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Clinical and epidemiological research
Concise report
Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study
  1. Lisa K Stamp1,2,
  2. Peter T Chapman2,
  3. Murray Barclay1,
  4. Anne Horne3,
  5. Christopher Frampton1,
  6. Paul Tan3,
  7. Jill Drake1,
  8. Nicola Dalbeth3
  1. 1Department of Medicine, University of Otago, Christchurch, New Zealand
  2. 2Department of Rheumatology, Immunology and Allergy, Christchurch Hospital, Christchurch, New Zealand
  3. 3Department of Medicine, University of Auckland, Auckland, New Zealand
  1. Correspondence to Professor Lisa K Stamp, Department of Medicine, University of Otago, Christchurch, P.O. Box 4345, Christchurch, New Zealand; lisa.stamp{at}cdhb.health.nz

Abstract

Objectives To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.

Methods People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.

Results The mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.

Conclusions The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.

Trial registration number ACTRN12611000845932

  • allopurinol
  • gout
  • serum urate

https://doi.org/10.1136/annrheumdis-2017-211873

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    Introduction

    Although other urate-lowering therapies (ULT) are available for gout, allopurinol is the mainstay of therapy due to its low-cost and widespread availability. Despite allopurinol being registered to 800 mg/day by the Food and Drug Administration and 900 mg/day in Europe, doses above 300 mg/day are used infrequently.1 2

    Use of allopurinol at higher than creatinine clearance (CrCL) based doses remains controversial due to concerns over increased risk of adverse events (AEs), particularly allopurinol hypersensitivity syndrome (AHS). While European League Against Rheumatism (EULAR) advocates changing ULT if target serum urate (SU) is not achieved with CrCL-based allopurinol,3 the American College of Rheumatology (ACR) advocates gradual escalation above CrCL-based doses to achieve target SU even in those with chronic kidney disease (CKD).4 We report the results of the 12-month open-label extension (OLE) of a previously reported randomised controlled trial of allopurinol dose escalation (DE).5 The aims were to determine whether target SU can be safely maintained over time, and the effects of DE to target SU strategy on clinical outcomes.

    Methods

    This paper reports the 12-month OLE of a previously published 12-month randomised, controlled, parallel-group, comparative clinical trial.5 Detailed study design and methods are available in online supplementary text 1.

    Supplementary Material

    Supplementary material 9

    Results

    Demographics

    Of the 183 participants (control/DE (n=93), DE/DE (n=90)) who entered the study, 73/93 (78.5%) control/DE and 70/90 (78.9%) DE/DE participants completed the month 12 and 68/93 (73.1%) control/DE and 69/90 (76.7%) DE/DE participants completed the month 24 (see online supplementary figure S1). Complete baseline demographics have been reported previously5 (see online supplementary table S1). Between baseline and month 24, two control/DE and five DE/DE participants discontinued allopurinol; of these only three in the DE/DE group discontinued allopurinol between months 12 and 24. Eighteen control/DE participants were not dose escalated after entering the DE phase as SU was <6 mg/dL during months 12–24.

    Supplementary Material

    Supplementary Figure 1

    Supplementary Material

    Supplementary Table 1

    Efficacy

    Primary endpoint

    The mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in the control/DE group and 0.1 (0.2) mg/dL in the DE/DE group (p<0.001); mean difference 1.3 mg/dL (95% CI 0.8 to 1.7, p<0.001). The mean (SE) change in SU from baseline to 24 months was −1.4 (0.1) mg/dL in the control/DE group and −1.7 (0.1) mg/dL in the DE/DE group (p=0.14); mean difference −0.3 mg/dL (95% CI −0.7 to 0.1, p=0.14). In the control/DE group, mean (SE) SU was 7.13 (0.16) mg/dL at baseline and 5.7 (0.2) mg/dL at final visit, and 7.18 (0.2) mg/dL and 5.4 (0.1) mg/dL in the DE/DE group (figure 1A).

    Figure 1
    Figure 1

    Mean (SEM) serum urate (A), percentage of participant achieving target serum urate (B), mean (SEM) percentage change in serum urate over the 24-month study period (C), mean (SEM) allopurinol dose in control/DE and DE/DE groups (D), percentage of participants reporting at least one gout flare in the preceding month (E), percentage of participants receiving anti-inflammatory prophylaxis (F) and mean (SD) size in tophi at each study visit (for those with measurable tophus at baseline) (G). The vertical line represents the start of the open-label extension phase of the study. DE, dose escalation.

    Secondary endpoints

    SU was <6 mg/dL at the final visit in 69.1% of the control/DE group and 79.7% in the DE/DE group (p=0.16); OR 1.8 (95% CI 0.8 to 3.8) (figure 1B). Of those not at target at month 24, nine (six control/DE and three DE/DE) had been at target for all other visits from month 12.

    The mean (SE) percentage change in SU from month 12 to final visit was −13.6% (2.6%) in the control/DE group compared with 3.4% (2.6%) in the DE/DE group (p<0.001); mean difference 17.0% (95% CI 9.8% to 24.1%) (figure 1C). The mean percentage change in SU from baseline to final visit was −16.0% in the control/DE group compared with −21.9% in the DE/DE group (p=0.10); mean difference −5.9% (95% CI −12.9% to 1.2%) (figure 1C).

    Between 12 and 24 months, there was a significantly higher time-adjusted area under the curve (AUCadj-t) in the control/DE group compared with the DE/DE group (0.83 mg/dL vs −0.22 mg/dL; p<0.001); mean difference 1.06 mg/dL (95% CI 0.69 to 1.43). Between baseline and 24 months, there was a significantly lower AUCadj-t in the control/DE group compared with the DE/DE group (0.61 mg/dL vs 1.29 mg/dL; p=0.004); mean difference 0.68 mg/dL (95% CI 0.22 to 1.14).

    The mean (range) allopurinol dose at month 24 was 391 mg/day (0–600 mg/day) in the control/DE and 410 mg/day (0–900 mg/day) in the DE/DE (figure 1D).

    Gout flares and other outcomes

    There was a significant reduction in the percentage of participants having a gout flare in the month prior to month 12 and month 24 in both groups compared with the month prior to baseline (p<0.001), but no difference between randomised groups (p=0.29) (figure 1E, see online supplementary table S2). There was a significant reduction in the percentage of individuals having gout flares between baseline and month 24 in both groups (p<0.001) (figure 1E, see online supplementary table S2). There was no difference in the flare reduction between groups (p=0.78).

    Supplementary Material

    Supplementary Table 2

    There was a significant reduction in the percentage of individuals using prophylaxis between months 12 and 24 in both groups (p<0.03), but no significant difference between randomised groups (p=0.84) There was a significant reduction in the use of prophylaxis over the 24-month period in both groups (p<0.001) but no significant difference between randomised groups (p=0.71) (figure 1F, see online supplementary table S2).

    Of those with a tophus at baseline, 6/37 (16.2%) of the control/DE group and 4/31 (12.9%) of the DE/DE group had complete resolution of all tophi between months 12 and 24 (p=0.75). Between baseline and month 24, of those with measurable tophi, 13/45 (28.9%) of the control/DE group and 11/38 (28.9%) of the DE/DE group had complete resolution of all tophi (p=1.0). In the entire group, there was a significant decline in the mean (SEM) tophus size over the 24 months (13.1±1.0 mm baseline vs 6.6±1.2 mm month 24; p<0.001) (figure 1G). There was no difference in the change in tophus size between randomised groups (p=0.27) (figure 1G).

    There was no significant difference in the mean change from month 12 to month 24 or from baseline to month 24 between randomised groups for Health Assessment Questionnaire, pain visual analogue scale, swollen joint count or tender joint count (see online supplementary table S2).

    Adverse events

    Serious adverse events

    From month 12 to 24, there were 38 serious adverse events (SAEs) in 14 control/DE participants and 33 SAEs in 22 DE/DE participants (table 1, see online supplementary table S3). None were considered related to allopurinol. Four control/DE and three DE/DE participants died between months 12 and 24. None of the deaths were attributed to allopurinol. In the control/DE group, deaths were attributed to infection (n=1) and heart failure (n=3) and in the DE/DE group acute coronary syndrome (n=1) and infection (n=2).

    Supplementary Material

    Supplementary Table 3
    View this table:
    Table 1

    Number (%) of participants with treatment emergent serious and non-adverse events in each category during year 1 and year 2

    Non-laboratory AEs

    From month 12 to 24, there were 279 non-laboratory AEs in 65 control/DE and 208 in 62 DE/DE participants (table 1, see online supplementary table S4). The number of participants experiencing at least one non-laboratory AE in each CTCAE (Common Terminology Criteria for Adverse Events) category is shown in table 1. Between months 12 and 24, seven control/DE participants developed rash; one was probably related to allopurinol, which was discontinued, and two were possibly related. In months 12–24, seven control/DE participants developed pruritus, one considered possibly related to allopurinol. In months 12–24, four DE/DE participants developed rash, none considered related to allopurinol, and four DE/DE participants developed pruritus, one possibly allopurinol related.

    Supplementary Material

    Supplementary Table 4

    Laboratory AEs

    Between months 12 and 24, the majority of elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were CTCAE grade 1 (figure 2A–D). For gamma-glutamyltransferase (GGT), 15 control/DE and 14 DE/DE participants had treatment emergent AEs between months 12 and 24, of which one control/DE and three DE/DE participants had increases over two CTCAE grades. For ALT, two DE/DE participants had increases by >1 CTCAE grade and ALP in one DE/DE participant increased by >1 CTCAE grade between months 12 and 24. There were no instances of AST increasing by >1 CTCAE grade.

    Figure 2
    Figure 2

    Treatment emergent or worsening laboratory adverse events. (A-D) Liver function over the 24-month study period by CTCAE grade in control/DE and DE/DE groups. (E) Percentage of participants with increase in creatinine over baseline and (F) percentage of participants with more than a 20% decrease (worsening) or increase (improvement) in CrCL from baseline. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, control; CrCL, creatinine clearance; CTCAE, Common Terminology Criteria for Adverse Events; DE, dose escalation; GGT, gamma-glutamyltransferase; ULN, upper limit of normal.

    For creatinine, an increase from baseline value was used to determine CTCAE grade. Between months 12 and 24, there were 154 events in 61 control/DE participants and 139 events in 53 DE/DE participants; the majority were CTCAE grade 1 (>1–10.5× above baseline) (figure 2E). Twenty-three control/DE and 19 DE/DE participants experienced more than a 20% decrease in CrCL between months 12 and 24 (figure 2F).

    Haematological treatment emergent or worsening AEs are shown in online supplementary table S5 and supplementary figure S1.

    Supplementary Material

    Supplementary Table 5

    Improvement in laboratory variables is available in online supplementary text 2.

    Supplementary Material

    Supplementary material 8

    Discussion

    These results provide further evidence that allopurinol DE is well tolerated and effective in people with gout including in those who have not been at target SU for some months. Once achieved, target SU can be maintained with ongoing allopurinol use.

    While there were a number of AEs/SAEs, only a few were considered related to allopurinol. The number and type of AEs/SAEs seen in those who dose escalated in months 12–24 were similar to those dose escalated in the first 12 months. During months 12–24, there was no obvious increase in AEs or SAEs in those dose escalated in the first 12 months. A number of laboratory AEs were noted, in particular GGT increases. This has been reported previously2 and the clinical significance is uncertain. Minor fluctuations in creatinine resulted in a large number of creatinine CTCAE grade 1 AEs (creatinine >1–10.5× baseline). Approximately 10%–20% of participants had a decrease in CrCL >20% at some point during the study with ~10% having an improvement in CrCL. No new safety signal was identified.

    The questionable safety of allopurinol above CrCL-based doses led to EULAR not supporting a DE strategy.3 Most of the concern relates to the increased risk of AHS and poorer outcomes associated with AHS in people with CKD.6 While no cases of AHS occurred during the study, it is important to note that AHS typically occurs in the first 8 weeks after commencing allopurinol7 and has been associated with a higher starting dose.8 The current study enrolled participants after the early risk period and was not powered to detect such a rare AE. Our study provides support for the approach advocated by the ACR, showing that for individuals tolerating the CrCL-based allopurinol dose, escalation to achieve target appears safe and effective.

    There was a reduction in the number of participants having gout flares over the study compared with prior to the study and a reduction in mean tophi size in both groups over the 24-month study period with no difference between randomised groups. The reduction in flares occurred between months 12 and 24, with no difference between baseline and month 12.5 This delay in flare reduction has been observed in other clinical trials9 and reflects the time it takes to deplete total body urate once target SU is achieved. The lack of difference between randomised groups raises several important issues. Flares are an important clinically relevant outcome, particularly from the patient’s perspective. Despite this, SU has been the primary efficacy endpoint for most ULT clinical trials.9–11 The use of SU as the primary outcome measure allows for shorter, cheaper trials but relies on SU being a ‘biomarker’ for clinically important outcomes such as flares. While there is a sound scientific rationale for assuming a reduction in SU below the point where monosodium urate crystals form, there have been concerns over whether SU is a true ‘biomarker’. SU fulfils many of the required characteristics for a biomarker12 and work is under way to determine whether it can fulfil more sophisticated criteria.13 The use of SU as a treatment target and outcome measure in clinical trials has become controversial with the American College of Physician Gout Guidelines advocating a ‘treat-to-symptom’ rather than a ‘treat-to-target SU’ approach to gout management.14

    Whether the target SU of <6 mg/dL, with <5 mg/dL for those with tophi, is the most appropriate remains to be determined. There is a linear relationship between SU and speed of tophus size reduction.15 In clinical trials of pegloticase, participants who maintained SU <6 mg/dL for ≥80% of the time were more likely to have complete remission of tophus at 6 months.16 In the Febuxostat Compared with Allopurinolin Patients with Hyperuricemia and Gout (FACT) study, the proportion of patients with gout flare between weeks 49 and 52 was lower among those with postbaseline SU <6 mg/dL than those with postbaseline SU ≥6 mg/dL (6% vs 14%; p=0.005).9 These studies did not examine whether one specific target SU is superior to another and there are no randomised controlled trials comparing clinical outcomes with different SU targets.

    There are a number of limitations with this study. The open label design introduces bias; however, this was minimised by the use of SU as the primary endpoint. Attribution of AEs/SAEs to allopurinol may have been more likely during the DE period. One of the key strengths of this study is the ‘real-life’ population recruited who had a significant number of significant comorbidities, including CKD.

    In conclusion, we have shown that allopurinol DE above CrCL-based doses is effective in maintaining SU at treatment target and is well tolerated. Gradual allopurinol DE with appropriate monitoring of kidney and liver function is an alternative to changing to an alternate ULT in people with gout.

    Supplementary Material

    Supplementary Figure 2

    Acknowledgments

    The authors are grateful to the Health Research Council of New Zealand Independent Data Safety Monitoring Committee for monitoring the study.

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    View Abstract

    Footnotes

    • Handling editor Tore K Kvien

    • Contributors LKS and ND: literature search, study design, data collection, data analysis, data interpretation, manuscript preparation. PTC and JD: study design, data collection, data analysis, data interpretation, manuscript preparation. MB and CF: study design, data analysis, data interpretation, manuscript preparation. AH and PT: data collection, data analysis, data interpretation, manuscript preparation.

    • Funding This study was funded by the Health Research Council of New Zealand.

    • Competing interests LKS reports grants from Health Research Council of New Zealand during the conduct of the study; grants from Ardea Biosciences; grants from Health Research Council of New Zealand, outside the submitted work. AH reports grants from Health Research Council of New Zealand during the conduct of the study. ND reports grants from Health Research Council of New Zealand during the conduct of the study; grants and personal fees from AstraZeneca and Ardea Biosciences; personal fees fromTakeda, Teijin and Menarini; grants from Fonterra; personal fees from Pfizer, Crealta and Cymabay, outside the submitted work. PTC, MB, CF, JD and PT have nothing to disclose.

    • Patient consent Obtained.

    • Ethics approval Multiregional ethics committee of New Zealand.

    • Provenance and peer review Not commissioned; externally peer reviewed.