Clinical trial NCT03179605
Conditions: Psoriasis
Sponsor: Primus Pharmaceuticals
Start date: 2017-05-02; Completion date: 2020-06-03
Enrollment: 22 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the potential of DFD-06 to suppress the hypothalamic-pituitary-adrenal (HPA) axis when applied twice daily for 15 days.

Detailed description:
This is a 15-day, single arm, multicenter, multi-dose, open-label, two stage, sequential study. In the first stage, subjects who are at least 12 years of age and not more than 16.9 years (16 years and 11 months) of age with moderate to severe plaque psoriasis will be treated with DFD-06 (at least 20 completed subjects). In the second stage subjects who are at least 6 years of age and not more than 11.9 years (11 years and 11 months) of age with moderate to severe plaque psoriasis will be treated with DFD-06 (at least 20 completed subjects). An attempt will be made to enroll subjects throughout the age range of each cohort including the lower age range. DFD-06 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.

Arms: arm 1: This is a single arm, open label study and there will be no reference or control product used in this study
Interventions: intervention 1: DFD06
Intervention descriptions: intervention 1: Apply twice per day for 15 days

Protocol documents:
Prot_SAP_001.pdf: 


 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL 
 
An Open Label, Multicenter Study to Assess the Potential for Adrenal Suppression and 
Systemic Drug Absorption Following Multiple Dosing with DFD-06 (Clobetasol Propionate 
Cream, 0.025%) in Pediatric Subjects with Moderate to Severe Plaque Psoriasis.  
 
Protocol Number:  
DFD-06-CD-011    
 
Version: 2.0  
 
 
Phase: 
2      
 
 
 
Date: 25 January 2017 
 
Sponsor: 
Promius Pharma, LLC 
 
107 College Rd East 
 
Princeton, NJ   08540 
 
Sponsor Contact: 
Carmela Fritz, MSH Sci 
 
107 College Rd East 
Princeton, NJ   08540 
 
Phone:  609-282-1425  
 
 
cfritz@promiuspharma.com 
 
Medical Monitor: 
Srinivas Sidgiddi, MD  
 
107 College Rd East 
Princeton, NJ   08540 
 
Phone:  609-375-9910 
 
srinivassidgiddi@drreddys.com 
 
CRO Contact: 
Grace Liu, CCRA 
 
Therapeutics Inc. 
 
9025 Balboa Avenue, Suite 100 
 
San Diego, CA 92123 
 
Phone: 858-571-1800 
 
gliu@therapeuticsinc.com 
 
Serious Adverse  
Events: 
Shahida Hasan, MD, MS 
 
Dr. Reddy's Laboratories, Inc. 
 
107 College Rd East 
Princeton, NJ   08540 
 
Fax:   609 228-5408 
 
 
  
 
Email: SAEreporting@promiuspharma.com 
 
 
 
 
 




 
 
 
 
 
 
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SYNOPSIS 
Title:    An Open Label, Multicenter Study to Assess the Potential for Adrenal Suppression and 
Systemic Drug Absorption Following Multiple Dosing with DFD-06 (Clobetasol Propionate 
Cream, 0.025%) in Pediatric Subjects with Moderate to Severe Plaque Psoriasis 
 
Sponsor:   
Promius Pharma, LLC 
 
107 College Road East 
 
Princeton, NJ 08540 
Study Centers:                ~15 
Number of Subjects:  50 
 
Study 
Treatment: 
             15 Days 
Clinical Phase: Phase 2 
 
Objectives: 
The objectives of this study are: 
• To evaluate the potential of DFD-06 to suppress the hypothalamic-pituitary-adrenal (HPA) 
axis, when applied twice daily for 15 days, in subjects age 6 to 16.9 years of age with 
moderate to severe plaque psoriasis under maximal use conditions with the final-to-be-
marketed formulation.  
• To assess the plasma concentrations of clobetasol propionate after multiple doses of DFD-06 
under maximal use condition with the final-to-be-marketed formulation.   
Methods:   
This is a 15-day, single arm, multicenter, multi-dose, open-label, two stage, sequential study. In 
the first stage, subjects who are at least 12 years of age and not more than 16.9 years (16 years 
and 11 months) of age with moderate to severe plaque psoriasis will be treated with DFD-06 (at 
least 20 completed subjects). In the second stage  subjects who are at least 6 years of age and 
not more than 11.9 years (11 years and 11 months) of age with moderate to severe plaque 
psoriasis will be treated with DFD-06 (at least 20 completed subjects). An attempt will be made 
to enroll subjects throughout the age range of each cohort including the lower age range. DFD-
06 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% BSA treated to achieve 
maximal use exposure.  
 
Subject visits will take place at Screening, Baseline (Day 1), Day 8, Day 15 and Day 43 (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 (i.e., a cosyntropin IV or IM 
injection) at the Screening Visit (at least 14 days and no more than 35 days prior to Baseline) 
and at Day 15. If HPA axis is suppressed at Day 15 Visit, another test will be administered at 
least 28 days later (at approximately Day 43) 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).   
 


 
 
 
 
 
 
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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). On Day 15, 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 – 
Day 15). 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 striae, hypopigmentation, fissuring, folliculitis, 
atrophy, telangiectasia, itching, and burning/stinging) will be performed at Visit 2 (Day 1), Visit 
3 (Day 8), and Visit 4 (Day 15). Other safety assessments include vital signs (blood pressure, 
pulse), urine pregnancy tests (only for females of child bearing potential), and collection of 
adverse event data.   
 
Number of Subjects: 
A total of approximately 50 subjects will be enrolled to get at least 40 completed subjects, at 
approximately 15 sites. Of the 50 subjects enrolled, 25 subjects in the age group of 12 to 16.9 
years will be enrolled in the first stage and 25 subjects in the age group of 6 to 11.9 years will be 
enrolled in the second stage. 
 
Diagnosis and Criteria for Inclusion / Exclusion: 
Inclusion: 
1. Subjects and the parent or legal guardian understand the study procedures and agree to 
participate by giving assent and written informed consent, respectively. Subject’s parent or 
legal guardian must be willing to authorize use and disclosure of protected health 
information collected for the study. 
2. Subjects must be at least 6 years and not more than 16.9 years of age, with body weight 
greater than or equal to 45 pounds at Screening. 
3. Subjects must present with a clinical diagnosis of stable (at least 3 months) plaque 
psoriasis. 
4. Subjects with psoriasis involving ≥10% BSA, not including the face, scalp, groin, axillae 
and other intertriginous areas at the Baseline Visit.   
5. Subjects must have an IGA grade of at least 3 (moderate) at the Baseline Visit. 
6. All women of childbearing potential must complete a urine pregnancy test (test must 
have a sensitivity of at least 25mIU/ml for human chorionic gonadotropin) at the Baseline 
Visit (Visit 2) and the test result must be negative to be eligible for enrollment.  
 
A female is considered of childbearing potential unless she is: 
a. pre-menarche (girls 10 and older should have UPT regardless of menarche); 
b. without a uterus and/or both ovaries; or has been surgically sterile for at least 6 
months prior to study product administration 
 
7. 
Female subjects of childbearing potential must agree to use contraception during the 
study which can include abstinence with an adequate secondary option should the 
subject become sexually active.   


 
 
 
 
 
 
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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. 
Exception:  Sexually inactive female subjects of childbearing potential are not required to 
practice a reliable method of contraception and may be enrolled at the investigator’s 
discretion provided that they are counseled to remain sexually inactive for the duration of 
the study and understand the possible risks involved in getting pregnant during the study. 
An abstinent female must agree that if she becomes sexually active during the study she 
will use an acceptable form of contraception 
 
8. Subjects must be in good general health as supported by the medical history, screening 
evaluations and the assessment(s) of the subject at Screening and Baseline with no 
clinically significant abnormalities that would preclude their participation in the study in 
the opinion of the investigator.  
 
9. Subjects whose results from the screening ACTH stimulation test, performed at least 14 
days and no more than 35 days prior to Baseline, which is considered normal defined as; 
1) a normal pre-stimulation cortisol level and 2) a cortisol level >18 ug/dL at 30 minutes 
post stimulation  
Exclusion: 
1. Subject has a current diagnosis of unstable forms of psoriasis including guttate, 
erythrodermic, exfoliative or pustular psoriasis. 
2. Subject has a history of organ transplant requiring immunosuppression, HIV, or other 
immunocompromised state. 
3. Subject has received treatment for any type of cancer within 5 years of the Baseline Visit 
except skin cancer and cervical cancer (in situ) are allowed if at least 1 year before the 
Baseline Visit. 
4. Subject has a history or presence of intracranial hypertension. 
5. Subject has had prolonged exposure to natural or artificial sources of ultraviolet radiation 
within 30 days prior to the initiation of treatment or is intending to have such exposure 
during the study that is thought by the investigator to likely modify the subject's disease. 
6. 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), or 4) topical or systemic 
retinoid treatment. 


 
 
 
 
 
 
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7. 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. 
8. Use within 30 days prior to the Screening Visit of any product containing corticosteroids. 
Inhaled, intraocular, intranasal, etc. steroids are not allowed. 
9. Subjects with known hypersensitivity to clobetasol propionate, any component of DFD-06. 
10. Subjects who have an abnormal sleep schedule or work at night. 
11. Subject is currently enrolled in an investigational drug or device study. 
12. Subject has used an investigational drug or investigational device treatment within 30 days 
prior to Visit 1 (Screening).  
13. Subjects unable to comply with study requirements.  
14. Female subjects who are pregnant (or planning to become pregnant) or breast-feeding. 
15. Subjects with a known history of acute adrenal crisis, Addison’s disease or decreased 
adrenal output, low pituitary function or pituitary tumors. 
16. Subjects who have a history of an adverse reaction to cosyntropin injection or similar test 
reagents. 
17. Subjects with any history of illegal drug or alcohol use.  
Investigational Product, Dose and Mode of Administration: 
DFD-06 (Clobetasol Propionate Cream, 0.025%)  
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 5 g per 
day. 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 15 days. Since the screening ACTH test must occur at least 
14 days before to the Baseline Visit, the total study duration is at least 29 days plus any 
additional wash-out period.  Some subjects may need to return for a follow-up visit at Day 43. 
 
Reference and Control Products, Dose and Mode of Administration: 
This is a single arm, open label study and there will be no reference or control product used in 
this study. 
 
Criteria for Evaluation: 
Safety criteria: 
The proportion of subjects with abnormal cortisol response for ACTH stimulation test at Day 15 
(cortisol level ≤18 µg/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 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screena 
Day 1 
(Baseline) Day 8b 
Day 15k 
(End of 
Treatment) 
Day 43c, k 
Informed Consent 
X 
 
 
 
 
Collect Demographic Data 
X 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
X 
 
 
 
Med History / Prior Meds 
X 
X 
 
 
 
Vital Signs (BP, Pulse) 
X 
X 
X 
X 
X 
Urine Pregnancy Testl 
Xd 
X 
X 
Xd 
Xd 
Height and weight 
X 
 
 
 
 
Determine BSA  
X 
X 
 
 
 
IGA 
X 
X 
X 
X 
 
ACTH stimulation testg 
Xe 
 
 
X 
Xh 
Local Cutaneous Safety Evaluation  
 
X 
X 
X 
 
Weigh and Dispense Medication (as needed) 
 
X 
X 
 
 
Supervised treatment 
 
Xi 
 
Xi 
 
Take Blood Samples for PK 
X 
 
 
Xj 
 
Dispense/Review/Collect Study Diary 
 
X 
X 
X 
 
Diagram affected areas to be treated 
 
X 
X 
 
 
Review Subject Instructions 
 
X 
X 
 
 
Collect and Weigh Used Containers 
 
 
X 
X 
 
Evaluate Compliance 
 
 
X 
X 
 
Review Concomitant Medications 
 
  
X 
X 
X 
Adverse Event Assessment 
 
Xf 
X 
X 
X 
End of Study  
 
 
 
X 
X 
a No more than 60 days before Visit 2  
b Allowed visit window ± 3 day 
c If needed due to abnormal ACTH test result from 
Day 15 Visit  
d Pregnancy test just prior to ACTH stimulation test  
e At least 14 days, and no more than 35 days, prior 
to Day 1   
f Related to study procedures only  
 
g ACTH stimulation test should be performed within +/-1 hour 
of time of when Screening test was performed 
h  ACTH stimulation test will be repeated until recovery (or is explained) 
i  Weigh tube before and after application 
j At 0, 1, 3, 6 hours (+/-5 minutes) after first application 
k  Allowed visit window + 3 days 
l  Only in females of child bearing potential 
 


 
 
 
 
 
 
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TABLE OF CONTENTS 
 
COMPLIANCE STATEMENT ..................................................................................................... 2 
SIGNATURES ............................................................................................................................... 2 
SYNOPSIS ..................................................................................................................................... 3 
Study Schedule........................................................................................................................... 7 
TABLE OF CONTENTS ............................................................................................................... 8 
LIST OF ABBREVIATIONS ...................................................................................................... 10 
LIST OF DEFINITIONS ............................................................................................................. 11 
1 
INTRODUCTION ............................................................................................................... 12 
2 
ETHICAL CONSIDERATIONS ......................................................................................... 13 
2.1 
Institutional Review Board Review .............................................................................. 13 
2.2 
Ethical Conduct of Study .............................................................................................. 13 
2.3 
Informed Consent .......................................................................................................... 14 
2.4 
Selection of Investigators .............................................................................................. 14 
3 
STUDY OBJECTIVES ........................................................................................................ 14 
4 
STUDY DESIGN................................................................................................................. 14 
5 
SELECTION OF STUDY POPULATION ......................................................................... 15 
5.1 
Number of Subjects ....................................................................................................... 15 
5.2 
Inclusion Criteria ........................................................................................................... 15 
5.3 
Exclusion Criteria .......................................................................................................... 16 
6 
SUBJECT TREATMENT ................................................................................................... 18 
6.1 
Investigational Products ................................................................................................ 18 
6.1.1 
Description ............................................................................................................. 18 
6.1.2 
Labels and Packing ................................................................................................ 18 
6.1.3 
Accountability ........................................................................................................ 19 
6.1.4 
Dispensing and Return ........................................................................................... 20 
6.1.5 
Storage ................................................................................................................... 20 
6.2 
Treatment Regimen ....................................................................................................... 20 
6.3 
Treatment and Protocol Compliance ............................................................................. 20 
6.4 
Method of Assigning Subjects to Treatment Groups .................................................... 21 
6.5 
Blinding ......................................................................................................................... 21 
6.5.1 
Method of Blinding ................................................................................................ 21 
6.5.2 
Unblinding ............................................................................................................. 21 
6.6 
Prior and Concomitant Therapy .................................................................................... 21 
7 
STUDY PROCEDURES AND EVALUATIONS .............................................................. 23 
7.1 
Informed Consent Process ............................................................................................. 23 
7.2 
Screening ....................................................................................................................... 23 
7.3 
Demographic and Baseline Characteristics ................................................................... 23 
7.4 
Efficacy Assessments .................................................................................................... 23 
7.4.1 
Investigator’s Global Assessment (IGA) ............................................................... 23 
7.5 
Safety Assessments ....................................................................................................... 24 
7.5.1 
ACTH Stimulation Test ......................................................................................... 24 
7.5.2 
Other Safety Assessments ...................................................................................... 25 
7.5.3 
Drug Concentration Measurements/PK Blood Sampling ...................................... 25 


 
 
 
 
 
 
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7.6 
Early Withdrawal of Subjects ....................................................................................... 26 
7.7 
Modification of Protocol ............................................................................................... 27 
7.8 
Early Termination of Study ........................................................................................... 27 
7.9 
Study Schedule .............................................................................................................. 27 
7.9.1 
Visit 1 - Screening Visit (60 days or less from Baseline Visit 2) .......................... 27 
7.9.2 
Visit 2 - Day 1 - Baseline Visit .............................................................................. 28 
7.9.3 
Visit 3 - Day 8 (± 3 days) ....................................................................................... 29 
7.9.4 
Visit 4 - Day 15 (End of Treatment – 7:00am to 9:30 am) (+3 days).................... 30 
7.9.5 
Visit 5 (Day 43 if required) – 7:00 am – 9:30 am (+ 2 days) ................................ 30 
8 
ADVERSE EVENTS ........................................................................................................... 31 
8.1 
Adverse Event Reporting Period ................................................................................... 32 
8.2 
Recording Adverse Events ............................................................................................ 32 
8.3 
Assessment of Adverse Events ..................................................................................... 32 
8.3.1 
Severity .................................................................................................................. 32 
8.3.2 
Relationship to Study Product (Causality) ............................................................. 33 
8.3.3 
Seriousness ............................................................................................................. 33 
8.4 
Reporting Serious Adverse Events ................................................................................ 34 
8.5 
Discontinuation Due to an Adverse Event .................................................................... 34 
8.6 
Exposure in utero (Pregnancy) ...................................................................................... 34 
9 
DATA HANDLING AND RECORD KEEPING ............................................................... 35 
9.1 
Confidentiality ............................................................................................................... 35 
9.2 
Source Documents......................................................................................................... 35 
9.3 
Screening/Enrollment Log ............................................................................................ 35 
9.4 
Case Report Forms ........................................................................................................ 35 
9.5 
Data Capture .................................................................................................................. 36 
9.6 
Archiving of Study Documentation .............................................................................. 36 
10 MONITORING AND DATA QUALITY ASSURANCE .................................................. 36 
11 STATISTICAL CONSIDERATIONS................................................................................. 37 
11.1 
Sample Size ............................................................................................................... 37 
11.2 
Analysis Data Set....................................................................................................... 37 
11.3 
Demographic and Baseline Data ............................................................................... 37 
11.4 
Efficacy Summary ..................................................................................................... 37 
11.5 
Safety Summaries ...................................................................................................... 37 
11.5.1 Extent of Exposure ................................................................................................. 38 
11.5.2 Local Safety Evaluation ......................................................................................... 38 
11.5.3 ACTH Stimulation Test ......................................................................................... 38 
11.5.4 Pharmacokinetics ................................................................................................... 38 
11.5.5 Adverse Events ...................................................................................................... 38 
11.5.6 Vital Signs .............................................................................................................. 39 
11.5.7 Safety Laboratory Values ...................................................................................... 39 
11.5.8 Subset Analyses ..................................................................................................... 39 
12 REFERENCES .................................................................................................................... 40 
APPENDIX 1 - Declaration of Helsinki (2013) .......................................................................... 41 
APPENDIX 2 - Subject Instructions / Subject Diary (2 pages) ................................................... 46 
 
 


 
 
 
 
 
 
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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 
eCRF 
Electronic case report form 
GCP 
 
ICH 
Good Clinical Practice 
 
International Conference on Harmonization 
 
IGA 
Investigator’s Global Assessment 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
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 enrollment 
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 enrollment and the first study product application. 
The first study product application is done at the site by the 
subject during the visit. 
 
 
Subject Number 
 
 
 
 
 
 
 
 
 
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).  
 
 
Study product(s) 
Investigational product(s) 
 
 
 


 
 
 
 
 
 
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1 INTRODUCTION 
Promius Pharma, LLC has developed a new formulation of clobetasol propionate cream with a 
lower strength (0.025%) compared to the currently available products (0.05%) for the topical 
treatment of moderate to severe plaque psoriasis.  
 
Clobetasol propionate is a synthetic, fluorinated corticosteroid that has been available since 
1974 and is highly effective in the treatment of psoriasis, atopic dermatitis, and many other 
inflammatory skin diseases. Many formulations are available including ointments, creams, gels, 
foams, shampoos, and solutions.   
 
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).  
Clobetasol propionate is a well-characterized active ingredient, and many studies have been 
conducted on the pharmacology, toxicology and clinical efficacy and safety of clobetasol 
propionate.  
In clinical trials, adverse events associated with the use of topical clobetasol propionate cream 
included burning and stinging in 1% of treated patients. Less frequent reactions were itch, skin 
atrophy, and cracking and fissuring of skin. With long-term use, generally more than 2-4 weeks, 
all topical steroids have been shown to cause skin atrophy, telangiectasia and HPA axis 
suppression.  


 
 
 
 
 
 
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Clobetasol Propionate Cream 0.025% was tested in a single dose patch study in healthy volunteers 
in Germany (Bioskin 2009).  In that study, the formulation suppressed UV-induced erythema to 
a similar extent as Temovate E Emollient Cream (0.05% clobetasol propionate), suggesting a 
possible similar efficacy profile for treatment of inflammatory skin diseases.  The results of a 
second study of efficacy and safety in the treatment of plaque psoriasis and potential for HPA axis 
suppression also suggest that the safety and efficacy profile of the new formulation is similar to 
Temovate E Emollient Cream.  
 
The current clinical study is intended to assess the potential for HPA axis suppression of this 
new formulation of clobetasol propionate in subjects 6 – 16.9 years of age with moderate to 
severe plaque 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 plasma cortisol level of more than 18 µg/dL 30 minutes 
after the ACTH is injected.   
 
The potential for HPA axis suppression of DFD-06 has been studied in adults with moderate to 
severe psoriasis (Study DFD06-CD-007).  After 15 days of treatment, the proportion of subjects 
who had abnormal ACTH stimulation test results (HPA axis suppression) post-stimulation at 
Day 15 was numerically lower in the DFD-06 group than in the Temovate Cream group, 12.5% 
versus 36.4%, and the difference approached statistical significance (p = 0.086).  
 
This study is to determine the potential for HPA axis suppression and extent of systemic drug 
exposure in children and adolescents 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). 


 
 
 
 
 
 
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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 
of any therapies prohibited during the study.  Subjects must provide 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-06 to suppress the hypothalamic-pituitary-adrenal (HPA) 
axis, when applied twice daily for 15 days, in subjects 6 to 16.9 years of age with moderate 
to severe plaque psoriasis under maximal use conditions with the final-to-be-marketed 
formulation.  
• To assess the plasma concentrations of clobetasol propionate after multiple doses of DFD-06 
under maximal use condition with the final-to-be-marketed formulation.   
 
4 
STUDY DESIGN 
This is a 15-day, single arm, multicenter, multi-dose, open-label, two stage, sequential study. In 
the first stage subjects who are at least 12 years of age and not more than 16.9 years (16 years 
and 11 months) of age with moderate to severe plaque psoriasis will be treated with DFD-06 (at 
least 20 completed subjects). In the second stage  subjects who are at least 6 years of age and 
not more than 11.9 years (11 years and 11 months) of age with moderate to severe plaque 
psoriasis will be treated with DFD-06 (at least 20 completed subjects). An attempt will be made 
to enroll subjects throughout the age range of each cohort including the lower age range.   
 
DFD-06 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% BSA treated to achieve 
maximal use exposure. 
 


 
 
 
 
 
 
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Subject visits will take place at Screening, Baseline (Day 1), Day 8, Day 15 and Day 43 (if 
needed to confirm recovery).  Clinical determinations of disease severity will be conducted 
using the Investigator Global Assessment (IGA) for overall severity at Screening, Baseline (Day 
1), Day 8, and Day 15.  
 
Subjects will be tested for HPA axis function using the ACTH stimulation test (i.e., a 
cosyntropin IV or IM injection) at the Screening Visit (at least 14 days and no more than 35 
days prior to Baseline) and at Day 15. If HPA axis is suppressed at Day 15 Visit, another test 
will be administered at minimum 28 days after Visit 4 (at approximately Day 43) 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 ACTH test should 
not be performed sooner than 28 days since the previous ACTH test. 
 
At the time of the screening ACTH stimulation test, a PK blood sample will be taken to obtain a 
baseline value (PK screening sample). On Day 15, 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 – 
Day 15). 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 striae, hypopigmentation, fissuring, folliculitis, 
atrophy, telangiectasia, itching and burning/stinging) will be performed at Visit 2, Visit 3, and 
Visit 4. Other safety assessments include vital signs (blood pressure, pulse), urine pregnancy 
tests (only for females of child bearing potential), and collection of adverse event data.   
 
Total blood sample volume taken at the Screening Visit will be approximately 14 mL and at the 
End of Treatment Visit approximately 26 mL.  
 
5 
SELECTION OF STUDY POPULATION 
5.1 Number of Subjects 
A total of approximately 50 subjects will be enrolled to get at least 40 completed subjects, at 
approximately 15 sites in the United States. Of the 50 subjects enrolled, 25 subjects in the age 
group of 12 to 16.9 years will be enrolled in the first stage and 25 subjects in the age group of 6 
to 11.9 years will be enrolled in the second stage.    
 
5.2 
Inclusion Criteria 
1. Subject and the parent or legal guardian understand the study procedures and agree to 
participate by giving assent and written informed consent, respectively. Subject’s parent or 
legal guardian must be willing to authorize use and disclosure of protected health 
information collected for the study. 
2. Subjects must be at least 6 years and not more than 16.9 years of age, with body weight 
greater than or equal to 45 pounds at Screening. 
3. Subjects must present with a clinical diagnosis of stable (at least 3 months) plaque 
psoriasis. 


 
 
 
 
 
 
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4. Subjects with psoriasis involving ≥10% BSA, not including the face, scalp, groin, axillae 
and other intertriginous areas at the Baseline Visit.   
5. Subjects must have an IGA grade of at least 3 (moderate) at the Baseline Visit. 
6. All women of childbearing potential must complete a urine pregnancy test (test must 
have a sensitivity of at least 25mIU/ml for human chorionic gonadotropin) at the Baseline 
Visit (Visit 2) and the test result must be negative to be eligible for enrollment.  
 
A female is considered of childbearing potential unless she is: 
a. pre-menarche (girls 10 and older should have UPT regardless of menarche); 
b. without a uterus and/or both ovaries; or has been surgically sterile for at least 6 
months prior to study product administration 
 
7. 
Female subjects of childbearing potential must agree to use contraception during the 
study which can include abstinence with an adequate secondary option should the 
subject become sexually active.   
 
 
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. 
Exception:  Sexually inactive female subjects of childbearing potential are not required to 
practice a reliable method of contraception and may be enrolled at the investigator’s 
discretion provided that they are counseled to remain sexually inactive for the duration of 
the study and understand the possible risks involved in getting pregnant during the study. 
An abstinent female must agree that if she becomes sexually active during the study she 
will use an acceptable form of contraception 
8. Subjects must be in good general health as supported by the medical history, screening 
evaluations and the assessment(s) of the subject at Screening and Baseline with no 
clinically significant abnormalities that would preclude their participation in the study in 
the opinion of the investigator.  
 
9. Subjects whose results from the screening ACTH stimulation test, performed at least 
14 days and no more than 35 days prior to Baseline, which is considered normal 
defined as; 1) a normal pre-stimulation cortisol level and 2) a cortisol level >18 ug/dL 
at 30 minutes post stimulation  
5.3 
Exclusion Criteria 
1. Subject has a current diagnosis of unstable forms of psoriasis including guttate, 
erythrodermic, exfoliative or pustular psoriasis. 
2. Subject has a history of organ transplant requiring immunosuppression, HIV, or other 
immunocompromised state. 


 
 
 
 
 
 
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3. Subject has received treatment for any type of cancer within 5 years of the Baseline Visit 
except skin cancer and cervical cancer (in situ) are allowed if at least 1 year before the 
Baseline Visit. 
4. Subject has a history or presence of intracranial hypertension. 
5. Subject has had prolonged exposure to natural or artificial sources of ultraviolet 
radiation within 30 days prior to the initiation of treatment or is intending to have such 
exposure during the study that is thought by the investigator to likely modify the 
subject's disease. 
6. 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), or 4) topical or 
systemic retinoid treatment. 
7. 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. 
8. Use within 30 days prior to the Screening Visit of any product containing 
corticosteroids. Inhaled, intraocular, intranasal, etc. steroids are not allowed. 
9. Subjects with known hypersensitivity to clobetasol propionate, any component of DFD-
06. 
10. Subjects who have an abnormal sleep schedule or work at night. 
11. Subject is currently enrolled in an investigational drug or device study. 
12. Subject has used an investigational drug or investigational device treatment within 30 
days prior to Visit 1 (Screening).  
13. Subjects unable to comply with study requirements.  
14. Female subjects who are pregnant (or planning to become pregnant) or breast-feeding. 
15. Subjects with a known history of acute adrenal crisis, Addison’s disease or decreased 
adrenal output, low pituitary function or pituitary tumors. 
16. Subjects who have a history of an adverse reaction to cosyntropin injection or similar 
test reagents. 
17. 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).   
 
 


 
 
 
 
 
 
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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). 
NA 
60 days 
Systemic anti-inflammatory agents 
(mycophenolate mofetil, sulfasalazine, 6-
thioguanine) 
PUVA therapy 
UVB therapy 
Topical antipsoriatic drugs (salicylic acid, 
anthralin, coal tar, calcipotriene) 
NA 
30 days 
Any product containing corticosteroids 
30 days 
Not Allowed 
between Visits 1 & 2 
 
6 SUBJECT TREATMENT 
6.1 
Investigational Products 
6.1.1 Description 
The investigational product is: 
 
DFD-06 (Clobetasol Propionate Cream, 0.025%) will be provided by Promius Pharma, LLC, 
Princeton, NJ 08540.  
 
Initially, 12 tubes (DFD-06) will be sent to each site.  Additional tubes will be sent as needed.   
 
6.1.2 Labels and Packing 
Tubes will be packed one to a box. Labels on the tubes will be in English and Spanish and 
include product name, protocol number, a unique tube number, investigational use warning, 
storage conditions, brief instructions for use, and sponsor name and address.  Subjects will be 
asked to return the tubes in the box. 
 


 
 
 
 
 
 
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Tube Label - Provided in English and Spanish Text  
DFD-06  
Protocol: DFD-06-CD-011        Tube ID: XXXX         
Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-
30°C (59°-86°F). For Topical Use Only. Apply a thin layer to affected skin areas 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 
 
Labels on the box will be in English and Spanish and include product name, protocol number, a 
unique tube 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 tube number.  The tear-off panel is to be affixed to the source document 
(drug dispensing record).  
 
Box Label - Provided in English and Spanish Text 
DFD-06  
Protocol: DFD-06-CD-011        Tube ID: XXXX       
Subject No.:                 Subject Initials:  ________       
 
Contents: One (1) 60g tube 
 
Store at controlled room temperature 20°-25°C (68°-77°F); excursions 
permitted to 15°-30°C (59°-86°F). For Topical Use Only. Apply a thin layer to 
affected skin areas 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-06  
Protocol: DFD-06-CD-011 
Tube ID: XXXX 
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 tubes that are not returned to the clinic 
must be documented on the log. 
 


 
 
 
 
 
 
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6.1.4 Dispensing and Return  
One or two tubes of study product will be dispensed to subjects at the Baseline Visit (Visit 2) by 
study staff. The weight of the tube(s) should be recorded before dispensing. Additional tubes 
will be dispensed as needed. Partially filled tubes can be re-dispensed back to the subject. 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.   
 
Dispensing and return of study product must be documented on the Investigational Product Site 
Dispensing and Return Log. 
 
Subjects must return the used tubes even if empty throughout the trial.  At the end of the trial, all 
used and unused tubes must be returned to the clinic for eventual destruction by the sponsor or 
designee. Any dispensed tubes 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 the help, if needed, of their legal 
guardian, twice daily with approximately 12 hours between applications for 15 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 5g per day (½ 
teaspoon of cream 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 applied 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. The number of missed 
applications should also be recorded in the CRF. By definition, there are no missed applications 
after the last date of treatment. 
 
The first and last application of study product will be applied by the subjects or their legal 
guardian at the site under supervision.  At Visit 4 the tube 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 for the study product 
(Appendix 2) 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 


 
 
 
 
 
 
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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 Sponsor Consultation Form. A Sponsor Consultation Form is not needed 
for 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, tubes 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 
All subjects will be treated with DFD-06.   
 
The investigator shall ensure that the study product is 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.  
 
New medications or the change in a dose of a current medication, required for another medical 
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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 (e.g., methotrexate, cyclosporine, hydroxyurea) 
• PUVA therapy 
• UVB therapy 
• topical antipsoriatic drugs (e.g., salicylic acid, anthralin, coal tar, calcipotriene) 
• topical corticosteroids 
• immunosuppressive drugs (e.g., tacrolimus, pimecrolimus) 
• topical retinoids (e.g., tazarotene, tretinoin) 
• systemic anti-inflammatory drugs (e.g., mycophenolate mofetil, sulfasalazine, 6-
thioguanine) 
• biologics (e.g., infliximab, adalimumab, etanercept, ustekinumab, secukinumab or alefacept)   
• oral retinoids (e.g., 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 enrollment, 
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 
 
If HPA axis suppression test is abnormal at the Day 15 Visit, subjects should be advised to 
avoid products containing corticosteroids until recovery is determined. Refer to Washout Table 
in Section 5, Table 1. 
 


 
 
 
 
 
 
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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 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 35 
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 form, and possibly performing some study related procedures but was not enrolled. 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, height 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 
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). 


 
 
 
 
 
 
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Table 2: Investigator’s Global Assessment (IGA) of Disease Severity 
Score  Grade  
Definition  
0 
Clear 
No signs of psoriasis 
Post-inflammatory hyperpigmentation may be present  
1 
 Almost 
clear 
No thickening to minimal plaque elevation 
Normal to slight pink coloration/faint erythema 
Focal to minimal scaling 
2 
Mild 
Slight elevation/thickening 
Pink to light red coloration 
Predominantly fine scaling partially or mostly covering lesions  
3 
Moderate 
Clearly distinguishable/distinct thickening 
Definite red coloration 
Coarse scaling covering most plaques  
4 
Severe 
Marked thickening with hard/sharp edges  
Bright to deep dark red coloration 
Thick/coarse scaling covering almost all or all lesions 
 
7.5 Safety Assessments  
7.5.1 ACTH Stimulation Test 
Subjects will be tested for HPA axis function using the ACTH stimulation test (cosyntropin IV 
or IM injection) at a Screening Visit and at Day 15 Visit.  If HPA axis is suppressed at Day 15, 
another test will be administered at least 28 days later (at approximately Day 43) 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. Follow-up ACTH tests 
should not be sooner than 28 days since the previous ACTH test. 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 µg/dL at 30 minutes post stimulation). The Day 15 test should 
be performed within 1 hour of the time when the Screening Visit test was performed. 
 
For female subjects of childbearing potential, 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. 
 
Procedure 
The entire test must be completed between approximately 7:00 am and 9:30 am, including pre- 
and post-stimulation blood samples. A pre-dose, control blood sample of 4 to 5 mL will be 
collected in a serum separator tube. 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 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 


 
 
 
 
 
 
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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.  
Sample Analysis 
The determination of the serum cortisol levels will be estimated by a validated method.  A 
normal response is defined as a serum cortisol level of more than 18 µg/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 (Day 15) Visit, the investigator will assess 
local cutaneous safety by examining treated areas for striae, hypopigmentation, fissuring, 
folliculitis, 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, 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 sign, the presence of the sign or symptom must be recorded as “Yes.”  
  
For female subjects of childbearing potential, 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 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 PK blood sample will be taken at the time of the screening ACTH stimulation test to obtain a 
baseline value. 
On Day 15, 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 – Day 15). 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 4 ml) will be collected in NaF/Na2EDTA 
blood collection tubes. The collected blood samples will be handled according to the laboratory 
manual. Approximately a total of 20 mL of blood per subject will be drawn for drug assays for 
clobetasol propionate during the study (4 mL at the Screening Visit and 16 mL at the End of 
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Thus the total volume of blood drawn from each subject during this study will be 40 mL (20 mL 
for ACTH tests and 20 mL for drug assays). This volume of blood draw is considered safe for 
children ≥6 years of age. 
 
Sample Processing 
Within approximately 1 hour of collection, plasma should be separated and processed.  Blood 
samples for plasma processing, storage and shipment will be handled according to the 
laboratory manual.  
 
Analytical Procedure 
Plasma clobetasol propionate will be measured by a validated, LC/MS/MS analytical method 
with a limit of quantitation of at least 10 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. Study sample analysis will be carried out 
as per approved bio-analytical study plan. 
A validation report describing the method accuracy, precision, linearity, and robustness must be 
available for the analytical procedure. Stability of analyte 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 
recorded in the subject’s chart and Sponsor Consultation form. 
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 
including ACTH evaluation. 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 
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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 page 7. 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). A 
supplemental Visit 5 (Day 43) 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 at Visit 2.  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 Visit 3, +3 days for 4).  If a subject misses a visit, they and their legal guardians, 
should be encouraged to attend the next visit scheduled from the Baseline 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 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.  
3. Collect demographic data – date of birth, sex, race, height, 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). 


 
 
 
 
 
 
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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 female subjects of childbearing potential (record on 
source only).  Test must be negative to proceed. 
11. If tentatively eligible, conduct ACTH stimulation test.  This test should be conducted at least 
14 days and no more than 35 days prior to Visit 2 (Baseline). The entire test, including pre- 
and post-stimulation blood samples (total 8-10 mL in serum separator tubes), should be 
completed between approximately 7:00 am and 9:30 am. Schedule for another day if needed. 
Also a screening PK blood sample (approximately 4 ml) for plasma clobetasol propionate 
will be drawn in NaF/Na2EDTA blood collection tubes to obtain a baseline value.   
Note: Subjects with an abnormal ACTH stimulation test (cortisol level < 18 µg/dL at 30 
minutes post stimulation) should be referred to their primary care physician, as needed.  
12. 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.).   
 
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 
medication dosing caused by a protocol procedure performed at the Screening Visit should 
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 of childbearing potential.  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 striae, hypopigmentation, fissuring, folliculitis, 
atrophy, and telangiectasia in areas to be treated. The investigator should also ask the 
subject if any burning/stinging, 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. Dispense study product to the subject/legal guardian. The tear-off panel from the box is to 
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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. Weigh 
tube before and after application.  
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 striae, hypopigmentation, fissuring, folliculitis, 
atrophy, and telangiectasia in the treated areas. The investigator should also ask the 
subject and legal guardian if any burning/stinging, 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). 
4. Conduct urine pregnancy test for female subjects of childbearing potential.  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 tubes. Re-dispense partially 
filled tubes.  
9. Schedule next visit. Remind the subject to come to the next visit well hydrated 
10. Complete CRF.  
 


 
 
 
 
 
 
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7.9.4 Visit 4 - Day 15 (End of Treatment – 7:00am to 9:30 am) (+3 days) 
1. Evaluate treatment and protocol compliance and record any deviations.  This includes a 
review of the diary card for missed applications. 
2. Collect diary 
3. Conduct clinical assessments: 
a. IGA (Table 2) 
b. Local cutaneous safety evaluation for striae, hypopigmentation, fissuring, folliculitis, 
atrophy and telangiectasia in the treated areas. The investigator should also ask the 
subject and legal guardian if any burning/stinging, or itching has occurred in the treated 
areas since the last visit. 
4. Collect vital signs (blood pressure, pulse). 
5. Collect adverse event data.  This includes a review of the diary card for potential AEs.   
6. Update concomitant medications data. 
7. Conduct a urine pregnancy test for female subjects of childbearing potential.   
8. Draw pre-treatment (0 hour) PK blood sample no more than 60 minutes before planned 
study product application and process sample. Blood (approximately 4 ml) will be collected 
in NaF/Na2EDTA blood collection tubes. 
9. Collect all study product tubes and record weight.   
10. Supervise last application of study product by subject. Record weight of tube after 
application.  
11. Draw post-treatment PK blood samples at 1, 3 and 6 hours after study product application.  
12. Conduct ACTH stimulation test after the last application. The entire test, including pre- and 
post-stimulation blood samples, should be completed within one hour of when the baseline 
visit and between approximately 7:00 am and 9:30 am.  
13. Complete CRF.  
 
7.9.5 Visit 5 (Day 43 if required) – 7:00 am – 9:30 am (+ 2 days) 
If the ACTH stimulation test is abnormal at the Day 15 Visit, another test will be administered 
approximately 28 days later (at approximately Day 43) 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).  
1. Collect vital signs (blood pressure, pulse). 
2. Perform urine pregnancy test for female subjects of childbearing potential.  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 
samples, should be completed between approximately 7:00 am and 9:30 am. 
4. Collect adverse event data.   


 
 
 
 
 
 
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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.  
In clinical trials, adverse events associated with the use of clobetasol propionate cream included 
burning and stinging in 1% of treated patients. Less frequent reactions were itch, skin atrophy, 
and cracking and fissuring of skin.  
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 atrophy or 
telangiectasia and report as an adverse event if severity is worse than baseline. The investigator 
will also ask the subject if any burning/stinging, 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.  An adverse event should be recorded if the severity is worse than Baseline. 
 
Abnormal screening test results should not be reported as adverse events. Clinically significant 
abnormal vital signs (systolic BP > 140 and < 90; diastolic BP > 100 and < 50; and pulse < 
50 and > 100 bpm) reported during study product treatment should also be reported as 
adverse events. 
 
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). 
Anticipated day-to-day fluctuations of pre-existing conditions should not be reported as adverse 
events.  Unexpected worsening of pre-existing conditions should be reported as adverse events. 
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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 
 
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 
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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: 
 
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 


 
 
 
 
 
 
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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:  SAEreporting@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 
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 
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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 eCRFs) 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, and date of visit.   
 
9.4 
Case Report Forms 
The sites will enter data onto electronic or paper case report forms (CRFs) in a timely manner.  
All data requested on the CRF must be recorded on source documentation.  The CRF cannot be 
the source document for any data.  Detailed instructions and training for completing the CRF 
will be provided to the sites. 
 


 
 
 
 
 
 
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Study subjects are not to be identified by name on eCRFs, but rather by coded identifiers 
(subject number and initials). The investigator or sub-investigator must review all eCRF pages 
for each subject and approve the group of eCRFs pages for each subject. 
 
9.5 
Data Capture 
Study data will be entered into and maintained in a 21 CFR Part 11 compliant database. If 
electronic data capture (EDC is used, a validated 21CFR Part 11 compliant (EDC) software will 
be used to collect data.  
 
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. 
 
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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 enrolled.  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 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 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 
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11.5.1 Extent of Exposure 
The extent of exposure to study product will be summarized as the total number of applications 
and the total amount of study product used based on tube weights. The amount of the last dose 
will be provided based on tube weight before and after treatment. 
 
11.5.2 Local Safety Evaluation 
Striae, hypopigmentation, fissuring, folliculitis, atrophy, telangiectasia, itching and burning 
/stinging will be summarized by 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 µg/dL at 30 minutes post stimulation) will be 
summarized. Additionally, the serum cortisol levels found pre-stimulation and post-stimulation 
will be summarized for the screening ACTH test and the Day 15 ACTH test. The sample size N, 
mean, median, standard deviation, minimum, and maximum 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 clobetasol propionate will be summarized (and will include 95% 
confidence intervals for the mean) for the PK Screening sample and for 0 hour (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 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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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 at each 
evaluation.  
 
11.5.7 Safety Laboratory Values 
Urine pregnancy tests will be performed at all visits for female subjects of childbearing potential 
and will be presented in subject data listings. 
  
11.5.8 Subset Analyses 
No subset analyses are planned. 
 
 
 


 
 
 
 
 
 
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REFERENCES 
Finlay AY. Current severe psoriasis and the rule of tens. Br J Dermatol. 2005;152:861-
867. 
 
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. 
 
 
 


 
 
 
 
 
 
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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 


 
 
 
 
 
 
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affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions 
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.  


 
 
 
 
 
 
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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 
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 


 
 
 
 
 
 
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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 
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 / Subject Diary (2 pages) 
 
 


 
 
 
 
 
 
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