blood and 
saliva samples, should be completed between approximately 7:00 am and 9:30 am and 
within one hour of the time of the screening ACTH stimulation test. 
12. Collect study diary. 
13. Complete CRF.  
 
7.9.6 Visit 5 (Day 43) or 6 (57)  (if required) 
If HPA axis is suppressed at End of Treatment Visit, another test will be administered at 
approximately Day 43 (for 15-day treatment groups) or Day 57 (for 29-day treatment group) to 
confirm recovery. The ACTH stimulation test will be repeated approximately every 28 days 
until HPA axis is stabilized (or explained). 
1. Collect vital signs (blood pressure, pulse). 


 
 
 
 
 
 
 
 
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2. Perform urine pregnancy test for female subjects.  Test must be negative to proceed with the 
ACTH stimulation test. 
3. Conduct ACTH stimulation test. The entire test, including pre- and post-stimulation blood 
and saliva samples, should be completed between approximately 7:00 am and 9:30 am. 
4. Collect adverse event data.   
5. Update concomitant medications data. 
6. Complete CRF.  
 
8 
ADVERSE EVENTS 
Adverse events will be collected by spontaneous reports from subjects and legal guardians, 
either verbal or recorded in the subject diary, by directed questioning of subjects, and by 
observation.  
Adverse events associated with the use of topical betamethasone dipropionate include erythema, 
folliculitis, pruritus, and vesiculation each occurring in less than 1% of patients. 
In addition, the following additional local adverse reactions have been reported with topical 
corticosteroids, and they may occur more frequently with the use of occlusive dressings and 
higher potency corticosteroids.  These reactions are listed in an approximately decreasing order 
of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform 
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary 
infection, skin atrophy, striae, and miliaria. 
The investigator is to pay special attention at each post-treatment visit to any signs of clinically 
significant atrophy or telangiectasia and report presence as an adverse event if severity is worse 
than baseline. The investigator will also ask the subject if any burning/stinging, pain, or itching 
has occurred in the treated areas since the last visit (for Visit 2 in the last 14 days). Baseline 
assessments are made prior to first application.  Subsequent to the Baseline Visit, for each 
symptom reported by subjects and/or each clinically significant sign, the presence of the sign or 
symptom must be recorded as “Yes” even if severity is not worse than Baseline. An adverse 
event should be recorded if the severity is worse than Baseline. 
 
An adverse event is any untoward medical occurrence in a subject participating in a clinical 
trial. The event does not necessarily have to have a causal relationship with the study product.  
An adverse event can therefore be any sign, symptom, or disease, or any worsening of an 
existing sign, symptom, or disease, whether or not considered related to the study product or 
trial procedures, including injuries.   
 
Any medical condition that is present at the time of Screening or Baseline should be considered 
as medical history and reported on the medical history CRF and should not be reported as an 
adverse event except for adverse events observed at the Baseline Visit due to study procedures 
performed at the Screening Visit which should be reported (except for worsening of psoriasis). 
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events.  Unexpected worsening of pre-existing conditions should be reported as adverse events. 
The disease or condition being studied or expected progression, signs, or symptoms of the 
disease or condition being studied should not be reported as an adverse event unless more severe 
than expected. 
 
All serious adverse events, all study-product-related adverse events and all adverse events 
leading to study product discontinuation must be followed until the clinical outcome is 
determined or until all attempts to determine resolution of the event are exhausted (“not 
recovered” is not an acceptable outcome for acute conditions). For other adverse events, the 
status at the last visit can be entered into the CRF. 
 
8.1 
Adverse Event Reporting Period 
Adverse event data must be collected from the time treatment is initiated until study product 
treatment is discontinued except for spontaneously reported serious adverse events which should 
be reported up to 30 days after discontinuing study product use and entered on the CRF. 
Adverse events occurring from the time of the Screening Visit until the Baseline Visit 
associated with study procedures should also be reported for all subjects including screen 
failures.  Abnormal screening ACTH stimulation test should not be reported as an adverse 
event.  Abnormal End of Treatment ACTH stimulation tests will be recorded as adverse events 
of HPA axis suppression related to study product and will be repeated until HPA axis is 
stabilized (or explained). 
 
8.2 
Recording Adverse Events 
The investigator will record all adverse events, regardless of relationship to study product on the 
adverse event CRF.  Standard medical terminology should be used when describing adverse 
events.  Whenever possible a diagnosis should be made and recorded on the CRF rather than 
listing signs and symptoms. Intermittent adverse events can be recorded once. The anatomical 
location of the adverse event must be specified, when applicable, as well as whether the location 
is a treatment area.  The following information should be recorded on the CRF: 
 
1. Description 
2. Start date 
3. Stop date or date of death, ongoing, or unknown 
4. Severity of the event (see 8.3.1: Severity for details) 
5. Study product use continued or not 
6. Outcome of the event (recovered/resolved, recovered/resolved with sequelae, not 
recovered/not resolved, unknown, fatal) 
7. Relationship to study product (see 8.3.2: Relationship to Study Product (Causality) for 
details) 
8. Indication of whether the event is serious (see 8.3.3: Seriousness for details) 
9. Actions taken including treatment with concomitant medication 
 


 
 
 
 
 
 
 
 
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8.3 
Assessment of Adverse Events 
8.3.1 Severity 
It is the investigator's responsibility to assess the severity of each adverse event. Descriptions of 
severity are as follows: 
 
1. Mild:  Awareness of sign or symptom, but easily tolerated. Not likely to interfere with 
normal activity or require medical attention. 
 
2. Moderate:  Discomfort enough to cause interference with usual activity. May require 
medical intervention. 
 
3. Severe:  Incapacitating such that normal activity is prevented.  Likely requires medical 
intervention and/or close follow-up. 
 
8.3.2 Relationship to Study Product (Causality) 
It is the investigator’s responsibility to assess the relationship between the study product and the 
adverse event.  The degree of “relatedness” of the adverse event to the study product should be 
described using the following categories: 
 
1. Not Related: The event is clearly due to extraneous causes (e.g., diseases, environment, 
etc.).  Specify if known.  Or, the event is most probably produced by other factors such 
as the subject’s clinical state, therapeutic interventions or concomitant therapy and does 
not follow a known response pattern to the study product. 
 
2. Possibly Related:  The event is temporally related to study product use but can be 
explained by another etiology. Information on the effect of study product withdrawal 
may be lacking. 
 
3. Probably Related:  The event is temporally related to study product use and is consistent 
with known effects of the study product and/or improves upon withdrawal of the study 
product.  
 
4. Definitely Related:  The event follows a reasonable temporal sequence from the time of 
study product administration and/or follows a known response pattern to the study 
product, and could not have been produced by other factors such as the subject’s clinical 
state, therapeutic intervention or concomitant therapy, and either occurs immediately 
following study product administration, or improves on stopping the product, or there is 
a positive reaction at the application site. 
 
8.3.3 Seriousness 
It is the investigator’s responsibility to determine the “seriousness” of an adverse event.  A 
serious adverse event (SAE) is any adverse event occurring at any dose that results in any of the 
following outcomes: 
 


 
 
 
 
 
 
 
 
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1. Death 
2. Life-threatening (subject at immediate risk of death) 
3. Inpatient hospitalization or prolongation of hospitalization 
4. Results in persistent or significant disability/incapacity 
5. Results in congenital anomaly/birth defect 
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
8.4 
Reporting Serious Adverse Events 
SAE information must be faxed or emailed within 24 hours of becoming aware of the event.  
The minimum initial information required to be reported on the Serious Adverse Event Form is: 
the protocol number, site number, subject number, subject initials, the event, the causality, the 
date of the event and the name and contact information (email, phone number) of the person 
reporting the event.  This initial report should be promptly followed up with a completed 
Serious Adverse Event Form.  
 
Serious Adverse Events: Shahida Hasan, M.D., M.S. 
 
Fax:  609 228-5408 
 
 
Email:  DFD01-CD-013@promiuspharma.com  
 
 
The initial information must include a causality assessment that is provided by the primary 
investigator or other medically qualified individual. The causality assessment can be amended 
as more information is available. Significant new information about ongoing SAEs should be 
reported promptly to the sponsor. 
 
Serious adverse events will be evaluated by the Medical Monitor within 24 hours of receipt and 
plans for management and further reporting (i.e. FDA) determined. 
 
8.5 
Discontinuation Due to an Adverse Event 
The sponsor must be notified within 5 days if any subject is withdrawn or discontinues study 
product use due to an adverse event if AE is related to the study product (see title page for 
contact information).   
 
8.6 
Exposure in utero (Pregnancy) 
If a female subject becomes pregnant during the study, study product must be discontinued 
immediately and she must be followed through the pregnancy and delivery. The investigator 
should report the event to the sponsor immediately (see contact information on title page) and 
complete the Pregnancy Surveillance Form.  The expected date of delivery or expected date of 
the end of the pregnancy should be included in this information. The investigator is instructed to 


 
 
 
 
 
 
 
 
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contact the subject every 3 months until the end of her pregnancy and report the outcome to the 
sponsor.  Details of the pregnancy, delivery and health of the infant should be recorded on the 
Pregnancy Surveillance Form.  
 
The following outcomes of pregnancy fall under the criteria for serious adverse events and 
should be reported as such: delivery complications prolonging hospitalization, spontaneous 
abortion, stillbirth, death of newborn baby, congenital anomaly, and anomaly in a miscarried 
fetus.  
 
9 
DATA HANDLING AND RECORD KEEPING 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act.  This regulation 
requires a signed authorization informing the subject’s legal guardian of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject’s legal guardian to revoke the authorization for 
use/disclosure of subject’s PHI 
• Expiration of authorization 
 
In the event that a subject’s legal guardian revokes authorization to collect and use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of authorization.  For subjects that have revoked authorizations to collect and use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
9.2 
Source Documents 
Investigators must keep accurate separate records (other than CRFs) of all subject visits which 
include all pertinent study related information including original signed/dated informed consent 
forms.  Source documents for this study include all written records of study data.   All study 
data must have a paper source document including investigator assessments.   
 
9.3 
Screening/Enrollment Log 
A subject Screening/Enrollment Log, noting reasons for screen failure where applicable, must 
be maintained for all subjects who are consented. The log should also include subject initials, 
screening date, subject number, randomization number, assigned product and date and time of 
randomization, where applicable.   
 
9.4 
Case Report Forms 
The study case report form (CRF) for the study is a paper document which will be completed by 
the sites.  All data requested on the CRF must be recorded on source documentation.  The CRF 


 
 
 
 
 
 
 
 
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cannot be the source document for any data.  Detailed instructions and training for completing 
the CRF will be provided to the sites. 
 
Study subjects are not to be identified by name on CRFs, but rather by coded identifiers (subject 
number and initials). The investigator or sub-investigator must review all CRF pages for each 
subject and approve the group of CRFs pages for each subject. 
 
9.5 
Data Capture 
Study data will be entered into and maintained in a 21 CFR Part 11 compliant database. 
 
9.6 
Archiving of Study Documentation 
The investigator must retain study records for 2 years following the date a marketing application 
is approved for the investigational product; or, if the application is not filed or is not approved, 
until 2 years after the investigation is discontinued and the FDA is notified. 
 
The sponsor will inform the investigator, in writing, as to when these documents no longer need 
to be maintained. 
 
All study documents, original source documents, correspondence, IRB documents, etc. are 
subject to sponsor and FDA inspection at any time.  
 
 
10 
MONITORING AND DATA QUALITY ASSURANCE 
Only persons who are appropriately trained and who have the scientific and clinical knowledge 
to adequately monitor the study will be selected for monitoring this study.  The monitor must 
have at least one year previous experience in monitoring clinical studies.  The monitor should be 
familiar with the etiology and signs and symptoms of psoriasis and the treatment options that are 
currently available.   
 
Before study initiation, the investigator and site personnel will receive protocol training from 
the sponsor’s representatives to ensure collection of accurate, consistent, complete and reliable 
data.  This training will take place either at an Investigator Meeting or individually on-site. 
 
During the course of the study, a monitor will make multiple site visits to check the progress of 
the study, review consent forms, review protocol compliance, assess drug accountability, and 
ensure that the study is being conducted according to the protocol and Good Clinical Practice.  
Any review of the subjects’ original medical records will be performed in a manner to ensure 
that subject confidentiality is maintained. The investigator will ensure that the monitor or other 
compliance auditor is given access to all study-related documents and has adequate time and 
space to conduct the monitoring visit including availability of the investigator and site personnel 
to discuss findings. 
 
Data capture methods will be designed to ensure accurate transfer of data to electronic media.  
 


 
 
 
 
 
 
 
 
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The sponsor’s Quality Assurance representative will conduct QA audits randomly or if needed 
at 5-10% of the investigator sites. 
 
11 
STATISTICAL CONSIDERATIONS 
All statistical processing will be performed using SAS® unless otherwise stated. Descriptive 
statistics will be used to summarize the data. No inferential testing will be performed. All 
summaries will be performed on the safety population.  
 
No interim analyses are planned.  
 
No imputations will be made for missing data. 
 
A Statistical Analysis Plan, describing all statistical analyses, will be provided as a separate 
document prior to database lock. 
 
11.1 
Sample Size 
Approximately 50 subjects will be randomized to the two treatment groups in a 1:1 ratio for 25 
subjects per group. No statistical justification has been made for the sample size. 
 
11.2    Analysis Data Set 
All summaries will be performed on the safety population. All subjects who receive at least one 
confirmed dose of study product and provide any post-baseline safety information will be 
included in the safety population.  No imputation will be made for missing safety data. 
 
11.3 
Demographic and Baseline Data 
Subject demographic and Baseline characteristics will be summarized by treatment group for 
the safety population. For continuous variables (e.g., age, BSA), descriptive statistics including 
sample size N, mean, median, standard deviation, minimum, and maximum will be presented. 
For categorical variables (e.g., IGA), descriptive statistics including N, frequency count and 
percentages will be presented.  
 
11.4 
Efficacy Summary 
Descriptive statistics will be used to summarize IGA by treatment group and visit and will 
include sample size, frequency counts, and percentages. 
 
11.5 
Safety Summaries 
Descriptive statistics will be presented to summarize the safety data. Continuous variables will 
be summarized with sample size N, mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized with sample size N, frequency counts and 
percentages.  
 


 
 
 
 
 
 
 
 
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11.5.1 Extent of Exposure 
The extent of exposure to study product in both treatment groups will be summarized as the 
total number of applications and the total amount of study product used based on bottle weights. 
The amount of the last dose will be provided based on bottle weight before and after treatment. 
 
11.5.2 Local Safety Evaluation 
Atrophy, telangiectasia, burning/stinging, pain, or itching will be summarized by treatment 
group and visit.  
 
11.5.3 ACTH Stimulation Test 
The proportion of subjects with abnormal serum cortisol response for ACTH stimulation test at 
the end of treatment (cortisol level ≤18 ug/dL at 30 minutes post stimulation) will be 
summarized by treatment group.  Additionally, the serum and saliva cortisol levels found pre-
stimulation and post-stimulation will be summarized for the screening ACTH test and the end of 
treatment ACTH test. The sample size N, mean, median, standard deviation, minimum, and 
maximum saliva cortisol levels will be provided for the subsets of subjects with abnormal and 
normal serum cortisol response. 
 
11.5.4 Pharmacokinetics 
The plasma concentrations of betamethasone, betamethasone-17-propionate, and betamethasone 
-17,21-dipropionate will be summarized (and will include 95% confidence intervals for the 
mean) for the PK Screening sample and for 0 (pre-treatment), 1, 3, and 6 hours (±5 minutes) 
after the last application of study product at the end of treatment. The average of the post-
treatment concentrations will also be summarized. Plasma concentrations that are taken more 
than 1 hour off-schedule will be included in data listings only and will not be included in the 
summarization of the concentration data.   
 
11.5.5 Adverse Events 
All AEs occurring during the study will be recorded and classified on the basis of MedDRA 
terminology. Treatment-emergent adverse events are those AEs with an onset on or after the 
date of the first study product administration. For the safety population, all reported treatment-
emergent AEs will be summarized by treatment group, the number of subjects reporting events, 
system organ class, preferred term, severity, relationship to study product, and seriousness. 
When summarizing AEs by causality and severity, each subject will be counted only once 
within a system organ class or a preferred term by using the event with the greatest relationship 
and highest severity within each classification. 
 
Serious adverse events (SAEs) will be summarized by treatment group, severity, and 
relationship to study product, and SAEs will be listed by subject. In addition, a list of subjects 
who prematurely discontinued from the study due to an AE will be provided. 
 
All information pertaining to AEs noted during the study will be listed by subject, detailing 
verbatim term given by the investigator, preferred term, system organ class, onset date, 


 
 
 
 
 
 
 
 
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resolution date, maximum severity, seriousness, action taken regarding study product, corrective 
treatment, outcome, and drug relatedness. The event onset will also be shown relative (in 
number of days) to date of first administration. 
 
AEs related to study procedures done before study product administration will be provided in a 
data listing. 
 
11.5.6 Vital signs 
Changes from Baseline in vital signs (blood pressure, pulse) will be summarized by treatment 
group at each evaluation.  
 
11.5.7 Safety Laboratory Values 
Urine pregnancy tests will be performed at all visits for female subjects and will be presented in 
subject data listings. 
  
11.5.8 Subset Analyses 
No subset analyses are planned. 
 
 
 


 
 
 
 
 
 
 
 
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12 
REFERENCES 
Finlay AY. Current severe psoriasis and the rule of tens. Br J Dermatol. 2005;152:861-
867. 
 
Gallagher P, Leitch MM, Massey AE, et al. Assessing cortisol and 
dehydroepiandrosterone (DHEA) in saliva: effects of collection method. J 
Psychopharmacol. 2006;20(5):643-9. 
 
Mendonca CO, Burden AD. Current concepts in psoriasis and its treatment, Pharmacol 
& Therapeutics. 2003;99(2):133-147. 
 
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. 
Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad 
Dermatol. 2008;58(5):826-850. 
 
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et.al 
Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad 
Dermatol. 2009;60(4):643-659. 
 
National Psoriasis Foundation. Psoriasis Prevalence. 
http://www.psoriasis.org/netcommunity/learn_statistics. Accessed October 27, 2010. 
 
Study BDS1307. A Randomized, Parallel, Open Label, Multicenter Study to Assess the 
Potential for Adrenal Suppression and Systemic Drug Absorption Following Multiple 
Dosing with Betamethasone Dipropionate Spray 0.05% versus Diprolene® (augmented 
betamethasone dipropionate) Lotion 0.05%  in Subjects with Moderate to Severe Plaque 
Psoriasis. February, 2015. 
 
 


 
 
 
 
 
 
 
 
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APPENDIX 1 
Declaration of Helsinki (2013) 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
A. PREAMBLE  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs.  
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
B. GENERAL PRINCIPLES 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the international Code of Medical Ethics declares that,”A 
physician shall act in the patient’s best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients,   
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty.  
5. Medical progress is based on research that ultimately must include studies involving human subjects.   
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality.  
7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects 
and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
or other health care professionals and never with the research subjects, even though they have given 
consent.  
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 


 
 
 
 
 
 
 
 
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12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional.  
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured.  
C. 
RISK, BURDENS AND BENEFITS 
16. In medical practice and in medical research, most interventions involve risks and burdens.  
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
D. 
VULNERABLE GROUPS AND INDIVIDUALS   
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical Research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
 
E. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
 
21. Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected. 
 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions 


 
 
 
 
 
 
 
 
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for treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study. In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions.   
 
F. RESEARCH ETHICS COMMITTEES 
 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. 
The researcher must provide monitoring information to the committee, especially information about 
any serious adverse events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
 
G. 
PRIVACY AND CONFIDENTIALITY 
 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 
 
H. 
INFORMED CONSENT 
 
25. Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other  relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver 
the information. After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential subject's freely-
given informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed. All medical research subjects should be 
given the option of being informed about the general outcome and results of the study.  
27. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed with 
persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden.  
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 


 
 
 
 
 
 
 
 
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the consent of the legally authorized representative. The potential subject's dissent should be 
respected.  
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative.  
31. The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
I. 
USE OF PLACEBO 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best proven intervention(s), except in the following circumstances: 
a. 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
b. Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not 
be subject to additional risks of serious or irreversible harm as a result of not receiving the 
best proven intervention. Extreme care must be taken to avoid abuse of this option. 
J. 
POST-TRIAL PROVISIONS 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
K. RESEARCH REGISTRATION AND PUBLICATION AND DISSEMINATION OF RESULTS 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject.  
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be declared in 
the publication. Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. This 


 
 
 
 
 
 
 
 
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intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.  
 
October 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
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APPENDIX 2 
Subject Instructions - Spray 
 
1. You have been given a bottle of study medication.  Shake well before using. Spray study 
medication directly onto each of your psoriasis lesions as instructed by the study nurse. 
Refer to the diagram provided. Apply study medication to all areas shown on the body 
diagram even if clear. Also apply study medication to new areas that may appear between 
visits. Apply study medication in the morning and at bedtime, approximately 12 hours 
apart. You will need to use at least 15-20 sprays of study medication each time. You can 
use more if needed.  Massage lightly after application until medication disappears.  If 
bathing at the treatment time, apply medication after bathing.  
 
2. The study medication is for external use only. The study medication should not be used 
on the scalp, face, underarms, or groin area. Also avoid contact with eyes and lips. The 
application areas must not be bandaged, covered, or wrapped. 
 
3. Always wash hands before applying the study medication and thoroughly after applying. 
 
4. Store medication at room temperature.  
 
5. If you have any questions, please ask the study coordinator or nurse. 
 
6. The study medication may cause some irritation or discomfort.  Tell your doctor about 
any reactions. If the reaction becomes severe, stop using the study medication and call the 
doctor. 
 
7. Write down the date and time (am or pm) when you apply the study medication in your 
study diary. 
 
8. Do not let anyone else use the study medication. Keep the medication out of the reach of 
children and pets. Use of the study product should be done under the supervision of the 
legal guardian. 
 
9. Return all containers in the box at every study visit. 
 
10. Bring your study diary to every visit. 
 
11. If you cannot make a scheduled visit, please contact the study office as soon as possible to 
re-schedule another date.   
 
12. Do not use study medication on the morning of your last study visit. 
 
13. If you have to discontinue participation in the study for any reason, notify the study office 
immediately.  A visit will be scheduled for a final examination of psoriasis and to collect 
the containers and your diary.  This visit is important for your safety.