Sarcoidosis
Conditions
Keywords
Ustekinumab, CNTO 1275, Stelara, Golimumab, CNTO 148, Simponi, Sarcoidosis, Sarcoid, Pulmonary Sarcoidosis, Skin Sarcoidosis
Brief summary
This study tests the safety and effectiveness of ustekinumab or golimumab compared to placebo (placebo looks like the drugs being studied, but has no active ingredients). The purpose of this research study is to determine if ustekinumab or golimumab is safe and to determine its effects (good and bad) on patients with chronic sarcoidosis with pulmonary and/or skin involvement. Patients with pulmonary involvement constitute the primary population for analysis, and patients with skin involvement constitute the secondary population; a patient may be in both populations. The study will be conducted at approximately 40 sites globally.
Detailed description
Ustekinumab is approved for dosing in patients with psoriasis and golimumab is approved for dosing in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. This study will use either drug in patients with chronic sarcoidosis. Ustekinumab and golimumab are being tested to see if they may be useful in treating chronic sarcoidosis. This study will compare the effects (both good and bad) of ustekinumab and golimumab to those of placebo. The purpose of this study is to evaluate the safety and effectiveness of ustekinumab and golimumab (administered as individual treatments) in patients with chronic sarcoidosis with lung and/or skin involvement who still have symptoms even though receiving current therapy. About 180 patients will take part in the study. While in this study, patients may not take part in any other medical research studies. Ustekinumab and golimumab are not approved by the national health authorities for treatment of chronic sarcoidosis; therefore, they can only be used in a research setting to treat this condition. The screening phase of the study, where the doctor will determine if a patient is eligible for the study, will last 1 to 4 weeks. Patients are put into 1 of 3 groups and each group will get a different treatment. The results of the golimumab group and the ustekinumab group are compared to placebo. Patients will either receive ustekinumab, golimumab or placebo. Placebo looks like ustekinumab and golimumab and is given in the same way, by injection, but contains no active drug. Patients will receive study agent until Week 24 and will continue to be followed through Week 44 for assessment of safety and any other effects after discontinuation of therapy. The patient will continue to take all sarcoidosis medication(s) at current, stable dose for the first part of the study. If the patient remained on a stable steroid dose from Week 0 through Week 16 of the study, the study doctor will begin to taper (lower) the steroid dose. The steroid taper will continue through to the end of the Week 28 visit. The patient will continue to take their other sarcoidosis medication(s) at the same dose for the rest of the study. An independent Data Monitoring Committee will be responsible for reviewing the safety data for the study. Patients will be in the study for about 48 weeks. The end of the study is defined as the last visit of the last patient. A site-specific substudy is being implemented to collect serum and lung samples from patients who are currently enrolled in this study. A separate protocol is being implemented to collect lung fluid and serum samples from normal, healthy subjects to be used as comparators for similar samples obtained in the 1275148SCD2001 substudy. Patients will be randomly assigned to 1 of 3 treatment groups: ustekinumab (180 mg at Week 0, followed by 90 mg at Weeks 8, 16, and 24 with placebo at Weeks 4, 12, and 20), golimumab (200 mg at Week 0, followed by 100 mg at Weeks 4, 8, 12, 16, 20, and 24) or placebo (at Weeks 0, 4, 8, 12, 16, 20, and 24) administered by SC injection.
Interventions
DRUGPlacebo
Matching Placebo will be administered subcutaneously (injected under the skin by way of a needle) every 4 weeks up to Week 24.
DRUGGolimumab
Golimumab will be administered subcutaneously at a dose of 200 milligram (mg) at Week 0 and thereafter at a dose of 100 mg every 4 weeks up to Week 24.
DRUGUstekinumab
Ustekinumab will be administered subcutaneously at a dose of 180 mg at Week 0 and thereafter at a dose of 90 mg at Week 8, 16 and 24 and matching Placebo was administered subcutaneously at Week 4, 12 and 20.
Sponsors
Centocor, Inc.
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 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have sarcoidosis with onset date of \>=2 years prior to screening with at least 1 of the following: a. pulmonary sarcoidosis defined as 1) a diagnosis of sarcoidosis with evidence of lung parenchymal disease (Stage II, III or IV on chest radiograph), and 2) an FVC of \>=45% and \<=80% of predicted normal value at screening, and 3) an MRC dyspnea score of \>2 at screening, and 4) a 6 minute walk distance between 100 to 550 meters at screening, and 5) \<=15% absolute change in percent-predicted FVC at baseline relative to screening AND/OR b. skin sarcoidosis defined as 1) active chronic skin lesions for \>=3 months either on face or elsewhere on body that have not resolved on current systemic and/or local therapy, and 2) have either: a single lesion of \>=2 cm in longest dimension or multiple (3 or more) lesions with at least 1 lesion having a longest dimension of \>=1 cm, and 3) have an SPGA score \>=2 at screening * have been receiving treatment with oral corticosteroids and/or 1 or more immunomodulators for \>=3-month period immediately prior to screening * on a stable dose of these medications for \>=4 weeks before screening
Exclusion criteria
* Have a diagnosis of other significant respiratory disorder other than sarcoidosis that would complicate the evaluation of response to treatment * Have a smoking history of \>=20 pack years * Have used an investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer * have received previous administration of a treatment with any other therapeutic agent targeted at reducing TNFalpha within 6 months or 5 half-lives of the agent, whichever is longer, prior to screening * Patients who have previously received biologic anti-TNFalpha agents outside of the above period are allowed to enter the study * Have previously used cyclophosphamide * Have previously used or received local therapy (including local injections) within 3 months before the screening visit or used or received treatment with prescription topical creams within 1 month before the screening visit for treatment of sarcoidosis skin lesions * Have used any therapeutic agent targeted at reducing IL-12 and/or IL-23, including but not limited to, ustekinumab and briakinumab within 6 months or 5 half-lives of the agent, whichever is longer, prior to the screening visit * have received natalizumab or agents that deplete or modulate the activity of B cells or T cells within 12 months of screening, or, if after receiving these agents, evidence is available at screening of persistent depletion of the targeted lymphocyte population * have used any antibody (monoclonal or polyclonal) or antibody-based agents \<= 6 months or within 5 half-lives of the biologic prior to the screening visit, whichever is longer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 16 | Baseline (Day 1) and Week 16 | Forced vital capacity (FVC) is a standard pulmonary function test used to quantify respiratory muscle weakness . FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted forced vital capacity is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change was calculated as the value at Week 16 minus the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 6-minute Walk Distance at Week 28 | Baseline (Day 1) and Week 28 | Change from Baseline in 6-minute walk distance at Week 28 was calculated as 6-minute walk distance at Week 28 minus 6-minute walk distance at Baseline. The 6-minute walk distance was the total distance walked during the 6-minute walk test. |
| Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 28 | Baseline (Day 1) and Week 28 | St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Change from Baseline was calculated as the value at Week 28 minus value at Baseline. |
| Percentage of Responders With a Score of Less Than or Equal to 1 on Skin Physician's Global Assessment (SPGA) Scale | Week 28 | The SPGA is 7-point scale used to assess the condition of skin in participants. The physician checks the state of the skin and gives them score from 0 (clear) to 5 (severe). Higher scores indicate worsening of skin condition. |
| Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 28 | Baseline (Day 1) and Week 28 | Forced vital capacity (FVC) is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted forced vital capacity is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change is calculated as the value at week 28 minus the baseline value. |
Countries
Belgium, Denmark, France, Germany, Netherlands, Norway, Romania, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo was administered subcutaneously (injected under the skin by way of a needle) every 4 weeks up to Week 24. | 58 |
| Golimumab Golimumab was administered subcutaneously at a dose of 200 milligram (mg) at Week 0 and thereafter at a dose of 100 mg every 4 weeks up to Week 24. | 55 |
| Ustekinumab Ustekinumab was administered subcutaneously at a dose of 180 mg at Week 0 and thereafter at a dose of 90 mg at Week 8, 16 and 24 and matching Placebo was administered subcutaneously at Week 4, 12 and 20. | 60 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 | 1 |
| Overall Study | Other | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | Golimumab | Ustekinumab | Total |
|---|---|---|---|---|
| Age, Continuous | 49.5 Years STANDARD_DEVIATION 9.51 | 50.0 Years STANDARD_DEVIATION 9.44 | 49.8 Years STANDARD_DEVIATION 10.17 | 49.8 Years STANDARD_DEVIATION 9.67 |
| Number of Participants by stratification factors Both Pulmonary and Skin | 6 participants | 4 participants | 7 participants | 17 participants |
| Number of Participants by stratification factors Pulmonary Only | 38 participants | 38 participants | 39 participants | 115 participants |
| Number of Participants by stratification factors Skin Only | 14 participants | 13 participants | 14 participants | 41 participants |
| Sex: Female, Male Female | 29 Participants | 27 Participants | 29 Participants | 85 Participants |
| Sex: Female, Male Male | 29 Participants | 28 Participants | 31 Participants | 88 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 | 52 / 58 | 49 / 55 | 52 / 60 |
| serious Total, serious adverse events | 9 / 58 | 7 / 55 | 10 / 60 |
Outcome results
Primary
Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 16
Forced vital capacity (FVC) is a standard pulmonary function test used to quantify respiratory muscle weakness . FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted forced vital capacity is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change was calculated as the value at Week 16 minus the baseline value.
Time frame: Baseline (Day 1) and Week 16
Population: Modified intent-to-treat (mITT) population included all the participants who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 16 | 2.02 percent of predicted FVC | Standard Error 1.35 |
| Golimumab | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 16 | 1.15 percent of predicted FVC | Standard Error 1.413 |
| Ustekinumab | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 16 | -0.15 percent of predicted FVC | Standard Error 1.279 |
p-value: 0.543ANCOVA
p-value: 0.126ANCOVA
Secondary
Change From Baseline in 6-minute Walk Distance at Week 28
Change from Baseline in 6-minute walk distance at Week 28 was calculated as 6-minute walk distance at Week 28 minus 6-minute walk distance at Baseline. The 6-minute walk distance was the total distance walked during the 6-minute walk test.
Time frame: Baseline (Day 1) and Week 28
Population: mITT population included all the participants who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 6-minute Walk Distance at Week 28 | 14.52 meters | Standard Error 14.223 |
| Golimumab | Change From Baseline in 6-minute Walk Distance at Week 28 | 12.53 meters | Standard Error 14.919 |
| Ustekinumab | Change From Baseline in 6-minute Walk Distance at Week 28 | -13.22 meters | Standard Error 13.584 |
p-value: 0.896Linear Contrasts Test
p-value: 0.063Linear Contrasts Test
Secondary
Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 28
Forced vital capacity (FVC) is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted forced vital capacity is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change is calculated as the value at week 28 minus the baseline value.
Time frame: Baseline (Day 1) and Week 28
Population: mITT population included all the participants who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 28 | 1.59 percent of predicted FVC | Standard Error 1.621 |
| Golimumab | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 28 | 0.29 percent of predicted FVC | Standard Error 1.697 |
| Ustekinumab | Change From Baseline in Percent-predicted Forced Vital Capacity (FVC) at Week 28 | 0.56 percent of predicted FVC | Standard Error 1.536 |
p-value: 0.451Linear Contrast Test
p-value: 0.546Linear Contrast Test
Secondary
Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 28
St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Change from Baseline was calculated as the value at Week 28 minus value at Baseline.
Time frame: Baseline (Day 1) and Week 28
Population: mITT population included all the participants who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 28 | -9.50 Units on a scale | Standard Error 2.79 |
| Golimumab | Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 28 | -6.86 Units on a scale | Standard Error 2.921 |
| Ustekinumab | Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 28 | -4.25 Units on a scale | Standard Error 2.662 |
p-value: 0.374Linear Contrasts Test
p-value: 0.073Linear Contrasts Test
Secondary
Percentage of Responders With a Score of Less Than or Equal to 1 on Skin Physician's Global Assessment (SPGA) Scale
The SPGA is 7-point scale used to assess the condition of skin in participants. The physician checks the state of the skin and gives them score from 0 (clear) to 5 (severe). Higher scores indicate worsening of skin condition.
Time frame: Week 28
Population: Secondary population included all the participants with chronic sarcoidosis with skin involvement who have received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Responders With a Score of Less Than or Equal to 1 on Skin Physician's Global Assessment (SPGA) Scale | 30.0 Percentage of Participants | 2.79 |
| Golimumab | Percentage of Responders With a Score of Less Than or Equal to 1 on Skin Physician's Global Assessment (SPGA) Scale | 52.9 Percentage of Participants | 2.921 |
| Ustekinumab | Percentage of Responders With a Score of Less Than or Equal to 1 on Skin Physician's Global Assessment (SPGA) Scale | 14.3 Percentage of Participants | 2.662 |
p-value: 0.1931Fisher Exact
p-value: 0.2772Fisher Exact