Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised controlled trial.

BACKGROUND: Early intervention and tight control of inflammation optimise outcomes in rheumatoid arthritis but these approaches have not yet been studied in psoriatic arthritis. We aimed to assess the effect of tight control on early psoriatic arthritis using a treat-to-target approach. METHODS: For this open-label multicentre randomised controlled trial, adult patients (aged ≥18 years) with early psoriatic arthritis (<24 months symptom duration), who had not previously received treatment with any disease-modifying anti-rheumatic drugs, were enrolled from eight secondary care rheumatology centres in the UK. Enrolled patients were randomly assigned in a 1:1 ratio to receive either tight control (with review every 4 weeks and with escalation of treatment if minimal disease activity criteria not met) or standard care (standard therapy according to the treating clinician, with review every 12 weeks) for 48 weeks. Randomisation was done by minimisation incorporating a random element, to ensure treatment groups were balanced for randomising centre and pattern of arthritis (oligoarticular vs polyarticular). The randomisation procedure was done through a central 24-h automated telephone system based at the Leeds Institute of Clinical Trials Research (Leeds, UK). This was an open-label study in which patients and clinicians were aware of treatment group assignment. Clinical outcomes were recorded by a masked assessor every 12 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology (ACR) 20% (ACR20) response at 48 weeks, analysed by intention to treat with multiple imputation for missing ACR components. Cost-effectiveness was also assessed. This trial is registered with ClinicalTrials.gov, number NCT01106079, and the ISCRCTN registry, number ISCRCTN30147736. FINDINGS: Between May 28, 2008, and March 21, 2012, 206 eligible patients were enrolled and randomly assigned to receive tight control (n=101) or standard care (n=105). In the intention-to-treat patient population, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control group than in the standard care group (odds ratio 1·91, 95% CI 1·03-3·55; p=0·0392). Serious adverse events were reported by 20 (10%) patients (25 events in 14 [14%] patients in the tight control group and eight events in six [6%] patients in the standard care group) during the course of the study. No unexpected serious adverse events or deaths occurred. INTERPRETATION: Tight control of psoriatic arthritis disease activity through a treat-to-target approach significantly improves joint outcomes for newly diagnosed patients, with no unexpected serious adverse events reported. FUNDING: Arthritis Research UK and Pfizer.

The 'Switch' study protocol: a randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug.

BACKGROUND: Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1% of the UK adult population. Patients suffer considerable pain, stiffness and swelling and can sustain various degrees of joint destruction, deformity, and significant functional decline. In addition, the economic burden due to hospitalisation and loss of employment is considerable, with over 50% of patients being work-disabled within 10 years of diagnosis. Despite several biologic disease modifying anti-rheumatic drugs (bDMARD) now available, there is a lack of data to guide biologic sequencing. In the UK, second-line biologic treatment is restricted to a single option, rituximab. The aim of the SWITCH trial is to establish whether an alternative-mechanism-TNF-inhibitor (TNFi) or abatacept are as effective as rituximab in patients with RA who have failed an initial TNFi drug. METHODS/DESIGN: SWITCH is a pragmatic, phase IV, multi-centre, parallel-group design, open-label, randomised, controlled trial (RCT) comparing alternative-mechanism-TNFi and abatacept with rituximab in patients with RA who have failed an initial TNFi drug. Participants are randomised in a 1:1:1 ratio to receive alternative mechanism TNFi, (monoclonal antibodies: infliximab, adalimumab, certolizumab or golimumab or the receptor fusion protein, etanercept), abatacept or rituximab during the interventional phase (from randomisation up to week 48). Participants are subsequently followed up to a maximum of 96 weeks, which constitutes the observational phase. The primary objective is to establish whether an alternative-mechanism-TNFi or abatacept are non-inferior to rituximab in terms of disease response at 24 weeks post randomisation. The secondary objectives include the comparison of alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety and structural and bone density outcomes over a 12-month period (48 weeks) and to evaluate the cost-effectiveness of switching patients to alternative active therapies compared to current practice. DISCUSSION: SWITCH is a well-designed trial in this therapeutic area that aims to develop a rational treatment algorithm to potentially inform personalised treatment regimens (as opposed to switching all patients to only one available (and possibly unsuccessful) therapy), which may lead to long-term improved patient outcomes and gains in population health. TRIAL REGISTRATION: UKCRN Portfolio ID: 12343; ISRCTN89222125 ; NCT01295151.

Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results.

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5.9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5.2% vs. CLO 5.8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3.7% vs. CLO 0.5%; P < 0.0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23.7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.

The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome.

BACKGROUND: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes. METHODS/DESIGN: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition. DISCUSSION: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity. TRIAL REGISTRATION: UKCRN Portfolio ID: 9809 ISRCTN65360827.

Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study.

PURPOSE: To investigate the prognostic value of minimal residual disease (MRD) assessment in patients with multiple myeloma treated in the MRC (Medical Research Council) Myeloma IX trial. PATIENTS AND METHODS: Multiparameter flow cytometry (MFC) was used to assess MRD after induction therapy (n = 378) and at day 100 after autologous stem-cell transplantation (ASCT; n = 397) in intensive-pathway patients and at the end of induction therapy in non-intensive-pathway patients (n = 245). RESULTS: In intensive-pathway patients, absence of MRD at day 100 after ASCT was highly predictive of a favorable outcome (PFS, P < .001; OS, P = .0183). This outcome advantage was demonstrable in patients with favorable and adverse cytogenetics (PFS, P = .014 and P < .001, respectively) and in patients achieving immunofixation-negative complete response (CR; PFS, P = .0068). The effect of maintenance thalidomide was assessed, with the shortest PFS demonstrable in those MRD-positive patients who did not receive maintenance and longest in those who were MRD negative and did receive thalidomide (P < .001). Further analysis demonstrated that 28% of MRD-positive patients who received maintenance thalidomide became MRD negative. MRD assessment after induction therapy in the non-intensive-pathway patients did not seem to be predictive of outcome (PFS, P = .1). CONCLUSION: MRD assessment by MFC was predictive of overall outcome in patients with myeloma undergoing ASCT. This predictive value was seen in patients achieving conventional CR as well as patients with favorable and adverse cytogenetics. The effects of maintenance strategies can also be evaluated, and our data suggest that maintenance thalidomide can eradicate MRD in some patients.

The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, "tight control" intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone. METHODS/DESIGN: TICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks. DISCUSSION: The TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients' disease activity and a reduction in radiological joint damage. TRIAL REGISTRATION: ISRCTN30147736, NCT01106079.

IMPROVDENT: improving dentures for patient benefit. A crossover randomised clinical trial comparing impression materials for complete dentures.

BACKGROUND: According to the UK Adult Dental Health Survey (2009) 15% of adults aged 65-74, 30% aged 75-84 and 47% aged >85 years are edentulous and require complete dentures. Patients' quality of life and nutrition status are affected by poor dentures. The quality of the dental impression is the most important issue for improving the fit and comfort of new dentures. There is paucity of RCT evidence for which impression material is best for complete dentures construction. This study aims to compare two impression materials for effectiveness and cost effectiveness. METHODS/DESIGN: IMPROVDENT is a double-blind crossover trial comparing the use of alginate and silicone, two commonly used denture impression materials, in terms of patient preference and cost-effectiveness. Eighty five edentulous patients will be recruited and provided with two sets of dentures, similar in all aspects except for the impression material used (alginate or silicone). Patients will try both sets of dentures for a two-week period, unadjusted, to become accustomed to the feel of the new dentures (habituation period). Patients will then wear each set of dentures for a period of 8 weeks (in random order) during which time the dentures will be adjusted for optimum comfort. Finally, patients will be given both sets of dentures for a further two weeks to wear whichever denture they prefer (confirmation period).Patients will be asked about quality of life and to rate dentures on function and comfort at the end of each trial period and asked which set they prefer at the end of the habituation period (unadjusted denture preference) and confirmation period (adjusted denture preference). A health economic evaluation will estimate incremental cost-effectiveness ratios of producing dentures from the two materials. A qualitative study will investigate the impact of dentures on behaviour and quality of life. FUNDING: IMPROVDENT is funded by NIHR RfPB (PB-PG-0408-16300). DISCUSSION: This trial aims to provide evidence on the costs and quality of dentures cast from two different commonly used impression materials; the intention is to significantly impact on the quality of denture production within NHS dentistry. TRIAL REGISTRATION: ISRCTN Register: ISRCTN01528038 UKCRN Portfolio ID: 8305.

Pressure and pain in systemic sclerosis/scleroderma--an evaluation of a simple intervention (PISCES): randomised controlled trial protocol.

BACKGROUND: Foot problems associated with Systemic Sclerosis (SSc)/Scleroderma have been reported to be both common and disabling. There are only limited data describing specifically, the mechanical changes occurring in the foot in SSc. A pilot project conducted in preparation for this trial confirmed the previous reports of foot related impairment and reduced foot function in people with SSc and demonstrated a link to mechanical etiologies. To-date there have been no formal studies of interventions directed at the foot problems experienced by people with Systemic Sclerosis. The primary aim of this trial is to evaluate whether foot pain and foot-related health status in people with Systemic Sclerosis can be improved through the provision of a simple pressure-relieving insole. METHODS: The proposed trial is a pragmatic, multicenter, randomised controlled clinical trial following a completed pilot study. In four participating centres, 140 consenting patients with SSc and plantar foot pain will be randomised to receive either a commercially available pressure relieving and thermally insulating insole, or a sham insole with no cushioning or thermal properties. The primary end point is a reduction in pain measured using the Foot Function Index Pain subscale, 12 weeks after the start of intervention. Participants will complete the primary outcome measure (Foot Function Index pain sub-scale) prior to randomisation and at 12 weeks post randomisation. Secondary outcomes include participant reported pain and disability as derived from the Manchester Foot Pain and Disability Questionnaire and plantar pressures with and without the insoles in situ. DISCUSSION: This trial protocol proposes a rigorous and potentially significant evaluation of a simple and readily provided therapeutic approach which, if effective, could be of a great benefit for this group of patients. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN02824122.

Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results.

BACKGROUND: Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. DESIGN AND METHODS: Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. RESULTS: The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44-2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. CONCLUSIONS: The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior in terms of survival outcomes to the standard infusional regimen of cyclophosphamide-vincristine-doxorubicin-dexamethasone. Based on its oral administration and the reduced incidence of infection and cytopenia, cyclophosphamide-thalidomide-dexa-methasone may be considered an effective induction therapy option for patients with newly diagnosed multiple myeloma. (ISRCTN: 68454111).

Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial.

BACKGROUND: Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events. METHODS: Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21-28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints--overall survival, progression-free survival, and overall response rate--and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111. FINDINGS: 1960 patients were randomly assigned and analysed--981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9-4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62-0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65-0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33-0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001). INTERPRETATION: The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline. FUNDING: Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.

BACKGROUND: Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. METHODS: Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3-4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. FINDINGS: 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137-632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9-4·7). Zoledronic acid reduced mortality by 16% (95% CI 4-26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74-0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0·88, 95% CI 0·80-0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0-38·0 vs 17·5 months, IQR 8·5-34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]). INTERPRETATION: Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits. FUNDING: Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.