Giant Cell Arteritis
Conditions
Keywords
GCA, temporal arteritis, Horton's disease
Brief summary
The primary objective of the study is to evaluate the efficacy of mavrilimumab (KPL-301) versus placebo, co-administered with a 26-week corticosteroid taper, for maintaining sustained remission for 26 weeks in subjects with new onset or relapsing/refractory giant cell arteritis (GCA).
Detailed description
This Phase 2 randomized, double-blind, placebo-controlled proof of concept study will evaluate the efficacy and safety of mavrilimumab co-administered with a 26-week corticosteroid taper in subjects with GCA. The study will consist of a screening period (up to 6 weeks), a 26-week double-blind placebo-controlled period during which subjects will receive blinded mavrilimumab or placebo co-administered with a 26-week corticosteroid taper, and a 12-week washout safety follow-up period during which subjects will discontinue and wash off blinded mavrilimumab or placebo.
Interventions
COMBINATION_PRODUCTplacebo
1 mL of placebo in a pre-filled syringe
COMBINATION_PRODUCTmavrilimumab
1 mL of 150 mg in a pre-filled syringe
DRUGprednisone
Prednisone tablets for oral administration containing either 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg or 50 mg of prednisone United States Pharmacopeia (USP)
Sponsors
Kiniksa Pharmaceuticals, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Upon successful completion of the screening procedures, diagnosis criteria will be entered into an interactive web response system, and eligible subjects will be stratified for randomized study treatment into two cohorts according to whether subjects have new-onset or relapsing/refractory disease.
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Selected Inclusion Criteria: 1. Subjects with new-onset or relapsing/refractory GCA. 2. Westergren erythrocyte sedimentation rate \> 30 mm/hour or c-reactive protein ≥ 1 mg/ dL. 3. Remission of GCA at or before Day 0. 4. Female subjects must be postmenopausal or permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the subject, or nonpregnant, nonlactating, and if sexually active having agreed to use a highly effective method of contraception. 5. Male subjects must have documented vasectomy or if sexually active must agree to use a highly effective method of contraception with their partners of childbearing potential. Selected
Exclusion criteria
1. Transplanted organs (except corneal transplant performed more than 3 months prior to randomization). 2. Concurrent enrollment in another interventional clinical study. 3. Treatment with non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the study agent, whichever was longer, prior to screening. 4. Cell-depleting biological therapies within 12 months prior to Day 0, or noncell-depleting biological therapies within 8 weeks (or 5 half-lives, whichever is longer) prior to screening. 5. Treatment with alkylating agents within 12 weeks prior to screening. 6. Intramuscular, Intra-articular or IV corticosteroids within 4 weeks prior to screening. 7. Receipt of live (attenuated) vaccine within the 4 weeks before Day 0. 8. Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of screening. 9. Female subjects who are pregnant, intending to become pregnant, or are breastfeeding. 10. Known history of allergy or reaction to any component of the mavrilimumab or placebo formulation or to any other biologic therapy or prednisone or any of its excipients. 11. Positive (or 2 indeterminate) QuantiFERON test results. 12. Clinically significant active infection or infection requiring hospitalization or IV antibiotics within 12 weeks before screening or opportunistic infection within 6 months before screening. 13. Chronic active hepatitis B infection. 14. Subjects at a high risk of infection, a history of an infected joint prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections. 15. History of cancer within the last 10 years, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. 16. Evidence of clinically-uncontrolled respiratory disease. 17. History of chronic respiratory tract infections.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Flare by Week 26 | Week 26 | Time to flare by Week 26 was defined as time from randomization to the date of first flare occurring within the 26-week period, as assessed by independent adjudication. Kaplan-Meier method used to estimate the survival functions for each treatment arm. Flare/relapse was defined as a C-reactive protein (CRP) of 1 mg/dL or greater and/or erythrocyte sedimentation rate (ESR) of 30 mm/h or greater AND at least one of the following signs or symptoms attributed to GCA: Cranial symptoms (new-onset localized headache; scalp or temporal artery tenderness; ischemic-related vision loss; unexplained mouth or jaw pain upon mastication; transient ischemic attack or stroke related to GCA); Extracranial symptoms (claudication of the extremities; symptoms of polymyalgia rheumatica); New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the aorta or other great vessels or via ultrasound of the temporal arteries. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Remission Rate at Week 26 | Week 26 | The sustained remission rate at Week 26 is defined as the percentage of participants with sustained remission, as assessed by independent adjudication, at Week 26, derived from the time to flare curve. Kaplan-Meier Survival Estimates with standard error and 95% CI for each arm. Participants who completed the treatment period without a flare by Week 26 were considered to have sustained remission. |
| Time to Elevated Erythrocyte Sedimentation Rate (ESR) by Week 26 | Week 26 | Elevated ESR is defined as first occurrence of ESR value ≥ 30 mm/hr. Participants with elevated ESR within 3 days of first dose are excluded from the analysis. Kaplan-Meier method used to estimate the survival functions for each treatment arm. |
| Time to Signs/Symptoms of Giant Cell Arteritis (GCA) or New or Worsening Vasculitis on Imaging by Week 26 | Week 26 | Kaplan-Meier method used to estimate the survival functions for each treatment arm. |
| Cumulative Corticosteroid Dose at Week 26 | Week 26 | — |
| Time to Elevated C-Reactive Protein (CRP) by Week 26 | Week 26 | Elevated CRP is defined as first occurrence of CRP value ≥ 1.0 mg/dL. Participants with elevated CRP within 3 days of first dose are excluded from the analysis. Kaplan-Meier method used to estimate the survival functions for each treatment arm. |
| Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal CRP Level | Week 26 | Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals. |
| Percentage of Participants Who Completed the 26-week Corticosteroid Taper and Who Had No Signs or Symptoms of GCA Nor New or Worsening Vasculitis by Imaging by Week 26 | Week 26 | Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals. |
| Cumulative Corticosteroid Dose at the End of the Washout Safety Follow-up Period | Final Safety Follow-up visit (Week 38) | — |
| Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal ESR | Week 26 | Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals. |
Countries
Australia, Belgium, Croatia, Estonia, Germany, Ireland, Italy, Netherlands, New Zealand, Poland, Serbia, Slovenia, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mavrilimumab Participants randomized to mavrilimumab receive 150 mg every other week by subcutaneous injection co-administered with a 26-week corticosteroid taper. | 42 |
| Placebo Participants randomized to placebo receive placebo every other week by subcutaneous injection co-administered with a 26-week corticosteroid taper. | 28 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Mavrilimumab |
|---|---|---|---|
| Age, Continuous | 69.7 years STANDARD_DEVIATION 8.31 | 69.7 years STANDARD_DEVIATION 7.48 | 69.7 years STANDARD_DEVIATION 6.98 |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 26 Participants | 67 Participants | 41 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 28 Participants | 68 Participants | 40 Participants |
| Sex: Female, Male Female | 18 Participants | 50 Participants | 32 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 28 |
| other Total, other adverse events | 33 / 42 | 25 / 28 |
| serious Total, serious adverse events | 2 / 42 | 3 / 28 |
Outcome results
Primary
Time to Flare by Week 26
Time to flare by Week 26 was defined as time from randomization to the date of first flare occurring within the 26-week period, as assessed by independent adjudication. Kaplan-Meier method used to estimate the survival functions for each treatment arm. Flare/relapse was defined as a C-reactive protein (CRP) of 1 mg/dL or greater and/or erythrocyte sedimentation rate (ESR) of 30 mm/h or greater AND at least one of the following signs or symptoms attributed to GCA: Cranial symptoms (new-onset localized headache; scalp or temporal artery tenderness; ischemic-related vision loss; unexplained mouth or jaw pain upon mastication; transient ischemic attack or stroke related to GCA); Extracranial symptoms (claudication of the extremities; symptoms of polymyalgia rheumatica); New or worsening angiographic abnormalities detected via MRI, CT/CTA, or PET-CT of the aorta or other great vessels or via ultrasound of the temporal arteries.
Time frame: Week 26
Population: Modified Intent to Treat (mITT) Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mavrilimumab | Time to Flare by Week 26 | NA weeks |
| Placebo | Time to Flare by Week 26 | 25.1 weeks |
p-value: 0.026395% CI: [0.15, 0.92]Log Rank
Secondary
Cumulative Corticosteroid Dose at the End of the Washout Safety Follow-up Period
Time frame: Final Safety Follow-up visit (Week 38)
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavrilimumab | Cumulative Corticosteroid Dose at the End of the Washout Safety Follow-up Period | 2464.93 mg | Standard Deviation 1106.636 |
| Placebo | Cumulative Corticosteroid Dose at the End of the Washout Safety Follow-up Period | 2845.45 mg | Standard Deviation 1320.115 |
p-value: 0.162995% CI: [-919.66, 158.02]ANCOVA
Secondary
Cumulative Corticosteroid Dose at Week 26
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mavrilimumab | Cumulative Corticosteroid Dose at Week 26 | 2074.15 mg | Standard Deviation 708.433 |
| Placebo | Cumulative Corticosteroid Dose at Week 26 | 2402.98 mg | Standard Deviation 1014.446 |
p-value: 0.066795% CI: [-675.99, 23.09]ANCOVA
Secondary
Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal CRP Level
Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mavrilimumab | Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal CRP Level | 23.8 percentage of participants |
| Placebo | Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal CRP Level | 14.3 percentage of participants |
p-value: 0.553395% CI: [-8.7, 27.8]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal ESR
Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mavrilimumab | Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal ESR | 45.2 percentage of participants |
| Placebo | Percentage of Participants Who Completed the 26-Week Corticosteroid Taper and Who Had a Normal ESR | 14.3 percentage of participants |
p-value: 0.020195% CI: [11.1, 50.8]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Completed the 26-week Corticosteroid Taper and Who Had No Signs or Symptoms of GCA Nor New or Worsening Vasculitis by Imaging by Week 26
Participants were considered to have completed the corticosteroid taper if by week 26 receiving 1 mg/day for those who start with 60 mg/day, or 0 mg/day for those who start with doses \< 60 mg/day. 95% CI calculated using Clopper-Pearson confidence intervals.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mavrilimumab | Percentage of Participants Who Completed the 26-week Corticosteroid Taper and Who Had No Signs or Symptoms of GCA Nor New or Worsening Vasculitis by Imaging by Week 26 | 71.4 percentage of participants |
| Placebo | Percentage of Participants Who Completed the 26-week Corticosteroid Taper and Who Had No Signs or Symptoms of GCA Nor New or Worsening Vasculitis by Imaging by Week 26 | 32.1 percentage of participants |
p-value: 0.003195% CI: [17.2, 61.3]Cochran-Mantel-Haenszel
Secondary
Sustained Remission Rate at Week 26
The sustained remission rate at Week 26 is defined as the percentage of participants with sustained remission, as assessed by independent adjudication, at Week 26, derived from the time to flare curve. Kaplan-Meier Survival Estimates with standard error and 95% CI for each arm. Participants who completed the treatment period without a flare by Week 26 were considered to have sustained remission.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mavrilimumab | Sustained Remission Rate at Week 26 | 83.2 percentage of participants |
| Placebo | Sustained Remission Rate at Week 26 | 49.9 percentage of participants |
Comparison: Secondary endpoints were analyzed in hierarchical order.p-value: 0.003895% CI: [10.7, 55.8]normal approximation
Secondary
Time to Elevated C-Reactive Protein (CRP) by Week 26
Elevated CRP is defined as first occurrence of CRP value ≥ 1.0 mg/dL. Participants with elevated CRP within 3 days of first dose are excluded from the analysis. Kaplan-Meier method used to estimate the survival functions for each treatment arm.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period. Participants with elevated CRP within 3 days of first dose are excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mavrilimumab | Time to Elevated C-Reactive Protein (CRP) by Week 26 | NA weeks |
| Placebo | Time to Elevated C-Reactive Protein (CRP) by Week 26 | 12.3 weeks |
Comparison: Secondary endpoints were analyzed in hierarchical order.p-value: 0.037895% CI: [0.19, 0.98]Log Rank
Secondary
Time to Elevated Erythrocyte Sedimentation Rate (ESR) by Week 26
Elevated ESR is defined as first occurrence of ESR value ≥ 30 mm/hr. Participants with elevated ESR within 3 days of first dose are excluded from the analysis. Kaplan-Meier method used to estimate the survival functions for each treatment arm.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period. Participants with elevated ESR within 3 days of first dose are excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mavrilimumab | Time to Elevated Erythrocyte Sedimentation Rate (ESR) by Week 26 | 26.1 weeks |
| Placebo | Time to Elevated Erythrocyte Sedimentation Rate (ESR) by Week 26 | 12.1 weeks |
Comparison: Secondary endpoints were analyzed in hierarchical order.p-value: 0.027795% CI: [0.27, 0.95]Log Rank
Secondary
Time to Signs/Symptoms of Giant Cell Arteritis (GCA) or New or Worsening Vasculitis on Imaging by Week 26
Kaplan-Meier method used to estimate the survival functions for each treatment arm.
Time frame: Week 26
Population: mITT Analysis Set: all randomized participants who received at least 1 dose of mavrilimumab or placebo and had at least 1 assessment in the double-blind treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mavrilimumab | Time to Signs/Symptoms of Giant Cell Arteritis (GCA) or New or Worsening Vasculitis on Imaging by Week 26 | NA weeks |
| Placebo | Time to Signs/Symptoms of Giant Cell Arteritis (GCA) or New or Worsening Vasculitis on Imaging by Week 26 | 25.1 weeks |
Comparison: Secondary endpoints were analyzed in hierarchical order.p-value: 0.065195% CI: [0.22, 1.06]Log Rank