Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis

Smith, Toby; Zou, Kun; Abdullah, Norazharuddin Shah; Chen, Xi; Kingsbury, Sarah R.; Doherty, Michael; Zhang, Weiya; Conaghan, Philip G.

doi:10.1136/annrheumdis-2015-208823

Cited by 10 publications

(5 citation statements)

References 60 publications

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“…Serum lutikizumab concentrations were stable throughout the duration of the study, and unaffected by development of antidrug antibodies and at exposures consistent with those observed in a previous phase I study . The probability of achieving positive results might have been improved by use of a flare study design, in which patients are enrolled only if disease activity increases when their usual treatment is stopped, although a difference in effect size has not been shown to be statistically significant versus a non‐flare study design . Although serum IL‐1α and IL‐1β levels could not be reliably quantified, similar reductions in absolute neutrophil count and hsCRP levels between the lutikizumab 100 mg and 200 mg groups suggested that maximum suppression of IL‐1α and IL‐1β was achieved in both dose groups.…”

Section: Discussionsupporting

confidence: 63%

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Fleischmann

Bliddal

Blanco

et al. 2019

Arthritis & Rheumatology

147

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Objective. To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis.Methods. Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26.Results. The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom-and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.Conclusion. The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.ClinicalTrials.gov identifier: NCT02087904.

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Section: Discussionsupporting

confidence: 63%

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Fleischmann

Bliddal

Blanco

et al. 2019

Arthritis & Rheumatology

147

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“…In the subgroup of patients who did experience a pain flare, treatment responses were greater than in those who did not, consistent with the greater treatment effect observed in OA trials employing a study design that required flare . One group reported that pain and functional scores in study designs that did not require pain flare may underestimate treatment effects by 37–50% , although another study, using a different methodology, did not observe such a difference . Clinical trials assessing the efficacy of fasinumab compared to NSAIDs have been initiated.…”

Section: Discussionmentioning

confidence: 70%

“…Evaluation of effect size must take into consideration trial design. Most OA analgesic trials enrolled patients who had experienced pain flare upon withdrawal of a prior analgesic therapy, with flare being identified by an increase of ≥10 points on the WOMAC 0–100 pain scale (or 1 point on a 0–10 scale) . In contrast, our study enrolled patients who had OA knee and/or hip pain both at screening and at baseline, but pain flare was not an enrollment criterion, and therefore patients were enrolled whose pain may not have been adequately treated with a prior analgesic.…”

Section: Discussionmentioning

confidence: 99%

The Efficacy, Tolerability, and Joint Safety of Fasinumab in Osteoarthritis Pain: A Phase IIb/III Double‐Blind, Placebo‐Controlled, Randomized Clinical Trial

Dakin

DiMartino

Gao

et al. 2019

Arthritis & Rheumatology

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ObjectiveTo prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti–nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain.MethodsPatients with moderate‐to‐severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow‐up, and if prompted, at the time of active joint symptoms.ResultsOf the 421 patients randomized, 342 completed the 36‐week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging −0.78 to −1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment‐emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab‐treated patients and 1% of placebo‐treated patients) occurred in a dose‐dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab.ConclusionFasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit‐to‐risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA.

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“… 16 Although OA does not typically have the same very obvious acute events as conditions like gout, flares in OA joints are encountered in practice, these phenomena appear in patient literature, 17 have been discussed in expert reviews 18 and are mentioned in ‘flare design’ trials in OA. 19 These studies induce acute episodes of pain or flare-ups by asking patients to withdraw their usual medication.…”

Section: Introductionmentioning

confidence: 99%

Defining acute flares in knee osteoarthritis: a systematic review

2018

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ObjectiveTo identify and critically synthesise definitions of acute flares in knee osteoarthritis (OA) reported in the medical literature.DesignSystematic review and narrative synthesis. We searched Medline, EMBASE, Web of science and six other electronic databases (inception to July 2017) for original articles and conference abstracts reporting a definition of acute flare (or synonym) in humans with knee OA. There were no restrictions by language or study design (apart from iatrogenic-induced flare-ups, eg, injection-induced). Data extraction comprised: definition, pain scale used, flare duration or withdrawal period, associated symptoms, definition rationale, terminology (eg, exacerbation or flare), baseline OA severity, age, gender, sample size and study design.ResultsSixty-nine articles were included (46 flare design trials, 17 observational studies, 6 other designs; sample sizes: 15–6085). Domains used to define flares included: worsening of signs and symptoms (61 studies, 27 different measurement tools), specifically increased pain intensity; minimum pain threshold at baseline (44 studies); minimum duration (7 studies, range 8–48 hours); speed of onset (2 studies, defined as ‘sudden’ or ‘quick’); requirement for increased medication (2 studies). No definitions included activity interference.ConclusionsThe concept of OA flare appears in the medical literature but most often in the context of flare design trials (pain increases observed after stopping usual treatment). Key domains, used to define acute events in other chronic conditions, appear relevant to OA flare and could provide the basis for consensus on a single, agreed definition of ‘naturally occurring’ OA flares for research and clinical application.PROSPERO registration numberCRD42014010169.

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Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis

Cited by 10 publications

References 60 publications

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

The Efficacy, Tolerability, and Joint Safety of Fasinumab in Osteoarthritis Pain: A Phase IIb/III Double‐Blind, Placebo‐Controlled, Randomized Clinical Trial

Defining acute flares in knee osteoarthritis: a systematic review

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