Clinical trial NCT03529955
Conditions: Dermatomyositis, Adult Type
Keywords: dermatomyositis apremilast recalcitrant cutaneous disease
Sponsor: Tulane University
Start date: 2018-06-12; Completion date: 2021-04-07
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
With limited treatment options available for dermatomyositis, the investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with refractory cutaneous dermatomyositis.

The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with refractory cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months.

Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, creatine kinase, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as 4 points increase in the cutaneous dermatomyositis disease area and severity index (CDASI) score, worsening of muscle disease by manual muscle testing (MMT-8) score and 5 points increase in dermatomyositis life quality index (DLQI).

5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.

Detailed description:
1. Sponsor Name (PI): Carole Bitar, MD
2. Sub-PI: Erin Boh, MD, PhD; Brittany Stumpf, MD; Collaborator: Nakhle Saba, MD
3. \# of Participants Sites: 1, Tulane University 4: Participant Countries: United States

II. PRODUCT INFORMATION

1. Study Title: A phase 2, open label single arm study for evaluating safety \& efficacy of apremilast in the treatment of cutaneous disease in patients with recalcitrant dermatomyositis.
2. Clinical Phase: Phase II clinical trial
3. Primary Celgene Product: Apremilast

III. CONCEPT DESIGN AND RATIONAL

1. Therapeutic Area: Immunology
2. Specialty: Connective tissue disease
3. Disease State: Dermatomyositis

4-If other specify: None

5\. Study Rationale: Dermatomyositis is an inflammatory disease that predominantly involves the skin with or without proximal muscle weakness. First line treatment for dermatomyositis is systemic steroids however due to long-term side effects, patients are usually treated with a steroid sparing agent. There is no known consensus on treatment guidelines for dermatomyositis and many anti- inflammatory medications have been successfully used. Tulane University is a referral center for recalcitrant dermatomyositis cases.The investigators present the case of a 57 y.o female patient with multidrug recalcitrant dermatomyositis showing complete remission of her skin disease with apremilast and improvement of her muscle disease. This patient was diagnosed with dermatomyositis. Over a 6-year period, she was treated with adequate trials of multiple immunosuppressive agents, including hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, soriatane, Intravenous immunoglobulin (IVIG), tacrolimus, chlorambucil, infliximab and rituximab. For the last four years, physicians were unable to lower corticosteroids below 40 mg per day. Her disease continued to flare despite these therapies. Chronic steroid use resulted in insulin dependent diabetes mellitus as well as other steroids associated side effects. While on stable doses of mycophenolate mofetil, prednisone and rituximab, the patient developed arthritis and was started on apremilast 30 mg twice a day. Two months into her treatment she noticed significant improvement of her skin disease and then nearly complete clearance of the skin. Her muscle weakness lagged behind and she noticed improvement after 9 months of being on apremilast with normalization of her aldolase and CK. The patient was able to wean off all immunosuppressive agents and prednisone. She was in remission for over 2 years and off all medications. She experienced a mild flare of skin disease recently and she resumed apremilast only and cleared immediately and continues on apremilast as a monotherapy. Patient experienced mild nausea and diarrhea with apremilast that improved four weeks into the treatment. She was able to discontinue insulin, lose weight and she has continued to be clear of both skin and muscle symptoms for over 1.5 years.

This case was accepted as a poster presentation at the 2018 Annual Meeting of the American Academy of Dermatology "Poster #: 6672 - Apremilast: a Potential Treatment for Dermatomyositis." Following this successful outcome, the investigators initiated apremilast in 3 other patients with recalcitrant dermatomyositis. Two patients had recalcitrant cutaneous disease and responded to add on therapy of apremilast in 2 months with significant improvement of their skin disease. The third patient had refractory dermatomyositis to several steroid-sparing agents and with severe muscle disease was started on apremilast for arthritis. She experienced significant improvement of her muscle weakness together with decrease in her muscle enzyme creatine kinase.

These very exciting findings triggered the idea of studying apremilast as an adjunct treatment for recalcitrant cutaneous disease in dermatomyositis patients. This is a novel idea; apremilast was never studied for dermatomyositis. Apremilast may have more advantages in dermatomyositis compared to other immunosuppressive treatments. Dermatomyositis patients may have lung involvement, and apremilast is an agent that doesn't have lung side effects in contrast to methotrexate for example which is one of the main steroid sparing agents used for dermatomyositis.

The pathogenesis of dermatomyositis is multifactorial with environmental, genetic and immune factors contribution.T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental role in dermatomyositis.There is increase in proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL) 1, IL 6, and interferon (INF) α,γ shifting the immune balance to a Th1 response.Th1 immune response was also involved in the pathogenesis of interstitial pneumonia in the setting of dermatomyositis.IL4 released by lymphocytes infiltrating skin and muscles in dermatomyositis patients contributes to increase in Th2 response in conjunction with Th1 response.

Apremilast is a PD4-E inhibitor currently used for psoriasis and psoriatic arthritis.However, its usage on patients with dermatomyositis has not been investigated.

By inhibiting PDE-4 apremilast increases the level of cyclic adenosine monophosphate (c-AMP), leading to decreased expression of proinflammatory cytokines including TNF-α and INF-γ thus inhibiting Th1 response. Apremilast can also block Th2 response by interfering with the level of IL6 secreted by type2 macrophages.While the mechanism of action of apremilast in dermatomyositis is unknown, we suggest that apremilast can be a potential treatment option for dermatomyositis through interfering with Th1 and Th2 response.

Apremilast is a well-tolerated oral medicine with transient gastrointestinal side effects. Apremilast offers an additional treatment option for those patients with recalcitrant dermatomyositis, unresponsive to more conventional therapy.

6\. Treatment and Dosing: Investigators will enroll patients seen at our facilities with a known diagnosis of dermatomyositis who are still experiencing cutaneous disease after a trial of systemic steroids and one steroid-sparing agent. Investigators will add apremilast to their treatment regimen according to the approved dosage for psoriasis and psoriatic arthritis: 10 mg orally one time on day 1, 10 mg orally twice daily on day 2, 10 mg orally in AM and 20 mg orally in PM on day 3, 20 mg orally twice daily on day 4, 20 mg orally in AM and 30 mg orally in PM on day 5, then 30 mg orally twice daily thereafter.

7\. Brief Study Synopsis: With limited treatment options available for dermatomyositis, investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with recalcitrant cutaneous dermatomyositis.

The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with recalcitrant cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months.

Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, CK, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as a 4 points increase in CDASI score, worsening of muscle disease by MMT-8 score and 5 points increase in DLQI.

5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.

8\. Sampling and correlative analysis

Although, the proposed mechanism of action of apremilast is though PDE-4 inhibition resulting in c-AMP upregulation, the exact biological process that leads to dermatological response in dermatomyositis remains ill-defined.Investigators propose to perform gene expression profiling (GEP) using RNA sequencing on skin biopsies collected before and after treatment with apremilast. In addition, we plan to confirm our GEP findings at the protein level using immunohistochemical (IHC) stains.

A. Tissue sampling and preparation

1. Tissue collection 5 mm punch biopsy from dermatomyositis skin lesions will be performed at baseline and another 5 mm punch biopsy will be performed at the 3-month time point. Each biopsy will be vertically split in two pieces and snap frozen on dry ice then it will be stored at -80C for further analysis with RNA sequencing and IHC stains.
2. RNA extraction At the end of all timeline collections, each skin biopsy will be mechanically broken down followed by mRNA extraction using the RNeasy extraction Kit from QIAGENzz. mRNA will then be stored at -80°C for subsequent RNA sequencing as detailed below.

B. Correlative Analysis

Determining the mechanism of action of apremilast in dermatomyositis.

1. Gene expression profiling RNA extracted form skin biopsies collected before and after in vivo treatment with apremilast (as detailed above) will be subjected to RNA sequencing. Illumina strand-specific TruSeq libraries will be prepared from the polyA selected RNA and subjected to 1x100 base sequencing on an Illumina HiSeq2500 machine. The number of samples proposed here (10 samples before treatment and 10 samples after treatment) is expected to yield sufficient statistical power for this approach; smaller numbers have been used in similar approaches to investigate drugs' mechanism of action (usually three samples).

   RNA-seq analysis will be performed in conjunction with the Tulane Cancer Crusaders Next Generation Sequence Analysis Core (Tulane Cancer Center - https://tulane.edu/som/cancer/research/core-facilities/cancer-crusaders/). Gene and isoform expression will be determined using RSEM and differential expression will be analyzed using EB-seq. Genes that are identified as differentially expressed between the two groups with a False Discovery Rate (FDR) of \< 0.05 will be subjected to analysis by Ingenuity (IPA, Redwood City, CA). This analysis will group the identified genes into specific pathways, cell types, or disease process. A similar approach will be conducted using Gene Set Enrichment Analysis (GSEA). These experiments and GEP analysis will be performed in conjunction with our collaborator's (Dr. Nakhle Saba) lab, given his extensive experience in this field.
2. Protein analysis Information identified by Ingenuity or GSEA (signaling pathways, regulatory molecules, etc…) will be verified using IHC staining on select samples.

Arms: arm 1: Patients with dermatomyositis and refractory skin disease on steroids and one steroid-sparing agent.
Interventions: intervention 1: Apremilast 30mg
Intervention descriptions: intervention 1: Patients with refractory cutaneous dermatomyositis will be started on apremilast 30 mg twice a day in addition to a stable dose of their treatment regimen (including steroids and steroid sparing agents).

Protocol documents:
Prot_SAP_001.pdf: 
 
Version: 07/18/2018 
1
 
 
 
 
 
 
A Phase 2, Open Label Single Arm Study for Evaluating 
Safety & Efficacy of Apremilast in the Treatment of 
Cutaneous Disease in Patients with Recalcitrant 
Dermatomyositis. 
 
 
NCT Number: NCT 03529955 
 
Protocol Date: 07/18/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Version: 07/18/2018 
2
 
 
I. PRINCIPAL INVESTIGATOR AND RESEARCH SITE 
 
1. Sponsor Name (PI): Carole Bitar, MD 
2. Sub-PI: Erin Boh, MD, PhD; Brittany Stumpf, MD; Katherine Brag, MD;  
Collaborator: Nakhle Saba, MD 
3. # of Participants Sites: 1, Tulane University 
4: Participant Countries: United States 
 
II. PRODUCT INFORMATION 
 
1. Study Title: A phase 2, open label single arm study for evaluating safety & efficacy of apremilast in 
the treatment of cutaneous disease in patients with recalcitrant dermatomyositis. 
 
2. Clinical Phase: Phase II clinical trial 
 
3. Primary Celgene Product: Apremilast 
 
4. Secondary Celgene Product: None 
 
5. Tertiary Celgene Product: None 
 
6. Non- Celgene Products: None 
 
 
III. CONCEPT DESIGN AND RATIONAL 
 
1. Therapeutic Area: Immunology 
 
2. Specialty: Connective tissue disease 
 
3. Disease State: Dermatomyositis 
 
4. if Other Specify: None 
 
5. Study Rationale: Dermatomyositis is an inflammatory disease that predominantly involves the skin 
with or without proximal muscle weakness. First line treatment for dermatomyositis is systemic 
steroids however due to long-term side effects, patients are usually treated with a steroid sparing 
agent. There is no known consensus on treatment guidelines for dermatomyositis and many anti- 
inflammatory medications have been successfully used. Tulane University is a referral center for 
recalcitrant dermatomyositis cases. We present the case of a 57 y.o female patient with multidrug 
recalcitrant dermatomyositis showing complete remission of her skin disease with apremilast and 
improvement of her muscle disease. This patient was diagnosed with dermatomyositis. Over a 6-year 
period, she was treated with adequate trials of multiple immunosuppressive agents, including 
hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, soriatane, Intravenous 
immunoglobulin (IVIG), tacrolimus, chlorambucil, infliximab and rituximab. For the last four years, we 
were unable to lower corticosteroids below 40 mg per day. Her disease continued to flare despite 
these therapies. Chronic steroid use resulted in insulin dependent diabetes mellitus as well as other 
steroids associated side effects. While on stable doses of mycophenolate mofetil, prednisone and 


 
Version: 07/18/2018 
3
rituximab, the patient developed arthritis and was started on apremilast 30 mg twice a day. Two 
months into her treatment she noticed significant improvement of her skin disease and then nearly 
complete clearance of the skin. Her muscle weakness lagged behind and she noticed improvement 
after 9 months of being on apremilast with normalization of her aldolase and CK. The patient was 
able to wean off all immunosuppressive agents and prednisone. She was in remission for over 2 
years and off all medications. She experienced a mild flare of skin disease recently and she resumed 
apremilast only and cleared immediately and continues on apremilast as a monotherapy. Patient 
experienced mild nausea and diarrhea with apremilast that improved four weeks into the treatment. 
She was able to discontinue insulin, lose weight and she has continued to be clear of both skin and 
muscle symptoms for over 1.5 years.  
This case will be presented as a poster presentation at the 2018 Annual Meeting of the 
American Academy of Dermatology “Poster #: 6672 - Apremilast: a Potential Treatment for 
Dermatomyositis.” 
Following our successful outcome, we initiated apremilast in 3 other patients with recalcitrant 
dermatomyositis. Two of them had recalcitrant cutaneous disease and responded to add on therapy 
of apremilast in 2 months with significant improvement of their skin disease. The third patient had 
refractory dermatomyositis to several steroid-sparing agents and with severe muscle disease was 
started on apremilast for arthritis. She experienced significant improvement of her muscle weakness 
together with decrease in her muscle enzyme creatine kinase.  
These very exciting findings triggered the idea of studying apremilast as an adjunct treatment for 
recalcitrant cutaneous disease in dermatomyositis patients. This is a novel idea; apremilast was 
never studied for dermatomyositis. Apremilast may have more advantages in dermatomyositis 
compared to other immunosuppressive treatments. Dermatomyositis patients may have lung 
involvement, and apremilast is an agent that doesn't have lung side effects in contrast to 
methotrexate for example which is one of the main steroid sparing agents used for dermatomyositis. 
The pathogenesis of dermatomyositis is multifactorial with environmental, genetic and immune factors 
contribution.[1] T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental role in 
dermatomyositis.[2] There is increase in proinflammatory cytokines including tumor necrosis factor 
alpha (TNF-α), interleukin (IL) 1, IL 6, and interferon (INF) α,γ shifting the immune balance to a Th1 
response.[1] Th1 immune response was also involved in the pathogenesis of interstitial pneumonia in 
the setting of dermatomyositis.[3] IL4 released by lymphocytes infiltrating skin and muscles in 
dermatomyositis patients contributes to increase in Th2 response in conjunction with Th1 response. [2] 
Apremilast is a PD4-E inhibitor currently used for psoriasis and psoriatic arthritis.[4] However, its 
usage on patients with dermatomyositis has not been investigated.  
By inhibiting PDE-4 apremilast increases the level of cyclic adenosine monophosphate (c-AMP), 
leading to decreased expression of proinflammatory cytokines including TNF-α and INF-γ thus 
inhibiting Th1 response.[5] Apremilast can also block Th2 response by interfering with the level of IL6 
secreted by type2 macrophages.[4] While the mechanism of action of apremilast in dermatomyositis is 
unknown, we suggest that apremilast can be a potential treatment option for dermatomyositis through 
interfering with Th1 and Th2 response.  
Apremilast is a well-tolerated oral medicine with transient gastrointestinal side effects.[4] Apremilast 
offers an additional treatment option for those patients with recalcitrant dermatomyositis, 
unresponsive to more conventional therapy. 
 
6. Treatment and Dosing: We will enroll patients seen at our facilities with a known diagnosis of 
dermatomyositis who are still experiencing cutaneous disease after a trial of steroid-sparing agent 
and/or systemic steroids. 
We will add apremilast to their treatment regimen according to the approved dosage for psoriasis and 
psoriatic arthritis: 10 mg orally one time on day 1, 10 mg orally twice daily on day 2, 10 mg orally in 


 
Version: 07/18/2018 
4
AM and 20 mg orally in PM on day 3, 20 mg orally twice daily on day 4, 20 mg orally in AM and 30 mg 
orally in PM on day 5, then 30 mg orally twice daily thereafter. 
 
7. Brief Study Synopsis: With limited treatment options available for dermatomyositis, we 
hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-
on treatment in patients with recalcitrant cutaneous dermatomyositis. 
The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to 
patients with recalcitrant cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 
months. Patients will also be evaluated for durability of their response for up to 6 months. 
Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, 
CMP, CK, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse 
events. Disease progression is defined as a 4 points increase in CDASI score, worsening of muscle 
disease by MMT-8 score and 5 points increase in DLQI. 
5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 
months of treatment for gene expression profiling and confirmatory immunohistochemical stains. 
 
8. Inclusion Criteria:  
 
• Must understand the risks and the benefits/purpose of the study and provide signed and dated 
informed consent. 
• Must be 18 years at time of signing the informed consent form. 
• Willing to participate in all required evaluations and procedures in the study including the ability 
to swallow pills without difficulty. 
• Patients must have a diagnosis of DM based upon the characteristic cutaneous findings 
proposed by Sontheimer[6] and/or a skin biopsy consistent with DM. 
• Patients must be candidate for systemic therapy for their DM skin disease defined by 
inadequate response to aggressive sun protection along with the use of potent topical 
corticosteroids and/or immunomodulators. 
• Patients with a diagnosis of dermatomyositis on steroid-sparing agent and/or systemic steroids 
(maximum dose of prednisone 1mg/Kg) and still having cutaneous disease activity of at least 5 
on the CDASI scale. 
• If on immunosuppressive treatments and/or steroids, patients must be on stable doses for at 
least 4 weeks (28 days).  
• Patients must undergo age appropriate cancer screening. 
• Females of childbearing potential (FCBP) must have a negative pregnancy test at screening 
(day 0 of the study and every month throughout the study). While on investigational product 
and for at least 28 days after taking the last dose of investigational product. 
 
• 9. Exclusion Criteria: 
 
• Increasing or changing dose of topical therapy within 14 days of study day 0 (including but not 
limited to topical corticosteroids, tacrolimus, pimecrolimus).  
• Increasing or changing systemic steroids dosing within 28 days of study day 0. 
• Increasing or changing dosing for concurrent therapy agents within 28 days or 5 half-lives of 
the biologic agent, whichever is longer, before study day 0: methotrexate, azathioprine, 
mycophenolate mofetil, hydroxychloroquine, dapsone, leflunomide, cyclosporine, biologic 
agents (anti-TNFs), IVIG, rituximab. 


 
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• History of any clinically significant (as determined by the investigators) cardiac, endocrinologic, 
pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major 
uncontrolled disease. 
• Any condition, including the presence of laboratory abnormalities, which places the patient at 
unacceptable risk if he/she were to participate in the study or confounds the ability to interpret 
data from the study. 
• Pregnant or breastfeeding. 
• Untreated Latent Mycobacterium tuberculosis infection or active tuberculosis infection as 
indicated by a positive Purified Protein Derivative (PPD) skin test or T-spot. 
• Any condition, including the presence of laboratory abnormalities that places the patient at 
unacceptable risk if he/she were to participate in the study or confounds the ability to interpret 
data from the study. 
• Patients with acute dermatomyositis onset and rapid progression of muscle disease or 
significant systemic involvement including pulmonary diseases associated with DM. 
• Prior major surgery or major life-threatening medical illness within 2 weeks. 
• Inflammatory bowel disease, malabsorption or any other gastrointestinal motility disorders that 
limit the absorption of the study drug. 
• Active hepatitis B or C infection with detectible viral nucleic acid in the blood or known Human 
Immunodeficiency Virus (HIV) positivity. 
• Prior history of suicide attempt at any time in the patient’s lifetime prior to screening or 
randomization, or major psychiatric illness requiring hospitalization within the last 3 years. 
• Active substance abuse or a history of substance abuse within 6 months prior to screening. 
• Use of any investigational drug within 4 weeks prior to randomization, or 
5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer). 
• Prior treatment with apremilast. 
• Any severe systemic illness requiring IV antibiotics within the two weeks prior to initiation of the 
study drug. 
• Malignancy or history of malignancy within the past four years, except for: 
o treated [ie, cured] basal cell or squamous cell in situ skin carcinomas;  
o treated [ie, cured] cervical intraepithelial neoplasia (CIN) or carcinoma in situ of cervix  
with no evidence of recurrence within the previous 4 years. 
 
10. Sampling and correlative analysis 
 
Although, the proposed mechanism of action of apremilast is though PDE-4 inhibition resulting in c-
AMP upregulation, the exact biological process that leads to dermatological response in 
dermatomyositis remains ill-defined. We propose to perform gene expression profiling (GEP) using 
RNA sequencing on skin biopsies collected before and after treatment with apremilast. In addition, we 
plan to confirm our GEP findings at the protein level using immunohistochemical (IHC) stains.  
 
A. Tissue sampling and preparation 
 
a. Tissue collection 
5 mm punch biopsy from dermatomyositis skin lesions will be performed at baseline and another 5 
mm punch biopsy will be performed at the 3-month time point. Each biopsy will be vertically split in 
two pieces and snap frozen on dry ice then it will be stored at -80C for further analysis with RNA 
sequencing and IHC stains.  


 
Version: 07/18/2018 
6
  
b. RNA extraction 
At the end of all timeline collections, each skin biopsy will be mechanically broken down followed 
by mRNA extraction using the RNeasy extraction Kit from QIAGENzz. mRNA will then be stored 
at -80°C for subsequent RNA sequencing as detailed below.  
 
B. Correlative Analysis 
 
Determining the mechanism of action of apremilast in dermatomyositis. 
 
a. Gene expression profiling 
RNA extracted form skin biopsies collected before and after in vivo treatment with apremilast (as 
detailed above) will be subjected to RNA sequencing. Illumina strand-specific TruSeq libraries will be 
prepared from the polyA selected RNA and subjected to 1x100 base sequencing on an Illumina 
HiSeq2500 machine. The number of samples proposed here (10 samples before treatment and 10 
samples after treatment) is expected to yield sufficient statistical power for this approach; smaller 
numbers have been used in similar approaches to investigate drugs’ mechanism of action (usually 
three samples).[7-9] 
RNA-seq analysis will be performed in conjunction with the Tulane Cancer Crusaders Next 
Generation Sequence Analysis Core (Tulane Cancer Center - 
https://tulane.edu/som/cancer/research/core-facilities/cancer-crusaders/). Gene and isoform 
expression will be determined using RSEM [10] and differential expression will be analyzed using EB-
seq.[11] Genes that are identified as differentially expressed between the two groups with a False 
Discovery Rate (FDR) of < 0.05 will be subjected to analysis by Ingenuity (IPA, Redwood City, CA).  
This analysis will group the identified genes into specific pathways, cell types, or disease process. A 
similar approach will be conducted using Gene Set Enrichment Analysis (GSEA). These experiments 
and GEP analysis will be performed in conjunction with our collaborator’s (Dr. Nakhle Saba) lab, 
given his extensive experience in this field.[12, 13]  
 
b. Protein analysis 
Information identified by Ingenuity or GSEA (signaling pathways, regulatory molecules, etc…) will be 
verified using IHC staining on select samples. 
 
 
IV. OBJECTIVES AND ENDPOINTS 
 
1.Primary Objective Description 
 
To determine the overall response rate (ORR) of apremilast in cutaneous disease of patients with 
recalcitrant dermatomyositis at 3 months. 
The ORR will be measured using the Cutaneous Dermatomyositis Activity and Severity Index 
(CDASI) at months 0, 1, and 3. 
CDASI is a validated tool to measure skin disease activity in dermatomyositis.[14] ORR includes partial 
and complete responses. Complete response is defined by a CDASI score of zero. Partial response 
is defined by a decrease of CDASI score of at least 4 points. Calculation is performed as the CDASI 
score at 1, and 3 month(s) minus the score at baseline.  
All investigators (PI and Sub-Is) will be trained on how to screen the patients per the CDASI score 
tool. 
Photograph of skin rash will be taken at months 0,1 and 3 and compared to baseline. 
 


 
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2. Secondary Objective(s) Description 
 
To determine the durability of responses for up to 6 months on apremilast for responders at 3 months. 
The durability of responses includes partial and complete response durability.  
The durability of response will be measured using the CDASI at 6 months minus CDASI at 3 months. 
Complete response durability is defined as zero or minus difference between CDASI score at 6 
months and CDASI score at 3 months. Partial response is defined as >4 points difference between 
CDASI score at 6 months and CDASI score at 3 months.  
 
We will assess the response of all patients at 6 months to identify possible delayed response. 
Complete response is defined by a CDASI score of zero at 6 months. Partial response is defined by a 
decrease of CDASI score of at least 4 points at 6 months compared to baseline. Calculation is 
performed as the CDASI score at 6 month(s) minus the score at baseline.  
 
Photograph of patient’s rash will be taken at 6 months and compared to 3 months and baseline. 
 
To determine the safety and toxicity of apremilast when administered at 30 mg twice daily in patients 
with dermatomyositis. The safety assessment will include the assessment of adverse events, serious 
adverse events, laboratory testing and physical examination. 
 
An additional secondary endpoint will be to determine if patients who experience remission of their 
disease can be maintained on apremilast as monotherapy. 
 
To determine the patient quality of life using the Dermatology Life Quality Index (DLQI)[15] at baseline, 
1, 3 and 6 months. 
 
Patient will be assessed 1 month after discontinuing apremilast (follow up visit) to assess change in 
response post discontinuation of apremilast. Patients will be examined and, CDASI, MMT-8 and DLQI 
will be performed. Photograph of patient’s rash will be taken. CBC, CMP, CK, aldolase and urine 
pregnancy test will be performed. 
 
3. Exploratory Objectives:  
We will measure muscle enzymes (creatine kinase (CK) and aldolase) at 0, 1, 3, and 6 month(s) of 
apremilast in patients with muscle disease.  
We will assess disease activity using the manual muscle testing-8 (MMT-8) in patients with muscle 
disease.[16] 
Skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months 
of treatment for gene expression profiling and IHC stain. IHC will be performed on the protein product 
of the genes showing the largest fold change from the RNA-sequencing. 
All investigators (PI and Sub-Is) will be trained on how to screen the patients per the MMT-8 score 
tool. 
 
V. STUDY ENROLLMENT AND TIMELINES 
 
1. # of Patients Expected to Enroll: 10 
 
2. Date of planned FSI: 04/02/2018 
 
3. Date of planned LSI: 11/01/2018 
 


 
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4. Date of planned LSO: 05/01/2019 
 
5. Patient treatment duration (# months): 6 months 
 
6. Is an interim Analysis Planned? Yes 
 
7. Date on planned Interim Analysis: 03/01/2019 
 
8. Date of planned final report: 06/03/2019 
 
9. Are patients reported outcomes measured: Yes 
 
VI. STATISTICAL PLAN: 
 
Results of the study will be analyzed using descriptive statistics: 
• Proportion of patients with complete ORR at 1,3 months 
• Proportion of patients with partial ORR at 1,3 months 
• Proportion of patients with complete durability response at 6 months for the 3 months 
responders 
• Proportion of patients with partial durability response at 6 months for the 3 months 
responders 
• Proportion of patients with complete response at 6 months 
• Proportion of patients with partial response at 6 months 
• Mean change from baseline in muscle enzymes (CK and aldolase in patients with muscle 
disease) 
• MMT-8 change will be calculated as mean change from baseline at 1,3 and 6 months 
• DLQI change will be calculated by identifying the proportion of patients with minimal 
clinically important difference of at least 5 points. 
Missing data will be handled using the last observation carried forward approach (LOCF). 
 
GEP will be analyzed using inferential statistics with a False Discovery Rate (FDR) of < 0.05. 
 
VII. INFORMED CONSENT: 
The protocol and the informed consent will be reviewed by the Institutional Review Board (IRB) prior 
to the start of the study. The proposed form must contain a full explanation of the possible risks, 
benefits and alternate treatment options. It should be written in a way that is easily understandable 
and comprehensible by the patient. If the patients does not understand English or is not fluent in the 
language than appropriate translation must be made available. It should also indicate that by 
signature, the patient or the legal guardian (where appropriate), permits access to medical records by 
the sponsor and by representatives of FDA. The primary investigator (PI) will be responsible for 
obtaining written informed consent from the patient prior to the study. A copy of the signed informed 
consent will be given to the patient and a copy will be submitted to the sponsor. 
 
1. Risks of Apremilast 
 
The PI will monitor patients for side effects of Apremilast throughout the study period. 
The most commonly reported side effects of apremilast include: headache, upper respiratory tract 
infections, nausea, vomiting and diarrhea. Most of these side effects are usually mild to moderate and 
resolve with continued treatment.  


 
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9
Depression has been reported with the use of apremilast. The PI will screen patients for any sign or 
symptom of depression using PHQ2 questionnaire. 
 
2. Pregnancy Risks 
 
The risks to an unborn child (fetus) or nursing child from apremilast are not known at this time. 
Results of the animal and in vitro studies can be found in the IB.    
Women of child bearing potential will be screened with urine pregnancy test at day zero of the study 
and every month through out the study. 
 
If a women of child bearing age engage in activity that could result in pregnancy, they must use one 
of the approved options for birth control while taking the study drug and for at least 28 days after the 
last dose of study drug. 
When a female patient of childbearing potential’s contraceptive measures or ability to become 
pregnant changes at the time of study entry or at any time during the study, the Investigator will 
educate the subject regarding options and correct and consistent use of effective contraceptive 
methods in order to successfully prevent pregnancy. 
 
Approved options for birth control are: 
 Option 1: Any one of the following: hormonal contraception (for example, birth control pills, 
injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation 
(tying your tubes); or a partner with a vasectomy 
OR 
 Option 2: Male or female condom (latex condom or any nonlatex condom NOT made out of 
natural [animal] membrane [for example, polyurethane]) PLUS one of the following additional 
barrier methods: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) 
contraceptive sponge with spermicide. 
In the event of any pregnancy, the PI will discontinue the study medication, and will follow on the 
patient through out her pregnancy.  
VIII. ADVERSE EVENT 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence occurring at any 
dose that may appear or worsen in a patient during the course of a study. It may be a new 
intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the 
patient’s health, including laboratory test values (as specified by the criteria below), regardless of 
etiology. Any medical condition that was present prior to study treatment and that remains unchanged 
or improved should not be recorded as an AE. If there is a worsening of that medical condition this 
should be considered an AE. A diagnosis or syndrome should be recorded on the AE page of the 
Case Report Form (CRF) rather than the individual signs or symptoms of the diagnosis or syndrome. 
All AEs will be recorded by the Investigator(s) from the time of signing the informed consent through 
the end of the designated follow-up period. 
1. Abnormal laboratory values defined as adverse events 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is characterized 
by any of the following: 
• Results in discontinuation from the study. 


 
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10 
• Requires treatment, modification/interruption of study drug dose, or any other therapeutic 
intervention. 
• Is judged by the Investigator(s) to be of significant clinical importance. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page of the CRF. If the abnormality was not a part of a 
diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
2. Serious adverse events 
A serious adverse event (SAE) is any AE which: 
• Results in death 
• Is life-threatening (i.e., in the opinion of the Investigator(s) the patient is at immediate risk of 
death from the AE) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient ’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
• Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or require 
medical or surgical intervention to prevent one of the other outcomes listed above.  Medical and 
scientific judgment should be exercised in deciding whether such an AE should be considered 
serious. 
Events not considered to be SAEs are hospitalizations which: were planned before entry into the 
clinical study; are for elective treatment of a condition unrelated to the studied indication or its 
treatment; occur on an emergency outpatient basis and do not result in admission (unless fulfilling 
other criteria above); are part of the normal treatment or monitoring of the studied indication and are 
not associated with any deterioration in condition. 
If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form must be 
completed. 
For each SAE, the Investigator(s) will provide information on severity, start and stop dates, 
relationship to study drug, action taken regarding study drug, and outcome. 
3. Classification of severity 
For both AEs and SAEs, the investigator(s) must assess the severity of the event. The AEs will be 
evaluated for severity according to the following scale: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
4. Classification of Relationship/Causality of adverse events (SAE/AE) to study drug 
The Investigator(s) must determine the relationship between the administration of study drug and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 


 
Version: 07/18/2018 
11 
Not 
suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event 
Suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship 
possible, and other medications, therapeutic 
interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 
5. Immediate reporting of serious adverse events 
Any AE that meets the criterion for a SAE requires the completion of an SAE Report Form in addition 
to being recorded on the AE pages of the CRF.  The Investigator(s) is required to ensure that the data 
on these forms is accurate and consistent.  This applies to all SAEs, regardless of relationship to 
study drug, that occur during the study, those made known to the Investigator(s) within 30 days after 
a patient’s last dose of study drug, and those made known to the investigator(s) at anytime that are 
suspected of being related to study drug. 
The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ knowledge of the 
event) to Celgene Safety by facsimile.  A written report (prepared by the Investigator(s) using an SAE 
Report Form or a 3500A Medwatch form is to be faxed to Safety (see below for contact information). 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
86 Morris Ave.  
Summit, NJ  07901       
Fax:                 (908) 673-9115 
E-mail:            drugsafety@celgene.com 
 
The SAE report should provide a detailed description of the SAE.  If a patient has died and an 
autopsy has been performed, copies of the autopsy report and death certificate are to be sent to 
Celgene as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE Report Form or Medwatch form and sent to Celgene. 
The Investigator(s) is responsible for informing the Institutional Review Board/Ethics Committee 
(IRB/IEC) of the SAE and providing them with all relevant initial and follow-up information about the 
event. The Investigator(s) must keep copies of all SAE information, including correspondence with 
Celgene and the IRB/IEC, on file.  All SAEs that have not resolved upon discontinuation of the 
patient’s participation in the study must be followed until either the event resolves completely, 
stabilizes/resolves with sequelae, or returns to baseline (if a baseline value is available). 
6. Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female or the female partner of a male patient occurring while the patient is on 
study drug, or within 30 days of the patient’s last dose of study drug, are considered immediately 
reportable events.  Study drug is to be discontinued immediately and the patient instructed to return 


 
Version: 07/18/2018 
12 
any unused portion of the study drug to the investigator(s).  The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Safety immediately facsimile using the 
Pregnancy Report form provided by Celgene. 
The female should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 
The Investigator(s) will follow the female patient until completion of the pregnancy, and must notify 
Celgene Safety of the outcome of the pregnancy as a follow-up on the follow up Pregnancy Reporting 
form. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
Investigator(s) should follow the procedures for reporting SAEs (i.e., report the event to Celgene 
Safety by facsimile within 24 hours of the Investigator’s knowledge of the event). 
In the case of a live “normal” birth, Celgene Safety should be advised by facsimile within 24 hours of 
the Investigator’s knowledge of the event. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to causality, 
as SAEs.  In addition, any infant death after 30 days that the Investigator(s) suspects is related to the 
in utero exposure to the study drug should also be reported to Celgene Safety by facsimile within 24 
hours of the Investigators’ knowledge of the event. 
If the female is found not to be pregnant, any determination regarding the patient’s continued 
participation in the study will be determined by the Investigator. 
 
7. Overdose 
 
Abuse, withdrawal, sensitivity, or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported as an AE.  Any sequela of an accidental or intentional overdose of an investigational product 
should be reported as an AE. 
 
If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form. The overdose resulting in the SAE should be identified as the cause of the event 
on the SAE report form but should not be reported as an SAE itself. 
 
In the event of an overdose, the patient should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for apremilast overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician. 
 
Overdose for this protocol, on a per dose basis, is defined as ingestion of any more than the amount 
prescribed of apremilast (or matching placebo) tablets in any 24 hour period whether by accident or 
intentionally.  
 
IX. PATIENT’S WITHDRAWAL 
 
The patient may withdraw from the study or withdrawn due to the many reasons: 
• Loss to follow-up 


 
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13 
• Adverse Event 
• Non-Compliance 
• Minimal/no therapeutic effect. 
• Withdrawal of the patient by the investigator. 
• Other reasons 
 
Efforts should be made to follow-up patients with adverse events to know the final outcome of the 
event. 
 
The patient and/or investigator, both have the right to terminate the patient’s participation in the study. 
The reason for termination/withdrawal will be documented. 
 
 
X. DATA MANAGEMENT 
 
All data must be entered into the clinical data management system before initiating treatment. 
Electronic case report form (CRF) will be used for the collection of all study data entry at the clinical 
trial site. The PI will enter the data. All requested information must be entered in the CRF in a timely 
manner and the CRF for each visit must be completed during the visit. The completed CRF must be 
reviewed, signed and dated by the PI as well as any missing data should be recorded. Files 
containing electronic data will be password protected and encrypted and will be closed when 
computers are left unattended. Contact lists, recruitment records, or other documents that contain 
Protected Personally Identifiable Information (PPII) will be stored securely in locked cabinets or 
rooms and access to key codes will be limited. 
 
XI. PUBLICATION PLAN 
 
1.Target Journal: JAAD 
 
2. If Other Specify: JAMA 
 
3. Date of Planned manuscript: September 2019 
 
XII. SUPPORT REQUESTED FROM CELEGENE RESOURCES 
 
1. Requesting Study Drug? Yes 
 
2. Requesting Study funding? Yes 
 
3. Support Requested from other companies? No 
 
4. Non-Celegene Support Sources: None 
 
XII. BUDGET 
 
1.Currency Type: US Dollars. 
 
 
3. Total requested Amount from Celgene: $ 40,000 
 


 
Version: 07/18/2018 
14 
 
 
Schedule of Events 
 
 
 
Procedure 
Screening 
phase 
Baseline 
(Day 0) 
Month 1  
Month 3 
Month 6 
Follow 
up visits 
 
Informed Consent 
X 
 
  
  
  
  
Demography 
X 
 
 
 
 
 
Medical History 
X 
X 
  
  
  
  
Inclusion/Exclusion Criteria 
Photograph 
X 
X 
X 
 
X  
 
X  
 
X  
  
Hematology 
Serum Chemistry   
Muscle enzymes (CK, aldolase) 
T-spot 
Skin biopsy 
 
Safety Assessments 
X  
X 
X 
X 
  
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X  
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Physical Examination  
X 
        X 
X  
X 
X  
X  
Weight 
 X  
X 
X 
X 
X 
X 
Urine Pregnancy test (every 
month) 
 X  
X 
X 
X 
X 
X 
Contraception Education 
X 
X 
X 
X 
X 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
CDASI 
MMT-8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI 
 
X 
X 
X 
X 
X 
PHQ-2 
X 
        X 
X 
X 
X 
X 
Dispense ID (every month) 
 
X 
X     
X 
          X 
 
 
 
Timeframe between screening phase and day 0 of the study should not exceed 1 month. 
 
I. 
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