Familial Cold Autoinflammatory Syndrome (FCAS), Familial Cold Urticaria, Genetic Diseases, Inborn, Muckle-Wells Syndrome (MWS)
Conditions
Keywords
Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), CIAS1, NLRP-3, PYPAF1, Cryopyrin, CAPS, Interleukin-1
Brief summary
Inflammatory symptoms of Cryopyrin-Associated Periodic Syndrome (CAPS) are due to mutations in a the NLRP-3 gene (previously known as Cold Induced Autoinflammatory Syndrome-1 or CIAS1). These mutations result in the body's overproduction of interleukin-1 (IL-1), a protein that stimulates the inflammatory process. IL-1 Trap (rilonacept) was designed to bind to the interleukin-1 cytokine and prevent it from binding to its receptors in the body.
Detailed description
Primary Objective: The primary objective of this study was to assess the effect of rilonacept on the clinical signs and symptoms of Cryopyrin-Associated Periodic Syndrome (CAPS) when used for chronic therapy as evaluated by the subjects themselves over time using a validated patient-reported outcomes tool. Secondary Objective(s): The secondary objectives were as follows: * To determine the safety and tolerability of rilonacept in subjects with CAPS * To assess the effect of rilonacept on laboratory measures of inflammation such as acute phase reactants This was a multi-center, two-part, double-blind, placebo-controlled study (Parts A and B) designed to assess the efficacy, safety, and tolerability of weekly subcutaneous (SC) doses of 160 mg of rilonacept in adult subjects with active CAPS. These phases were followed by extended open-label phases. After written informed consent was obtained, subjects who met the protocol eligibility criteria were enrolled at one of 27 study sites in the United States. The study consisted of a 3-week screening period preceding Part A, a 6-week long double-blind, randomized phase of the study. All subjects were then treated with single-blind rilonacept for 9-weeks, followed by a subsequent 9-week, double-blind, withdrawal phase during which subjects were re-randomized to either rilonacept or placebo. Subjects then continued treatment in a 24-week open-label extension phase (OLE) and a further 112-week long-term open-label extension (LTOLE), during which all subjects received rilonacept and a 6-week post-treatment follow-up period. Amendments 4 and 6 allowed eligible adult and pediatric subjects aged 7 and above to enroll directly into the open-label phases of the trial. For reporting purposes, the 24-week OLE and the 112-week LTOLE was considered one Open Label Extension (OLE) phase. This occurred after the 24-week double blind (Parts A and B ) phase. In other words, OLE Week 1 corresponded to the week 25 in the study. OLE Week 72 was the final timepoint where efficacy was measured. Safety continued after that timepoint until the end of the study.
Interventions
Rilonacept was given by subcutaneous injection. It was administered weekly at the dose of 160mg. On Day 1, subjects received two injections of rilonacept (for a total of 320 mg).
DRUGPlacebo
Subcutaneous injection of Placebo occurred during first 6 weeks of the study or during randomized withdrawal (weeks 15-24). On Day 1, subjects received two placebo injections.
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Double-blind phases: adults age 18 and above; Open-label extension: Adults and children aged 7 years and older. * Was diagnosed with Familial Cold Auto-inflammatory Syndrome (FCAS) or Muckle-Wells Syndrome (MWS) based upon clinical signs and symptoms * Had documented mutation in NLRP-3 (Cold Induced Autoinflammatory Syndrome-1 or CIAS1) in subject or relative, and willingness to have a confirmatory genetic (Deoxyribonucleic acid or DNA) test (cheek swab). * Was able to understand and comply with study procedures and was able to provide informed consent * If female, was not currently pregnant and was willing to use contraception during the study
Exclusion criteria
* Had evidence of untreated tuberculosis or other conditions/therapies that made the subject inappropriate for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Baseline (Days -21 to -1) and Week 6 (Days 21-42) | The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was averaged over two 21-day daily reporting periods (the 3 weeks prior to both baseline and week 6). In part A, a negative change in mean values indicated improvement under treatment with rilonacept in symptoms. The DHAF was used because it is a validated instrument to collect subject's self-reported responses. |
| Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Week 15 through Week 24 (randomized withdrawal) | The mean Key Symptom Score (KSS --from the validated, patient-administered DHAF) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). Subjects all received rilonacept 160 mg from week 6 through week 14. At week 15, subjects were re-randomized in a 1:1 ratio between Placebo and rilonacept 160 mg. Subjects baseline period was the 21-day period prior to week 15 randomization. A positive score indicated a worsening of symptoms versus an active treatment rilonacept baseline period. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Baseline to Week 6 (Part A) | The Patient's Global Assessment was a question on the Daily Health Assessment Form Considering all the ways that Familial Cold Autoinflmatory Syndrome (FCAS) /Muckle-Wells Syndrome (MWS) affects you, please rate how you are doing based on the following scale 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement. |
| Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Baseline to Endpoint of Part A | An abnormal value for CRP was considered \> 8.4 mg/L. |
| Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Baseline to Endpoint of Part A | An abnormal value for SAA was considered \> 6.4 mg/L. |
| Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | Baseline to Endpoint (Week 6) | The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). |
| Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Baseline to Week 6 (Part A) | A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The KSS was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was calculated for 21 Day Periods at baseline and at the endpoint (from Weeks 3 - 6). The difference in the number of flares between the two periods was averaged for all subjects. The DHAF was used because it is a validated instrument to collect subject's self-reported responses. It was the basis for the KSS and the flare day count. |
| Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | Baseline to Week 6 (Part A) | The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). |
| Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS | From Baseline (week 0) to OLE Week 72 | OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis. The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). A negative change in mean values indicated improvement in symptoms. |
| Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment | From Baseline (Week 0) to OLE Week 72 | The Patient's Global Assessment was a question on the Daily Health Assessment Form Considering all the ways that FCAS/MWS affects you, please rate how you are doing based on the following scale 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement. OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis. |
| Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days | From Baseline (Week 0) to OLE Week 72 | OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis. A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). |
| Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | Baseline to Week 6 (Part A) | The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). |
| Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Baseline to Week 6 (Part A) | The Physician's Global Assessment was an evaluation at each visit on a scale of 0=no disease activity to 10=severe disease activity. A negative value in change in Physician's Global Assessment is indicative of an improvement. |
Countries
United States
Participant flow
Recruitment details
47 subjects were randomized into Part A. 44 of these subjects continued into the open label extension (OLE). 57 subjects were enrolled directly into the OLE without completing parts A and B of the study. 104 total subjects were in the entire study. 101 were in the OLE.
Pre-assignment details
The study population included male or female adult subjects (Parts A and B), and adult and pediatric subjects (OLE phase), with confirmed NLRP-3 (Cold Induced Autoinflammatory Syndrome-1 or CIAS1) gene mutation. Only one person per household was enrolled into Parts A and B of the study. However, multiple family members went into the OLE.
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 24 |
| Rilonacept 160 mg | 23 |
| Open-Label Rilonacept 160 mg 57 new subjects entered the study directly into the OLE. This was not part of the double blind or randomized withdrawal portion of the results. The 44 subjects who completed Parts A and B were not included in this category for baseline characteristics. Pediatric subjects , age 7 or older, received rilonacept dosed 2.2 mg/kg weekly up to 160 mg during the OLE. | 57 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-Label Extension (OLE) Weeks 24-117 | Adverse Event | 0 | 0 | 1 |
| Open-Label Extension (OLE) Weeks 24-117 | Death | 0 | 0 | 2 |
| Open-Label Extension (OLE) Weeks 24-117 | Pregnancy | 0 | 0 | 1 |
| Open-Label Extension (OLE) Weeks 24-117 | Sponsor Decision | 0 | 0 | 15 |
| Open-Label Extension (OLE) Weeks 24-117 | Withdrawal by Subject | 0 | 0 | 1 |
| Part A, Double Blind, Weeks 1-6 | Pre-dose Condition | 0 | 1 | 0 |
| Part B, Randomized Withdrawal, Wks 15-24 | Adverse Event | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Rilonacept 160 mg | Open-Label Rilonacept 160 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 8 Participants | 8 Participants |
| Age, Categorical >=65 years | 7 Participants | 3 Participants | 3 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 20 Participants | 46 Participants | 83 Participants |
| Age Continuous | 55.5 years STANDARD_DEVIATION 14.7 | 45.9 years STANDARD_DEVIATION 16 | 37.7 years STANDARD_DEVIATION 17.2 | 43.6 years STANDARD_DEVIATION 17.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 23 Participants | 56 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 23 Participants | 57 Participants | 104 Participants |
| Region of Enrollment United States | 24 participants | 23 participants | 57 participants | 104 participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 37 Participants | 68 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 20 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 23 | 13 / 24 |
| serious Total, serious adverse events | 7 / 104 | 0 / 24 |
Outcome results
Primary
Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS)
The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was averaged over two 21-day daily reporting periods (the 3 weeks prior to both baseline and week 6). In part A, a negative change in mean values indicated improvement under treatment with rilonacept in symptoms. The DHAF was used because it is a validated instrument to collect subject's self-reported responses.
Time frame: Baseline (Days -21 to -1) and Week 6 (Days 21-42)
Population: Cryopyrin Associated Autoinflammatory Syndrome (CAPS) is a rare, orphan, hereditary disease. There are several hundred CAPS cases in the United States.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Baseline Part A | 2.4 Units of a Scale | Standard Deviation 1.5 |
| Placebo | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Endpoint Part A (Week 6) in KSS | 2.1 Units of a Scale | Standard Deviation 1.6 |
| Placebo | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Change to Week 6 in KSS | -0.3 Units of a Scale | Standard Deviation 0.7 |
| Rilonacept 160 mg | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Baseline Part A | 3.1 Units of a Scale | Standard Deviation 1.9 |
| Rilonacept 160 mg | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Endpoint Part A (Week 6) in KSS | 0.5 Units of a Scale | Standard Deviation 0.5 |
| Rilonacept 160 mg | Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) | Change to Week 6 in KSS | -2.6 Units of a Scale | Standard Deviation 1.9 |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001ANCOVA
Primary
Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B)
The mean Key Symptom Score (KSS --from the validated, patient-administered DHAF) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). Subjects all received rilonacept 160 mg from week 6 through week 14. At week 15, subjects were re-randomized in a 1:1 ratio between Placebo and rilonacept 160 mg. Subjects baseline period was the 21-day period prior to week 15 randomization. A positive score indicated a worsening of symptoms versus an active treatment rilonacept baseline period.
Time frame: Week 15 through Week 24 (randomized withdrawal)
Population: Subjects were re-randomized as part of the randomized withdrawal period (Part B). Subjects were not necessarily assigned the same treatment as in the first double-blind portion (Part A). Subjects were analyzed using last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Baseline Part B | 0.2 Units of a Scale | Standard Deviation 0.4 |
| Placebo | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Endpoint Part B (Week 24) in KSS | 1.2 Units of a Scale | Standard Deviation 1 |
| Placebo | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Change to Week 24 in KSS | 0.9 Units of a Scale | Standard Deviation 0.9 |
| Rilonacept 160 mg | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Baseline Part B | 0.3 Units of a Scale | Standard Deviation 0.3 |
| Rilonacept 160 mg | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Endpoint Part B (Week 24) in KSS | 0.4 Units of a Scale | Standard Deviation 0.5 |
| Rilonacept 160 mg | Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) | Change to Week 24 in KSS | 0.1 Units of a Scale | Standard Deviation 0.4 |
Comparison: Subjects received rilonacept 160 mg for 9 weeks (weeks 6-15), and then were re-randomized 1:1 into either Placebo or rilonacept 160 mg. The endpoint for the period was 9 weeks later (week 24).~The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.001ANCOVA
Other Pre-specified
Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment
The Physician's Global Assessment was an evaluation at each visit on a scale of 0=no disease activity to 10=severe disease activity. A negative value in change in Physician's Global Assessment is indicative of an improvement.
Time frame: Baseline to Week 6 (Part A)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Baseline Part A | 4.7 Units of a Scale | Standard Deviation 2 |
| Placebo | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Endpoint Part A in Physician's Global Assessment | 5.0 Units of a Scale | Standard Deviation 2.5 |
| Placebo | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Change to Week 6 in Physician's Global Assessment | 0.2 Units of a Scale | Standard Deviation 2.1 |
| Rilonacept 160 mg | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Baseline Part A | 5.6 Units of a Scale | Standard Deviation 1.7 |
| Rilonacept 160 mg | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Endpoint Part A in Physician's Global Assessment | 1.5 Units of a Scale | Standard Deviation 1.4 |
| Rilonacept 160 mg | Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment | Change to Week 6 in Physician's Global Assessment | -4.2 Units of a Scale | Standard Deviation 2.4 |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001ANCOVA
Other Pre-specified
Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days
OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis. A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).
Time frame: From Baseline (Week 0) to OLE Week 72
Population: 44 subjects entered from part A of the study, and 12 subjects entered directly into the OLE. No placebo subjects were in the OLE.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days | Baseline | 7.3 Number of Days | Standard Deviation 6.4 |
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days | Endpoint in OLE Week 72 Disease Flare Days | 0.6 Number of Days | Standard Deviation 3 |
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days | Change to OLE Week 72 in Disease Flare Days | -6.7 Number of Days | Standard Deviation 6.9 |
Other Pre-specified
Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment
The Patient's Global Assessment was a question on the Daily Health Assessment Form Considering all the ways that FCAS/MWS affects you, please rate how you are doing based on the following scale 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement. OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis.
Time frame: From Baseline (Week 0) to OLE Week 72
Population: 44 subjects entered from part A of the study, and 12 subjects entered directly into the OLE. No placebo subjects were in the OLE.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment | Baseline | 3.4 Units of a Scale | Standard Deviation 1.9 |
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment | OLE Week 72 in Patient's Global Assessment | 0.4 Units of a Scale | Standard Deviation 0.6 |
| Placebo | Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment | Change to OLE Wk 72 in Patient's Global Assessment | -3.0 Units of a Scale | Standard Deviation 2 |
Other Pre-specified
Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient
A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The KSS was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was calculated for 21 Day Periods at baseline and at the endpoint (from Weeks 3 - 6). The difference in the number of flares between the two periods was averaged for all subjects. The DHAF was used because it is a validated instrument to collect subject's self-reported responses. It was the basis for the KSS and the flare day count.
Time frame: Baseline to Week 6 (Part A)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Baseline Part A | 6.2 Days | Standard Deviation 6 |
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Endpoint Part A (Week 6) in Flare Days | 5.0 Days | Standard Deviation 6.1 |
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Change to Week 6 in Flare Days | -1.2 Days | Standard Deviation 3.6 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Baseline Part A | 8.6 Days | Standard Deviation 7.2 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Endpoint Part A (Week 6) in Flare Days | 0.1 Days | Standard Deviation 0.5 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient | Change to Week 6 in Flare Days | -8.4 Days | Standard Deviation 7.1 |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001ANCOVA
Other Pre-specified
Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment
The Patient's Global Assessment was a question on the Daily Health Assessment Form Considering all the ways that Familial Cold Autoinflmatory Syndrome (FCAS) /Muckle-Wells Syndrome (MWS) affects you, please rate how you are doing based on the following scale 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement.
Time frame: Baseline to Week 6 (Part A)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Baseline in Part A | 3.1 Visual Analog Scale | Standard Deviation 2 |
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Endpoint Part A in Patient's Global Assessment | 2.7 Visual Analog Scale | Standard Deviation 1.8 |
| Placebo | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Change to Week 6 in Patient's Global Assessment | -0.4 Visual Analog Scale | Standard Deviation 1.1 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Baseline in Part A | 3.6 Visual Analog Scale | Standard Deviation 2.1 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Endpoint Part A in Patient's Global Assessment | 0.9 Visual Analog Scale | Standard Deviation 1.1 |
| Rilonacept 160 mg | Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment | Change to Week 6 in Patient's Global Assessment | -2.7 Visual Analog Scale | Standard Deviation 2.2 |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001ANCOVA
Other Pre-specified
Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L)
An abnormal value for CRP was considered \> 8.4 mg/L.
Time frame: Baseline to Endpoint of Part A
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Baseline Part A | 25.2 Milligrams per Liter | Standard Deviation 15.7 |
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Endpoint Part A in CRP | 21.8 Milligrams per Liter | Standard Deviation 23.9 |
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Change to Part A Endpoint in CRP | -2.1 Milligrams per Liter | Standard Deviation 15.5 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Baseline Part A | 20.1 Milligrams per Liter | Standard Deviation 14.7 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Endpoint Part A in CRP | 1.3 Milligrams per Liter | Standard Deviation 2.2 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) | Change to Part A Endpoint in CRP | -18.4 Milligrams per Liter | Standard Deviation 14.3 |
Comparison: Please note that the changes are medians (not means).~The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001ANCOVA
Other Pre-specified
Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L)
An abnormal value for SAA was considered \> 6.4 mg/L.
Time frame: Baseline to Endpoint of Part A
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Baseline Part A | 63.5 Milligrams per Liter | Standard Deviation 122.3 |
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Endpoint Part A in SAA | 39.7 Milligrams per Liter | Standard Deviation 153.7 |
| Placebo | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Change to Endpoint in SAA | -2.8 Milligrams per Liter | Standard Deviation 79.7 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Baseline Part A | 49.5 Milligrams per Liter | Standard Deviation 48.3 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Endpoint Part A in SAA | 2.5 Milligrams per Liter | Standard Deviation 4 |
| Rilonacept 160 mg | Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) | Change to Endpoint in SAA | -48.5 Milligrams per Liter | Standard Deviation 48.5 |
Comparison: Please note that the changes are medians (not means).~The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.01ANCOVA
Other Pre-specified
Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).
Time frame: Baseline to Endpoint (Week 6)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 7 Participants |
| Rilonacept 160 mg | Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 22 Participants |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001Fisher Exact
Other Pre-specified
Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).
Time frame: Baseline to Week 6 (Part A)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 2 Participants |
| Rilonacept 160 mg | Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 20 Participants |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001Fisher Exact
Other Pre-specified
Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).
Time frame: Baseline to Week 6 (Part A)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 0 Participants |
| Rilonacept 160 mg | Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) | 16 Participants |
Comparison: The sample size calculations at the time suggested 50 subjects would be enrolled at baseline. The Full Analysis Set (FAS) was used. The FAS included subjects who received at least one dose of rilonacept. Last observation carried forward was used.p-value: <0.0001Fisher Exact
Other Pre-specified
Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS
OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis. The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). A negative change in mean values indicated improvement in symptoms.
Time frame: From Baseline (week 0) to OLE Week 72
Population: 44 subjects entered from part A of the study, and 12 subjects entered directly into the OLE. No placebo subjects were in the OLE.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS | Baseline | 2.6 Units of a scale | Standard Deviation 1.6 |
| Placebo | Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS | Endpoint (OLE Week 72) in KSS | 0.4 Units of a scale | Standard Deviation 0.5 |
| Placebo | Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS | Change to Endpoint (OLE Week 72) in KSS | -2.3 Units of a scale | Standard Deviation 1.6 |