Apremilast for RAS

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03690544
• Collaborator: Celgene (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 33.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Determination of treatment efficacy and safety of Apremilast in patients with RAS

Condition or Disease	Intervention/Treatment	Phase
Recurrent Aphthous Stomatitis	Drug: Apremilast 30mg	Phase 4

Detailed Description

The study will be a pilot study using apremilast 30mg orally twice daily, for treatment of RAS in males and females between 18 and 70 years old.

Subjects will be recruited from the clinical practice of the Department of Dermatology or Division of Rheumatology at Mayo Clinic Florida. Fifteen males and females with RAS will be enrolled.

The study will consist of 3 phases: a screening phase, a 16 week treatment phase and an 8 week posttreatment observational follow-up phase.

The screening phase will consist of: obtaining informed consent, demographic information, medical history, inclusion and exclusion criteria, prior and concomitant medication use, adverse events; collecting vital signs and weight; performing complete physical examination and limited physical examination; obtaining hematology, serum chemistry, urinalysis, pregnancy test and providing contraception education.

During the 16-week treatment phase, all subjects receive apremilast.

All subjects who complete the active treatment phase are to enter the 8-week posttreatment observational follow-up phase.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Apremilast 30mg orally twice daily for 16 weeksApremilast 30mg orally twice daily for 16 weeks
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Evaluating the Efficacy of Apremilast in the Treatment of Subjects With Severe Recurrent Aphthous Stomatitis (RAS)
• Actual Study Start Date: Oct 12, 2018
• Actual Primary Completion Date: Jul 14, 2021
• Actual Study Completion Date: Jul 14, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS)

Drug: Apremilast 30mg; Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.

Outcome Measures

Primary Outcome Measures

1. Duration of RAS Lesions [24 weeks]

   The total length of time (duration) subjects experienced RAS lesions. Measured in weeks

2. Change in Number of RAS Lesions [baseline, 24 weeks]

   Number of participants with fewer oral ulcers at Week 24 compared to Baseline

3. Duration of the Remission Period Between Ulcer Episodes [24 weeks]

   The length of time of remission of RAS lesions experienced by the subjects. As measured in months.

Secondary Outcome Measures

1. Adverse Events [24 weeks]

   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

2. Discontinuation of Study Participants [24 weeks]

   Number of subjects who prematurely discontinue treatment with apremilast due to any adverse event.

3. Change in Visual Analog Scale Pain Score (VAS) From Baseline to 16 Weeks and Baseline to 24 Weeks. [baseline, 16 weeks, 24 weeks]

   The Visual Analog Scale (VAS) for Pain is a validated tool used to measure pain. A 100mm horizontal line anchored by "no pain" (score of 0) and "pain as bad as it could be" (score of 100).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Male and female subjects between 18 and 70 years of age

2. Oral ulcers that occurred at least monthly in the 6 month period prior to enrollment

3. Had at least 2 oral ulcers in the 4 weeks prior to enrollment at baseline

4. At least 3 oral ulcers during an ulcer flare

5. Patients must be candidates for systemic therapy for the treatment of oral ulcers, those that are considered unsuitable for topical therapy alone based on severity of disease, or whose oral ulcers cannot be adequately controlled with topical therapy.

6. Female premenopausal subjects must use one of the approved contraceptive options while taking apremilast and for at least 28 days after administration of the last dose of apremilast

7. Patients are able and willing to provide written informed consent after the nature of the study is fully explained.

8. No evidence of systemic disease

Exclusion Criteria

1. Prior use of apremilast.

2. Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).

3. Having received concomitant immune modulating therapy 12 weeks prior to enrollment, systemic steroids 6 weeks prior to enrollment or topical steroids within 4 weeks prior to enrollment.

4. Pregnant women or breast-feeding mothers.

5. Systemic or opportunistic fungal infection.

6. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (tuberculosis and atypical mycobacterial disease, hepatitis B and C and herpes zoster, histoplasmosis, coccidiomycosis) or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks of the screening phase.

7. History of positive test for, or any clinical suspicion of, human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency.

8. History of depression.

9. Malignancy or history of malignancy, except for:

a - treated (ie, cured) basal cell or squamous cell in situ skin carcinomas; b - treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of cervix with no evidence of recurrence within the previous 5 years.

1. Other than disease under study, any clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major disease that is currently uncontrolled.

2. Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she were to participate in the study.

3. Prior history of suicide attempt at any time in the subject's life time prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.

4. Active substance abuse or a history of substance abuse within 6 months prior to screening.

5. Presence of any of the following vitamin deficiencies - B1, B2, B6, B12, vitamin C, zinc, folate, iron.

6. Celiac disease.

7. Inflammatory Bowel Disease.

8. Genital aphthous ulcers.

9. Behçet's disease.

10. History of positive patch test for allergic contact stomatitis.

11. Positive anti-endomysial or anti-gliadin antibodies.

12. A diagnosis of uveitis (current or previous).

13. Erythema nodosum-like lesions (current or previous).

14. An established diagnosis of a systemic disease (SLE, Reiter's, Sweet's and MAGIC syndrome).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224

Sponsors and Collaborators

• Mayo Clinic
• Celgene

Investigators

• Principal Investigator: Alison J Bruce, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 2, 2017

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Alison J. Bruce, Principle Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03690544
• Other Study ID Numbers: 18-002914
• First Posted: Oct 1, 2018
• Last Update Posted: Jul 14, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Stomatitis; Stomatitis, Aphthous; Apremilast

Study Results

Participant Flow

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Overall Participants	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	11 73.3%
Male	4 26.7%
Race/Ethnicity, Customized (Count of Participants)
White	14 93.3%
Hispanic or Latino	1 6.7%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Duration of RAS Lesions
Description	The total length of time (duration) subjects experienced RAS lesions. Measured in weeks
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
Mean (Standard Deviation) [weeks]	1.57 (0.68)

2. Primary Outcome

Title	Change in Number of RAS Lesions
Description	Number of participants with fewer oral ulcers at Week 24 compared to Baseline
Time Frame	baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
Number [participants]	11 73.3%

3. Primary Outcome

Title	Duration of the Remission Period Between Ulcer Episodes
Description	The length of time of remission of RAS lesions experienced by the subjects. As measured in months.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
Mean (Standard Deviation) [months]	2.00 (0.85)

4. Secondary Outcome

Title	Adverse Events
Description	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
Count of Participants [Participants]	11 73.3%

5. Secondary Outcome

Title	Discontinuation of Study Participants
Description	Number of subjects who prematurely discontinue treatment with apremilast due to any adverse event.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
Count of Participants [Participants]	3 20%

6. Secondary Outcome

Title	Change in Visual Analog Scale Pain Score (VAS) From Baseline to 16 Weeks and Baseline to 24 Weeks.
Description	The Visual Analog Scale (VAS) for Pain is a validated tool used to measure pain. A 100mm horizontal line anchored by "no pain" (score of 0) and "pain as bad as it could be" (score of 100).
Time Frame	baseline, 16 weeks, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
Measure Participants	15
baseline to 16 weeks	-4 (3.0)
baseline to 24 weeks	-2 (4.0)

Adverse Events

Time Frame	Adverse events were collected from baseline to end of study, approximately 24 weeks
Arm/Group Title	Single Arm
Arm/Group Description	Subjects received Apremilast 30mg orally twice daily for 16 weeks, sixteen weeks on active study. Post treatment follow-up period of 8 weeks, in the Treatment of Subjects with Severe Recurrent Aphthous Stomatitis (RAS) Apremilast 30mg: Apremilast is an oral small-molecule inhibitor of phosphodiesterase (PDE) 4 that works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE 4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alfa, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. Apremilast has immunomodulatory activity and, therefore, has the potential to be effective in the treatment of RAS.
All Cause Mortality
	Single Arm
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)
Gastrointestinal disorders
Diarrhea	5/15 (33.3%)
General disorders
Nausea	9/15 (60%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.