Behcet Syndrome
Conditions
Brief summary
The purpose of this study is to assess whether Apremilast is safe and effective in the treatment of patients with Behcet Disease.
Interventions
Treatment Phase Days 1-7: Titration from 10 mg BID apremilast tablets arm A (or matching placebo arm B) to 30 mg BID apremilast arm A(or matching placebo arm B) Day 8-84: Maintenance of 30 mg BID apremilast arm A (or matching placebo arm B) Dose reductions to 20 mg BID apremilast arm A (or matching placebo arm B) are permitted. Extension Phase All subjects will be given active drug Days 85-91: All placebo subjects from Treatment phase will be dose titrated from 10 mg BID apremilast tablets arm A to 30 mg BID Apremilast. Day 92-169: Maintenance of 30 mg BID apremilast arm A or dose reductions to 20 mg BID apremilast arm A (if not previously down titrated)
DRUGPlacebo
Treatment Phase Days 1-7: Titration from 10mg BID matching placebo (arm B) to 30mg BID placebo (arm B) Day 8-84: Maintenance of 30mg BID placebo (arm B). Dose reductions to 20 mg BID matching placebo (arm B) are permitted. Extension Phase All subjects will be given active drug Days 85-91: All placebo subjects from Treatment phase will be dose titrated from 10 mg BID apremilast tablets arm A to 30 mg BID Apremilast. Day 92-169: Maintenance of 30 mg BID apremilast or dose reductions to 20 mg BID apremilast (if not previously down titrated)
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Behçet Disease. At the time of diagnosis, subjects must meet the international study group criteria for Behçet Disease * Females of childbearing potential (FCBP) must have negative pregnancy tests and agree to use two forms of contraception throughout the study. * Males must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with FCBP * Laboratory criteria: Hgb ≥ 9 g/dL, WBC count ≥ 3000 /microL and ≤14,000/microL, platelet count ≥ 100,000 /microL,, serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L), total bilirubin ≤ 2.0 mg/dL, AST and ALT ≤ 1.5 X ULN * Two or more oral ulcers over the 28 day period before screening, with or without current treatment * Two or more oral ulcers at the time of randomization (Visit 2, Baseline)
Exclusion criteria
* Pregnant or breast feeding * Any condition which places the subject at risk * Systemic fungal infection * History of TB infection within 3 years * History of recurrent bacterial infection * Mycobacterium TB as indicated by a positive PPD skin test * History of incompletely treated Mycobacterium tuberculosis * Clinically significant chest x-ray abnormality at screening. * Clinically significant ECG abnormality at screening * History of HIV infection * History of congenital or acquired immunodeficiency * Hepatitis B surface antigen positive or Hepatitis B core antibody positive at screening * Antibodies to Hepatitis C at screening * History of malignancy (except for treated basal-cell skin carcinomas \> 3 years prior to screening) * Any active major organ involvement of Behçet Disease * Use of concomitant immune modulating therapy or topical corticosteroids. * Use of ocular corticosteroids * Use of any investigational medication within 4 weeks prior to randomization or 5 PK/PD half-lives (whichever is longer)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oral Ulcers at Day 85 | Day 85 | The number of oral ulcers were counted at each visit and at the end of the treatment period (starting point was at baseline). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase | Day 1 to Day 85 | A flare was defined as the development of new manifestations of BD or worsening of existing disease, meeting the following criteria: 1. Organ involvement: any major organ involvement (eg, central nervous system, gastrointestinal tract); 2. Oral/genital ulcers: ≥ 100% increase in the number of oral or genital ulcers from Day 1 or a minimum increase of 3 in the number of oral or genital ulcers, whichever is greater; 3. Arthritis: ≥ 50% increase in the number of swollen joints, or a minimum increase of 3 swollen joints, whichever is greater; 4. Skin lesions (non-oral/genital ulcers): ≥ 50% increase in the total score of the Physician's Global Assessment of Skin Lesions, or a minimum increase of 2 in the total score of the Physician's Global Assessment of Skin Lesions, whichever is greater' 5. New onset or worsening of existing Behçet Disease-related inflammatory eye disease requiring initiation of immunosuppressive therapy (uveitis). |
| Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) at Day 197 | Day 1 to Day 197 | A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
| Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 197 | Day 1 to Day 197 | The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement. |
| Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Day 1 to Day 197; maximum exposure was 25.1 weeks | A Treatment Emergent Adverse Event (TEAE) is as any AE occurring or worsening on or after the first treatment of any study drug, and within 28 days after the last dose of the last study drug. A treatment related toxicity was considered by the investigator to be not suspected or suspected. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. |
| Pain of Oral Ulcers as Measured by Visual Analog Scale (VAS) at Day 85 | Day 85 | A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
| Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) Scores at Day 85 | Baseline to Day 85 | A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
| Area Under the Curve (AUC) for the Number of Oral Ulcers From Day 1 to 85 | Day 1 to Day 85 | Area under curve (AUC\^85) from Day 1 to Day 85 for the number of oral ulcers per day was determined using the trapezoidal rule and divided by the days between the date of the last observation and baseline. The AUC was determined using the LOCF approach to impute missing values. |
| Area Under the Curve for the Number of Genital Ulcers From Day 1 to 85 | Day 1 to Day 85 | Area under curve (AUC\^85) from Day 1 to Day 85 for the number of genital ulcers per day was not analyzed. |
| Area Under the Curve (AUC) for the Number of Oral Plus Genital Ulcers From Day 1 to 85 | Day 1 to Day 85 | Area under curve (AUC) from Day 1 to Day 85 (AUC\^85) for the number of oral plus genital ulcers per day was determined using the trapezoidal rule and divided by the days between the date of the last observation and baseline. The AUC was determined using the LOCF approach to impute missing values. |
| Sum of the Number Oral Ulcers, Genital Ulcers or Oral Plus Genital Ulcers at Day 85 | Day 85 | Sum of the number oral ulcers, genital ulcers or oral plus genital ulcers at Day 85 |
| Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response) | Baseline and Day 85 | Comparison of the percentage of participants who were oral ulcer-free (complete response: free from active oral ulcers), or whose oral ulcers were reduced by ≥ 50%, (partial response) between the apremilast-treated and the placebo-treated groups. In this case, partial response also includes complete response. |
| Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 85 | Day 1 to Day 85 or to early termination visit | The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement. |
| Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Day 1 to Day 85; maximum exposure to study drug was 13 weeks during treatment phase | A Treatment Emergent Adverse Event (TEAE) was defined as any AE occurring or worsening on or after the first treatment of any study drug, and within 28 days after the last dose of the last study drug. A treatment related toxicity was considered by the investigator to be not suspected or suspected. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. |
| Number of Oral Ulcers at Day 169 | Day 169 | The number of oral ulcers were counted at Day 169 in reference to the participants' first day of active treatment (Day 1 or Day 85). |
| Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 169 | Day 169 | A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
| Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) at Day 169 | Day 1 to Day 169 | A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
| Behçet's Disease (BD) Current Activity Index Form Score at Day 169 | Day 169 | The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement. |
| Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1 | Day 1 to Day 169 | A flare was defined as the development of new manifestations of BD or worsening of existing disease, meeting the following criteria: 1. Organ involvement: any major organ involvement (eg, central nervous system, gastrointestinal tract); 2. Oral/genital ulcers: ≥ 100% increase in the number of oral or genital ulcers from Day 1 or a minimum increase of 3 in the number of oral or genital ulcers, whichever is greater; 3. Arthritis: ≥ 50% increase in the number of swollen joints, or a minimum increase of 3 swollen joints, whichever is greater; 4. Skin lesions (non-oral/genital ulcers): ≥ 50% increase in the total score of the Physician's Global Assessment of Skin Lesions, or a minimum increase of 2 in the total score of the Physician's Global Assessment of Skin Lesions, whichever is greater; 5. New onset or worsening of existing Behçet Disease-related inflammatory eye disease requiring initiation of immunosuppressive therapy (uveitis). |
| Number of Oral Ulcers at Day 197 | Day 197 | The number of oral ulcers were counted at each visit and at the end of the treatment period (starting point was at baseline). |
| Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 197 | Day 197 | A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Genital Ulcer-free (Complete Response) | Day 1 to Day 197 | The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers) |
| Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 169 | Day 1 to Day 169 | The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers) |
| Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 85 | Baseline to Day 85 | The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers) |
Countries
Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted at 3 study sites in Turkey and 3 sites in the United States. The first participant enrolled was enrolled on October 23, 2009 and the last participant enrolled was enrolled on May 08, 2012.
Pre-assignment details
Eligible participants were randomized 1:1 to receive study drug (apremilast or placebo). Since the incidence and severity of Behçet's Disease differ between males and females, randomization was stratified by gender.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Oral) BID Treatment Phase (Days 1 to 85): Participants administered identically matching placebo tablets BID in the 12-week placebo-controlled phase. | 56 |
| Apremilast 30mg (Oral) BID Treatment Phase (Days 1 to 85): Participants administered 30 mg Apremilast tablets BID during the 12-week placebo-controlled treatment phase. | 55 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extension Phase (Day 86 to 169) | Adverse Event | 0 | 0 | 1 | 3 |
| Treatment Phase (Days 1 to 85) | Adverse Event | 5 | 4 | 0 | 0 |
| Treatment Phase (Days 1 to 85) | Lack of Efficacy | 3 | 0 | 0 | 0 |
| Treatment Phase (Days 1 to 85) | Other | 1 | 0 | 0 | 0 |
| Treatment Phase (Days 1 to 85) | Protocol Violation | 1 | 1 | 0 | 0 |
| Treatment Phase (Days 1 to 85) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (Oral) BID | Apremilast 30mg (Oral) BID | Total |
|---|---|---|---|
| Age, Continuous | 34.7 years STANDARD_DEVIATION 10.97 | 34.3 years STANDARD_DEVIATION 9.11 | 34.5 years STANDARD_DEVIATION 10.05 |
| Duration of Behçet's disease | 5.72 years STANDARD_DEVIATION 6.084 | 4.92 years STANDARD_DEVIATION 3.982 | 5.33 years STANDARD_DEVIATION 5.143 |
| Sex: Female, Male Female | 38 Participants | 39 Participants | 77 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 56 | 47 / 55 | 82 / 100 |
| serious Total, serious adverse events | 3 / 56 | 2 / 55 | 6 / 100 |
Outcome results
Primary
Number of Oral Ulcers at Day 85
The number of oral ulcers were counted at each visit and at the end of the treatment period (starting point was at baseline).
Time frame: Day 85
Population: Intent to Treat (ITT) = all randomized participants with at least one oral ulcer evaluation (including the baseline visit). A Last Observation Carried Forward (LOCF) approach was applied for participants terminated early. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Number of Oral Ulcers at Day 85 | 2.0 ulcers/participants | Standard Error 0.28 |
| Apremilast 30mg (Oral) BID | Number of Oral Ulcers at Day 85 | 0.4 ulcers/participants | Standard Error 0.28 |
p-value: <0.000195% CI: [-2.4, -0.9]ANCOVA
Secondary
Area Under the Curve (AUC) for the Number of Oral Plus Genital Ulcers From Day 1 to 85
Area under curve (AUC) from Day 1 to Day 85 (AUC\^85) for the number of oral plus genital ulcers per day was determined using the trapezoidal rule and divided by the days between the date of the last observation and baseline. The AUC was determined using the LOCF approach to impute missing values.
Time frame: Day 1 to Day 85
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Area Under the Curve (AUC) for the Number of Oral Plus Genital Ulcers From Day 1 to 85 | 193.95 total AUC (#ulcers*days) | Standard Deviation 161.492 |
| Apremilast 30mg (Oral) BID | Area Under the Curve (AUC) for the Number of Oral Plus Genital Ulcers From Day 1 to 85 | 65.79 total AUC (#ulcers*days) | Standard Deviation 108.037 |
Secondary
Area Under the Curve (AUC) for the Number of Oral Ulcers From Day 1 to 85
Area under curve (AUC\^85) from Day 1 to Day 85 for the number of oral ulcers per day was determined using the trapezoidal rule and divided by the days between the date of the last observation and baseline. The AUC was determined using the LOCF approach to impute missing values.
Time frame: Day 1 to Day 85
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Area Under the Curve (AUC) for the Number of Oral Ulcers From Day 1 to 85 | 157.82 total AUC (#ulcers*days) | Standard Error 12.89 |
| Apremilast 30mg (Oral) BID | Area Under the Curve (AUC) for the Number of Oral Ulcers From Day 1 to 85 | 67.74 total AUC (#ulcers*days) | Standard Error 13.267 |
p-value: <0.000195% CI: [-125.32, -54.82]ANCOVA
Secondary
Area Under the Curve for the Number of Genital Ulcers From Day 1 to 85
Area under curve (AUC\^85) from Day 1 to Day 85 for the number of genital ulcers per day was not analyzed.
Time frame: Day 1 to Day 85
Population: No population analyzed due to small number of participants with genital ulcers; not considered meaningful.
Secondary
Behçet's Disease (BD) Current Activity Index Form Score at Day 169
The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement.
Time frame: Day 169
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Behçet's Disease (BD) Current Activity Index Form Score at Day 169 | 1.4 units on a scale | Standard Deviation 1.18 |
| Apremilast 30mg (Oral) BID | Behçet's Disease (BD) Current Activity Index Form Score at Day 169 | 1.6 units on a scale | Standard Deviation 1.62 |
Secondary
Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 197
The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement.
Time frame: Day 1 to Day 197
Population: Includes participants who entered the Observational Follow-up Phase from either the Treatment Phase or the Extension Phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 197 | -0.6 units on a scale | Standard Deviation 1.28 |
| Apremilast 30mg (Oral) BID | Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 197 | -1.2 units on a scale | Standard Deviation 1.65 |
Secondary
Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 85
The Behçet's Disease Current Activity Index consists of three component scores, a participant's perception of disease activity, a clinician's overall perception of disease activity and a Behçet's Disease Current Activity Index Score. The score ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening) and a negative change from baseline indicates improvement.
Time frame: Day 1 to Day 85 or to early termination visit
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 85 | -0.1 units on a scale | Standard Error 0.22 |
| Apremilast 30mg (Oral) BID | Change From Baseline in the Disease Activity as Measured by BD Current Activity Form/Index Score on Day 85 | -1.2 units on a scale | Standard Error 0.22 |
p-value: 0.000795% CI: [-1.7, -0.5]ANCOVA
Secondary
Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase
A flare was defined as the development of new manifestations of BD or worsening of existing disease, meeting the following criteria: 1. Organ involvement: any major organ involvement (eg, central nervous system, gastrointestinal tract); 2. Oral/genital ulcers: ≥ 100% increase in the number of oral or genital ulcers from Day 1 or a minimum increase of 3 in the number of oral or genital ulcers, whichever is greater; 3. Arthritis: ≥ 50% increase in the number of swollen joints, or a minimum increase of 3 swollen joints, whichever is greater; 4. Skin lesions (non-oral/genital ulcers): ≥ 50% increase in the total score of the Physician's Global Assessment of Skin Lesions, or a minimum increase of 2 in the total score of the Physician's Global Assessment of Skin Lesions, whichever is greater' 5. New onset or worsening of existing Behçet Disease-related inflammatory eye disease requiring initiation of immunosuppressive therapy (uveitis).
Time frame: Day 1 to Day 85
Population: Safety population included all participants who were randomized and received at least 1 dose of Investigational Product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase | Participants who had disease flare | 27 participants |
| Placebo (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase | Participants with new onset or worsening uveitis | 3 participants |
| Apremilast 30mg (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase | Participants who had disease flare | 12 participants |
| Apremilast 30mg (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare During the Placebo Controlled Treatment Phase | Participants with new onset or worsening uveitis | 0 participants |
Secondary
Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1
A flare was defined as the development of new manifestations of BD or worsening of existing disease, meeting the following criteria: 1. Organ involvement: any major organ involvement (eg, central nervous system, gastrointestinal tract); 2. Oral/genital ulcers: ≥ 100% increase in the number of oral or genital ulcers from Day 1 or a minimum increase of 3 in the number of oral or genital ulcers, whichever is greater; 3. Arthritis: ≥ 50% increase in the number of swollen joints, or a minimum increase of 3 swollen joints, whichever is greater; 4. Skin lesions (non-oral/genital ulcers): ≥ 50% increase in the total score of the Physician's Global Assessment of Skin Lesions, or a minimum increase of 2 in the total score of the Physician's Global Assessment of Skin Lesions, whichever is greater; 5. New onset or worsening of existing Behçet Disease-related inflammatory eye disease requiring initiation of immunosuppressive therapy (uveitis).
Time frame: Day 1 to Day 169
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1 | Participants who experienced a disease flare | 15 participants |
| Placebo (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1 | Participants with new onset or worsening uveitis | 1 participants |
| Apremilast 30mg (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1 | Participants who experienced a disease flare | 19 participants |
| Apremilast 30mg (Oral) BID | Number of New Manifestations of Behçet's Disease or Flare That Were Not Present at Day 1 | Participants with new onset or worsening uveitis | 2 participants |
Secondary
Number of Oral Ulcers at Day 169
The number of oral ulcers were counted at Day 169 in reference to the participants' first day of active treatment (Day 1 or Day 85).
Time frame: Day 169
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Number of Oral Ulcers at Day 169 | 0.4 ulcers/participant | Standard Deviation 1.31 |
| Apremilast 30mg (Oral) BID | Number of Oral Ulcers at Day 169 | 0.6 ulcers/participant | Standard Deviation 1.27 |
Secondary
Number of Oral Ulcers at Day 197
The number of oral ulcers were counted at each visit and at the end of the treatment period (starting point was at baseline).
Time frame: Day 197
Population: Includes participants who entered the Observational Follow-up Phase from either the Treatment Phase or the Extension Phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Number of Oral Ulcers at Day 197 | 1.6 ulcers/participants | Standard Deviation 1.78 |
| Apremilast 30mg (Oral) BID | Number of Oral Ulcers at Day 197 | 1.7 ulcers/participants | Standard Deviation 2.06 |
Secondary
Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase
A Treatment Emergent Adverse Event (TEAE) was defined as any AE occurring or worsening on or after the first treatment of any study drug, and within 28 days after the last dose of the last study drug. A treatment related toxicity was considered by the investigator to be not suspected or suspected. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE.
Time frame: Day 1 to Day 85; maximum exposure to study drug was 13 weeks during treatment phase
Population: Safety Population defined as all participants who were randomized and received at least 1 dose of Investigational Product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any severe TEAE | 5 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any serious drug related TEAE | 1 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE leading to drug interruption | 0 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any drug related TEAE | 24 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE leading to drug withdrawal | 5 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any serious TEAE | 3 participants |
| Placebo (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE | 50 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any serious drug related TEAE | 0 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE | 49 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any drug related TEAE | 30 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any severe TEAE | 5 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any serious TEAE | 2 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE leading to drug interruption | 1 participants |
| Apremilast 30mg (Oral) BID | Number of Treatment Emergent Adverse Events (TEAE) During the Placebo Controlled Treatment Phase | Any TEAE leading to drug withdrawal | 4 participants |
Secondary
Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) at Day 169
A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Day 1 to Day 169
Population: Not analyzed due to low numbers of genital ulcers; not considered meaningful.
Secondary
Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) at Day 197
A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Day 1 to Day 197
Population: Not analyzed due to low numbers of genital ulcers; not considered meaningful.
Secondary
Pain of Genital Ulcers as Measured by Visual Analog Scale (VAS) Scores at Day 85
A 100-mm VAS pain scale for genital ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Baseline to Day 85
Population: Not analyzed due to low numbers of genital ulcers; not considered meaningful.
Secondary
Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 169
A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Day 169
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 169 | 9.6 units on a scale | Standard Deviation 21.13 |
| Apremilast 30mg (Oral) BID | Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 169 | 9.7 units on a scale | Standard Deviation 20.33 |
Secondary
Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 197
A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Day 197
Population: Includes participants who entered the Observational Follow-up Phase from either the Treatment Phase or the Extension Phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 197 | 21.0 units on a scale | Standard Deviation 22.26 |
| Apremilast 30mg (Oral) BID | Pain of Oral Ulcers as Measured by VAS (VAS Score) at Day 197 | 27.2 units on a scale | Standard Deviation 28.71 |
Secondary
Pain of Oral Ulcers as Measured by Visual Analog Scale (VAS) at Day 85
A 100-mm VAS pain scale for oral ulcers was completed by the participant at timepoints specified in the protocol. Each 100-mm VAS was presented to the participant on a single sheet of bond paper. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was measured by ruler and recorded. When responding to a VAS item, participants specify their level of agreement to a statement by indicating a position along a continuous line between two end-points.
Time frame: Day 85
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Pain of Oral Ulcers as Measured by Visual Analog Scale (VAS) at Day 85 | 36.7 units on a scale | Standard Error 3.23 |
| Apremilast 30mg (Oral) BID | Pain of Oral Ulcers as Measured by Visual Analog Scale (VAS) at Day 85 | 9.9 units on a scale | Standard Error 3.3 |
p-value: <0.000195% CI: [-35.5, -18]ANCOVA
Secondary
Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response)
Comparison of the percentage of participants who were oral ulcer-free (complete response: free from active oral ulcers), or whose oral ulcers were reduced by ≥ 50%, (partial response) between the apremilast-treated and the placebo-treated groups. In this case, partial response also includes complete response.
Time frame: Baseline and Day 85
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Oral) BID | Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response) | Complete Response | 28.6 percentage of participants |
| Placebo (Oral) BID | Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response) | Partial Response | 50.0 percentage of participants |
| Apremilast 30mg (Oral) BID | Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response) | Complete Response | 70.9 percentage of participants |
| Apremilast 30mg (Oral) BID | Percentage of Participants Who Were Oral Ulcer-free (Complete Response), or Whose Oral Ulcers Were Reduced by ≥ 50%, (Partial Response) | Partial Response | 89.1 percentage of participants |
p-value: <0.000195% CI: [23.6, 54.5]Cochran-Mantel-Haenszel
Secondary
Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase
A Treatment Emergent Adverse Event (TEAE) is as any AE occurring or worsening on or after the first treatment of any study drug, and within 28 days after the last dose of the last study drug. A treatment related toxicity was considered by the investigator to be not suspected or suspected. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE.
Time frame: Day 1 to Day 197; maximum exposure was 25.1 weeks
Population: Safety analyses for the apremilast-exposure period was based on the apremilast participants as treated (AAT) Population, and included those who were randomized (at the randomization visit) or switched (at the Day 85 visit) to apremilast 30 mg BID, and received at least one dose of apremilast after the initial randomization or switch to 30 mg BID.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any drug related TEAE | 20 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any serious TEAE | 1 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any serious drug related TEAE | 0 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | TEAE leading to drug interuption | 0 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any severe TEAE | 1 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | TEAE leading to drug withdrawal | 1 particpants |
| Placebo (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any TEAE | 39 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | TEAE leading to drug withdrawal | 7 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any TEAE | 50 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any serious drug related TEAE | 1 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any drug related TEAE | 33 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any severe TEAE | 11 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | Any serious TEAE | 5 particpants |
| Apremilast 30mg (Oral) BID | Summary of Treatment Emergent Adverse Events During the Active Treatment-Extension Phase | TEAE leading to drug interuption | 1 particpants |
Secondary
Sum of the Number Oral Ulcers, Genital Ulcers or Oral Plus Genital Ulcers at Day 85
Sum of the number oral ulcers, genital ulcers or oral plus genital ulcers at Day 85
Time frame: Day 85
Population: The ITT population included all randomized participants with at least one oral ulcer evaluation (including the baseline evaluation). A LOCF approach was applied for participants terminated early from the study. If a participant had no post-baseline oral ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Oral) BID | Sum of the Number Oral Ulcers, Genital Ulcers or Oral Plus Genital Ulcers at Day 85 | 2.3 Ulcers/participants | Standard Error 0.35 |
| Apremilast 30mg (Oral) BID | Sum of the Number Oral Ulcers, Genital Ulcers or Oral Plus Genital Ulcers at Day 85 | 0.6 Ulcers/participants | Standard Error 0.36 |
p-value: 0.000795% CI: [-2.7, -0.8]ANCOVA
Other Pre-specified
Percentage of Participants Who Were Genital Ulcer-free (Complete Response)
The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers)
Time frame: Day 1 to Day 197
Population: Intent to Treat (ITT) = all randomized participants with at least one genital ulcer at baseline. A Last Observation Carried Forward (LOCF) approach was applied for participants terminated early. If a participant had no post-baseline genital ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) | 100 percentage of participants |
| Apremilast 30mg (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) | 100 percentage of participants |
Other Pre-specified
Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 169
The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers)
Time frame: Day 1 to Day 169
Population: Intent to Treat (ITT) = all randomized participants with at least one genital ulcer at baseline visit. A Last Observation Carried Forward (LOCF) approach was applied for participants terminated early. If a participant had no post-baseline genital ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 169 | 66.7 percentage of participants |
| Apremilast 30mg (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 169 | 100 percentage of participants |
Other Pre-specified
Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 85
The percentage of participants who were genital ulcer-free (complete response: free from active genital ulcers)
Time frame: Baseline to Day 85
Population: Intent to Treat (ITT) = all randomized participants with at least one genital ulcer at baseline. A Last Observation Carried Forward (LOCF) approach was applied for participants terminated early. If a participant had no post-baseline genital ulcer assessment, the baseline value was carried forward for calculation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 85 | 50 percentage of participants |
| Apremilast 30mg (Oral) BID | Percentage of Participants Who Were Genital Ulcer-free (Complete Response) at Day 85 | 100 percentage of participants |