Gout
Conditions
Brief summary
These are two replicate studies to evaluate the safety and efficacy of PEG (polyethylene glycol)-uricase in controlling the uric acid level in symptomatic gout patients with high uric acid levels who are unable to take standard gout therapies, or for whom those therapies have been unsuccessful in controlling their uric acid level.
Detailed description
The primary objective of each of the studies is to demonstrate superiority in the response rate (control of uric acid levels to below 6 mg/dL) in the PEG-uricase treatment groups compared to the placebo-control group. While reduction or resolution of tophi have been reported in the setting of prolonged urate-lowering therapy, there is photographic and additional anecdotal evidence from the Phase 2 PEG-uricase study of resolution or significant reduction of tophi after 3 months of therapy. Therefore, an assessment of changes in tophi over time will be conducted through the use of digital photographs obtained in a standardized manner from all subjects during the study. The effect on other clinical outcomes, including quality of life, health-related disability measures, gout flares and the number of swollen and tender joints will also be compared between the treatment groups and control group. Subjects will be randomized to one of the three treatment arms in a 2:2:1 ratio: 8 mg PEG-uricase every 2 weeks; 8 mg PEG-uricase every 4 weeks; or placebo. All subjects will receive an intravenous infusion (PEG-uricase or placebo) every two weeks in order to maintain the blind throughout the study. Study duration is approximately 26 weeks, including two weeks for screening and 24 weeks (6 months) of treatment.
Interventions
OTHERplacebo
placebo by intravenous infusion every 2 weeks
BIOLOGICALpegloticase
8 mg pegloticase by intravenous infusion
Sponsors
Savient Pharmaceuticals
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
1. Outpatients of either gender, age 18 or older ( no upper age limit). 2. Patient is hyperuricemic: screening serum uric acid must be ≥8 mg/dL. 3. Patient has symptomatic gout (presence of at least 3 gout flares in the 18 months prior to entry, or at least one gout tophus, or gouty arthritis). 4. Conventional therapy is contraindicated or has been ineffective in this patient, i.e., patient has a history (either by medical record or patient interview) of hypersensitivity or of failure to normalize SUA with at least 3 months treatment with allopurinol at the maximum labeled dose (800 mg/dL in the U.S.), or at a medically appropriate lower dose based on dose-limiting toxicity or dose-limiting co-morbidity. 5. Patient is willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed, including washout). 6. If the patient is a woman of childbearing potential, she must have had a negative screening serum pregnancy test and must use a medically approved form of birth control during her participation in the protocol. Such methods include oral, injectable or implantable contraceptives; IUDs and barrier contraceptives in combination with spermicide. (If male or surgically sterile, check N/A.)
Exclusion criteria
1. The patient has unstable angina. 2. The patient has uncontrolled arrhythmia. 3. The patient has non-compensated congestive heart failure. 4. The patient has uncontrolled hypertension (above 150/95). 5. The patient has a history of end stage renal disease requiring dialysis. 6. The patient has hemoglobin \< 8 g/dL (males) or \< 7 g/dL (females). 7. The patient is an organ transplant recipient 8. The patient has had prior treatment with PEG-uricase, or other recombinant uricase, or any concomitant therapy with a PEG-conjugated drug. 9. The patient has had a gout flare at screening that is resolved for less than one week prior to first treatment with study drug (exclusive of chronic synovitis/ arthritis). 10. The patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency. 11. The patient has a history of anaphylactic reaction to a recombinant protein or porcine product, or hypersensitivity to PEG. 12. The patient is pregnant or breast feeding. 13. The patient has taken an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study. 14. The patient has a known allergy to urate oxidase or PEGylated products. 15. The patient has any other medical or psychological condition which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Uric Acid (PUA) Responder | Months 3 and 6 | PUA Responder was defined as a participant who achieved and maintained plasma uric acid concentrations \< 6 mg/dL for at least 80% of the time during months 3 and 6 combined. Participants who withdrew from the study before month 6 were considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Tophus Burden | Baseline and Final Visit (6 months or LOCF) | percentage of tophaceous subjects who demonstrated a complete resolution (100 % decrease in measured area or complete disappearance)of at least one tophus in the absence of other tophus progression or new tophi, as assessed by a blinded Central Reader using standardized digital photographs and image analysis software. |
| Percentage of Subjects With Gout Flare Per 3-month Period | Months 1-3 and Months 4-6 | Percent of participants reporting a gout flare during Months 1-3 and Months 4-6. Denominator during the respective period was based upon number of participants during that period. |
| Change in Number of Swollen Joints | Baseline and Final Visit (Month 6 or LOCF) | Change from Baseline to Month 6 (or last observation carried forward)in number of swollen joints per subject. Values were inputed using last observation carried forward analysis for subjects who did not complete the studies. |
| Change in Number of Tender Joints | Baseline and Final Visit (Month 6 or LOCF) | Change from Baseline to Month 6 (or last observation carried forward) in number of tender joints per participant |
| Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | Baseline to Final Visit (Month 6 or LOCF) | Health Assessment Questionnaire(HAQ: VAS pain scale where 0 (no pain)-100 (severe pain); HAQ disability index (HAQ-DI) on a scale from 0(no disability) to 3 (completely disabled), and a unit change of \> or =0.22 is considerd a mimimal clinically important difference(MCID). SF-36 Physical Component Summary Score (SF36-PCS), a composite score where 0 is the worst score and 100 the best possible, and where a change of \> or =2.5 units in the PCS is considered a MCID. |
Countries
Canada, Mexico, United States
Participant flow
Recruitment details
Rheumatology practices across the US, Canada and Mexico
Pre-assignment details
13 subjects were randomized but withdrew before intervention. These subjects were not part of the modified Intent to Treat Population, which included only subjects who received at least one dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| q2 Wks 8 mg pegloticase every 2 weeks | 85 |
| q4 Wks 8 mg pegloticase every 4 weeks (alternating with placebo infusion every 4 weeks) | 84 |
| Placebo placebo infusion every 2 weeks | 43 |
| Total | 212 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomized | Not dosed | 5 | 5 | 3 |
| Received Intervention: ITT Population | Adverse Event | 15 | 17 | 1 |
| Received Intervention: ITT Population | Death | 3 | 1 | 0 |
| Received Intervention: ITT Population | Lost to Follow-up | 0 | 0 | 2 |
| Received Intervention: ITT Population | Protocol violation/non-compliance | 1 | 1 | 0 |
| Received Intervention: ITT Population | Withdrawal by Subject | 7 | 6 | 1 |
Baseline characteristics
| Characteristic | q2 Wks | q4 Wks | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 29 Participants | 19 Participants | 12 Participants | 60 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 65 Participants | 31 Participants | 152 Participants |
| Age Continuous | 56.3 years STANDARD_DEVIATION 15.53 | 54.5 years STANDARD_DEVIATION 13.34 | 55.4 years STANDARD_DEVIATION 12.21 | 55.4 years STANDARD_DEVIATION 14.01 |
| Region of Enrollment Canada | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Mexico | 11 participants | 6 participants | 3 participants | 20 participants |
| Region of Enrollment United States | 73 participants | 77 participants | 39 participants | 189 participants |
| Sex: Female, Male Female | 17 Participants | 15 Participants | 7 Participants | 39 Participants |
| Sex: Female, Male Male | 68 Participants | 69 Participants | 36 Participants | 173 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 | 69 / 85 | 79 / 84 | 36 / 43 |
| serious Total, serious adverse events | 20 / 85 | 19 / 84 | 5 / 43 |
Outcome results
Primary
Plasma Uric Acid (PUA) Responder
PUA Responder was defined as a participant who achieved and maintained plasma uric acid concentrations \< 6 mg/dL for at least 80% of the time during months 3 and 6 combined. Participants who withdrew from the study before month 6 were considered non-responders.
Time frame: Months 3 and 6
Population: Modified ITT (all patients receiving at least one dose of study drug). Participants dropping out before Week 25 were imputed as Non-Responders
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| q2 Wks | Plasma Uric Acid (PUA) Responder | 36 Participants |
| q4 Wks | Plasma Uric Acid (PUA) Responder | 29 Participants |
| Placebo | Plasma Uric Acid (PUA) Responder | 0 Participants |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Change in Number of Swollen Joints
Change from Baseline to Month 6 (or last observation carried forward)in number of swollen joints per subject. Values were inputed using last observation carried forward analysis for subjects who did not complete the studies.
Time frame: Baseline and Final Visit (Month 6 or LOCF)
Population: All ITT participants with baseline and at least one post-baseline assessment were included in analysis. LOCF was used for participants dropping out early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| q2 Wks | Change in Number of Swollen Joints | -5.5 Swollen joints | Standard Deviation 10.47 |
| q4 Wks | Change in Number of Swollen Joints | -5.1 Swollen joints | Standard Deviation 7.83 |
| Placebo | Change in Number of Swollen Joints | -2.6 Swollen joints | Standard Deviation 11.64 |
p-value: 0.166t-test, 2 sided
p-value: 0.17t-test, 2 sided
Secondary
Change in Number of Tender Joints
Change from Baseline to Month 6 (or last observation carried forward) in number of tender joints per participant
Time frame: Baseline and Final Visit (Month 6 or LOCF)
Population: All ITT participants with baseline and at least one post-baseline assessment were included in analysis. LOCF was used for participants dropping out early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| q2 Wks | Change in Number of Tender Joints | -7.4 Tender joints | Standard Deviation 11.95 |
| q4 Wks | Change in Number of Tender Joints | -6.1 Tender joints | Standard Deviation 10.64 |
| Placebo | Change in Number of Tender Joints | -1.2 Tender joints | Standard Deviation 12.3 |
p-value: 0.008t-test, 2 sided
p-value: 0.024t-test, 2 sided
Secondary
Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life
Health Assessment Questionnaire(HAQ: VAS pain scale where 0 (no pain)-100 (severe pain); HAQ disability index (HAQ-DI) on a scale from 0(no disability) to 3 (completely disabled), and a unit change of \> or =0.22 is considerd a mimimal clinically important difference(MCID). SF-36 Physical Component Summary Score (SF36-PCS), a composite score where 0 is the worst score and 100 the best possible, and where a change of \> or =2.5 units in the PCS is considered a MCID.
Time frame: Baseline to Final Visit (Month 6 or LOCF)
Population: Number of participants analyzed was based upon the number who had baseline and at least one follow-up assessment, with the final visit for each subject included (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| q2 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-DI | -0.22 Units on a scale | Standard Deviation 0.64 |
| q2 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-VAS Pain | -11.4 Units on a scale | Standard Deviation 33.8 |
| q2 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | SF-36 PCS | 4.4 Units on a scale | Standard Deviation 9.4 |
| q4 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-DI | -0.20 Units on a scale | Standard Deviation 0.55 |
| q4 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-VAS Pain | -6.9 Units on a scale | Standard Deviation 27 |
| q4 Wks | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | SF-36 PCS | 4.9 Units on a scale | Standard Deviation 8.5 |
| Placebo | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-VAS Pain | 1.4 Units on a scale | Standard Deviation 30 |
| Placebo | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | SF-36 PCS | -0.3 Units on a scale | Standard Deviation 9 |
| Placebo | Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | HAQ-DI | 0.0 Units on a scale | Standard Deviation 0.41 |
Secondary
Percentage of Subjects With Gout Flare Per 3-month Period
Percent of participants reporting a gout flare during Months 1-3 and Months 4-6. Denominator during the respective period was based upon number of participants during that period.
Time frame: Months 1-3 and Months 4-6
Population: Number analyzed in each period was based upon number of participants remaining in study during the assessed treatment period: 85/84/43 in Months 1-3 and 69/69/43 in Months 4-6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| q2 Wks | Percentage of Subjects With Gout Flare Per 3-month Period | Months 1-3 | 75 Percent subjects reporting flares |
| q2 Wks | Percentage of Subjects With Gout Flare Per 3-month Period | Months 4-6 | 41 Percent subjects reporting flares |
| q4 Wks | Percentage of Subjects With Gout Flare Per 3-month Period | Months 1-3 | 81 Percent subjects reporting flares |
| q4 Wks | Percentage of Subjects With Gout Flare Per 3-month Period | Months 4-6 | 56 Percent subjects reporting flares |
| Placebo | Percentage of Subjects With Gout Flare Per 3-month Period | Months 1-3 | 54 Percent subjects reporting flares |
| Placebo | Percentage of Subjects With Gout Flare Per 3-month Period | Months 4-6 | 67 Percent subjects reporting flares |
Comparison: % of pegloticase q2 participants reporting flares compared to placebo pts during Months 4-6 treatment periodp-value: 0.007Fisher Exact
Comparison: % of pegloticase q4 participants reporting flares compared to placebo pts during Months 4-6 treatment periodp-value: 0.321Fisher Exact
Secondary
Reduction in Tophus Burden
percentage of tophaceous subjects who demonstrated a complete resolution (100 % decrease in measured area or complete disappearance)of at least one tophus in the absence of other tophus progression or new tophi, as assessed by a blinded Central Reader using standardized digital photographs and image analysis software.
Time frame: Baseline and Final Visit (6 months or LOCF)
Population: Number of participants analyzed was based upon the number of patients who had one or more tophus at Baseline, as determined by the PI, AND who had at least one follow-up assessment, with the final visit for each subject included (last observation carried forward).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| q2 Wks | Reduction in Tophus Burden | 40 Percent subjects with resolved tophus |
| q4 Wks | Reduction in Tophus Burden | 21 Percent subjects with resolved tophus |
| Placebo | Reduction in Tophus Burden | 7 Percent subjects with resolved tophus |
p-value: <0.002Fisher Exact
p-value: 0.2Fisher Exact