Giant Cell Arteritis, Horton's Disease, Temporal Arteritis
Conditions
Brief summary
The purpose of this study is to determine whether ustekinumab is effective in the treatment of Giant Cell Arteritis (GCA)
Detailed description
The objective of this study is to evaluate the efficacy and safety of ustekinumab, an interleukin (IL)-12/23 inhibitor, in patients with GCA Hypothesis IL-12/23 pathway blockade may maintain disease remission in patients with GCA Specific Aims * To evaluate the safety and tolerability of ustekinumab administration in 20 patients with GCA * To evaluate the efficacy of ustekinumab for remission maintenance and glucocorticoid sparing in 20 patients with GCA
Interventions
DRUGUstekinumab
Ustekinumab is a humanized monoclonal antibody that targets the p40 subunit of IL-12 and IL-23 and inhibits cytokine - cytokine receptor coupling and signaling
DRUGPrednisone
Prednisone is an anti-inflammatory medication
Sponsors
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must meet the following criteria 1. Able and willing to provide written informed consent and to comply with the study protocol 2. Diagnosis of GCA classified according to the following criteria: * Age 50 years or older * History of erythrosedimentation rate (ESR) ≥ 50 mm/hour or C-reactive protein (CRP) ≥ 10 mg/L AND at least one of the following: * Cranial symptoms of GCA * Symptoms of polymyalgia rheumatica (PMR) AND at least one of the following: * Temporal artery biopsy revealing features of GCA * Evidence of large-vessel vasculitis by angiography or cross-sectional imaging 3. Active new-onset or relapsing active disease
Exclusion criteria
1. Allergies: Subjects who have history of previous severe allergic or anaphylactic reaction associated with the administration of monoclonal antibodies or antibody fragments. 2. Systemic infection: Subjects who have an active systemic infection. 3. Serious infection: Subjects who have had serious infections, or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of enrollment. 4. Chronic or recurrent infection: Subjects who have chronic or recurrent bacterial, viral, fungal, mycobacterial, or protozoan infection. 5. Opportunistic infection: Subjects who have, or have had, an opportunistic infection within 6 months prior to enrollment. 6. Subjects who have active hepatitis B or active hepatitis C or a documented history of HIV 7. Latent tuberculosis infection 8. Malignancy 9. Subjects with evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, immunologic, psychiatric or gastrointestinal disease that could interfere with participation in the trial according to the protocol. 10. Subjects with transplanted organs (with the exception of a corneal transplant \> 3 months prior to screening) 11. Major surgery within 8 weeks prior to Screening or planned major surgery within 12 months after Baseline 12. Pregnancy 13. The following laboratory abnormalities * Hemoglobin \< 8 gr/dL * Platelets \< 100/mm3 * White blood cell count (WBC) \< 3000/mm3 * Absolute neutrophil count \< 2000/mm3 * Absolute lymphocyte count \< 500/mm3 * Serum creatinine \> 1.4 mg/dL in female subjects and \> 1.6 mg/dL in male subjects * Total bilirubin \> 2 mg/dL * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 1.5 X upper limit of normal * Positive hepatitis B surface antigen, hepatitis B core antibody or hepatitis C antibody 14. Prohibited medications: * Subjects who received methotrexate (MTX) \> 30 mg weekly, azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil, tacrolimus, leflunomide, canakinumab, belimumab, abatacept, tocilizumab, secukinumab, infliximab, etanercept, adalimumab, golimumab, or certolizumab within the 3-month period prior to enrollment. * Subjects who had treatment with any anti-cluster designation antigen (CD)20 agent (e.g., rituximab) within the 9-month period prior to enrolment * Subjects who used any investigational drug within 1 month prior to enrollment or within 5 half-lives of the investigational agent, whichever is longer. * Low dose MTX: Patients on \< 30 mg of MTX weekly will be eligible for enrollment after a 2-week washout interval before receiving ustekinumab * Vaccines: Subjects who received any live virus or bacterial vaccinations other than bacille Calmette-Guerin (BCG) within the 3 months before the first administration of the study agent, or are expected to receive any live virus or live bacterial vaccinations during the study, or up to 3 month after the last administration of ustekinumab are not eligible. Subjects who received BCG vaccines within the 12 months before the first administration of the study agent, or are expected to receive BCG vaccines during the study, or up to 12 month after the last administration of ustekinumab are also not eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients in Glucocorticoid-free Remission | 52 weeks | The primary study endpoint, prednisone-free remission, was defined as: 1) absence of relapse from the time that remission was achieved through week 52; 2) normalization of ESR (\<40 mm/hour) and CRP (\<10 mg/L); and, 3) adherence to the protocol prednisone taper. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Flare | 52 weeks | Disease relapse was defined as the recurrence of signs or symptoms of GCA (e.g., cranial or PMR) that required treatment intensification, regardless of the ESR and CRP levels. |
| Cumulative Prednisone Dose | 52 weeks | — |
Other
| Measure | Time frame |
|---|---|
| Number of Participants With at Least One Adverse Event | 52 weeks |
Countries
United States
Participant flow
Recruitment details
Between December 2016 and August 2018, we screened 16 GCA patients for this trial. Three patients failed the screening process and 13 patients were enrolled.
Pre-assignment details
Three patients failed the screening due to dementia (N = 1), severe prednisone-induced depression (N = 1), and positive hepatitis B core antibody (N = 1)
Participants by arm
| Arm | Count |
|---|---|
| Ustekinumab Plus Prednisone 1. Ustekinumab: 90 mg of ustekinumab will be administered subcutaneously at baseline, week 4, week 12, week 20, week 28, week 36 and week 44.
2. Prednisone: All patients will receive a prednisone course tapered according to predefined schedules starting at either 60 mg, 40 mg or 20 mg. The initial dose of prednisone will be chosen by the investigators according to disease severity and comorbid medical conditions. The duration of the prednisone taper will be 6 months in all cases.
Ustekinumab: Ustekinumab is a humanized monoclonal antibody that targets the p40 subunit of IL-12 and IL-23 and inhibits cytokine - cytokine receptor coupling and signaling
Prednisone: Prednisone is an anti-inflammatory medication | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Ustekinumab Plus Prednisone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 71 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 4 / 13 |
| serious Total, serious adverse events | 1 / 13 |
Outcome results
Primary
Percentage of Patients in Glucocorticoid-free Remission
The primary study endpoint, prednisone-free remission, was defined as: 1) absence of relapse from the time that remission was achieved through week 52; 2) normalization of ESR (\<40 mm/hour) and CRP (\<10 mg/L); and, 3) adherence to the protocol prednisone taper.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ustekinumab Plus Prednisone | Percentage of Patients in Glucocorticoid-free Remission | 3 Participants |
Secondary
Cumulative Prednisone Dose
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ustekinumab Plus Prednisone | Cumulative Prednisone Dose | 2289 mg of prednisone | Standard Deviation 498 |
Secondary
Number of Participants With Disease Flare
Disease relapse was defined as the recurrence of signs or symptoms of GCA (e.g., cranial or PMR) that required treatment intensification, regardless of the ESR and CRP levels.
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ustekinumab Plus Prednisone | Number of Participants With Disease Flare | 7 Participants |
Other Pre-specified
Number of Participants With at Least One Adverse Event
Time frame: 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ustekinumab Plus Prednisone | Number of Participants With at Least One Adverse Event | 12 Participants |