The performance of a Bayesian value-based sequential clinical trial design in the presence of an equivocal cost-effectiveness signal: evidence from the HERO trial.

BACKGROUND: There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations - including the costs of the trial - might inform the design and conduct of adaptive clinical trials. METHODS: We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the 'Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis' (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design's operating characteristics with those of a conventional fixed length design. RESULTS: In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. CONCLUSION: Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: An interrupted time series analysis.

BACKGROUND: We assessed the impact of the coronavirus disease 2019 (COVID-19) epidemic in India on the consumption of antibiotics and hydroxychloroquine (HCQ) in the private sector in 2020 compared to the expected level of use had the epidemic not occurred. METHODS AND FINDINGS: We performed interrupted time series (ITS) analyses of sales volumes reported in standard units (i.e., doses), collected at regular monthly intervals from January 2018 to December 2020 and obtained from IQVIA, India. As children are less prone to develop symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a predominant increase in non-child-appropriate formulation (non-CAF) sales. COVID-19-attributable changes in the level and trend of monthly sales of total antibiotics, azithromycin, and HCQ were estimated, accounting for seasonality and lockdown period where appropriate. A total of 16,290 million doses of antibiotics were sold in India in 2020, which is slightly less than the amount in 2018 and 2019. However, the proportion of non-CAF antibiotics increased from 72.5% (95% CI: 71.8% to 73.1%) in 2019 to 76.8% (95% CI: 76.2% to 77.5%) in 2020. Our ITS analyses estimated that COVID-19 likely contributed to 216.4 million (95% CI: 68.0 to 364.8 million; P = 0.008) excess doses of non-CAF antibiotics and 38.0 million (95% CI: 26.4 to 49.2 million; P < 0.001) excess doses of non-CAF azithromycin (equivalent to a minimum of 6.2 million azithromycin treatment courses) between June and September 2020, i.e., until the peak of the first epidemic wave, after which a negative change in trend was identified. In March 2020, we estimated a COVID-19-attributable change in level of +11.1 million doses (95% CI: 9.2 to 13.0 million; P < 0.001) for HCQ sales, whereas a weak negative change in monthly trend was found for this drug. Study limitations include the lack of coverage of the public healthcare sector, the inability to distinguish antibiotic and HCQ sales in inpatient versus outpatient care, and the suboptimal number of pre- and post-epidemic data points, which could have prevented an accurate adjustment for seasonal trends despite the robustness of our statistical approaches. CONCLUSIONS: A significant increase in non-CAF antibiotic sales, and particularly azithromycin, occurred during the peak phase of the first COVID-19 epidemic wave in India, indicating the need for urgent antibiotic stewardship measures.

Real-world medication use and economic outcomes in incident systemic lupus erythematosus patients in the United States.

Aims: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disease involving multiple organs systems and places a significant economic burden on SLE patients. There is a literature gap regarding the standard of care and economic burden in SLE patients, their families, and society. This study assessed medication use patterns among SLE patients and generated the annual and total economic burden associated with the illness.Materials and methods: Adult patients with ≥2 medical claims on different dates for SLE diagnoses were identified from 01 January 2013 to 31 December 2015 using two large administrative claims databases representative of the commercially insured US population. Patient demographics and clinical characteristics during 1-year pre-SLE diagnosis were assessed. Outcomes including the proportion of patients who used SLE medications and annual costs were assessed 1-year post-SLE diagnosis. Total costs related to SLE were extrapolated to the US population to estimate the economic burden based on SLE prevalence.Results: A total of 30,086 SLE patients were identified. The most common baseline comorbidities were hypertension and infections. Corticosteroids and hydroxychloroquine were the most common SLE medications. Biologics utilization was minimal. SLE patients had, on average, 26.0 physician visits, 23.7 prescription claims, 1.7 inpatient admissions, and 2.0 hospital days per patient 1-year post-SLE diagnosis. Annual all-cause median costs among all SLE patients were $8712 per patient per year. Total costs ranged between $1.4-1.6 and $2.8-3.2 billion per year, depending on prevalence estimates.Conclusions: Our findings indicate a nominal use of biologics (∼2%) among SLE patients; despite belimumab being one of the few approved treatments for SLE in the USA. These data reveal an unmet need for availability of advanced SLE therapy, and future studies are warranted concerning the underlying causes. SLE is also associated with a substantial economic burden of ≤3.2 billion per year. These findings may assist in future planning and resource allocation.

New use for an old treatment: Hydroxychloroquine as a potential treatment for systemic vasculitis.

Antimalarials have been an effective and safe treatment for autoimmune rheumatic diseases such as systemic lupus erythematosus for more than a hundred years. There are surprisingly few reports of hydroxychloroquine use in the systemic vasculitides. Hydroxychloroquine has antithrombotic, cardiovascular, antimicrobial and antineoplastic effects, making it a potentially valuable treatment for patients with systemic vasculitis who are at risk of infections, malignancy and thrombotic events. We report the successful use of hydroxychloroquine in patients with ANCA vasculitis, Henoch Schonlein purpura/IgA vasculitis, Takayasu's arteritis and polyarteritis nodosa. We review the immunomodulatory mechanisms of action of hydroxychloroquine and the existing evidence for its use in the treatment of vasculitis, with a particular focus on ANCA subtypes.

Cost-Effectiveness of Triple Therapy Versus Etanercept Plus Methotrexate in Early Aggressive Rheumatoid Arthritis.

OBJECTIVE: To evaluate the cost-effectiveness of all 4 interventions in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) clinical trial: immediate triple (IT), immediate etanercept (IE), step-up triple (ST), and step-up etanercept (SE). Step-up interventions started with methotrexate and added either etanercept or sulfasalazine plus hydroxychloroquine to patients with persistent disease activity. METHODS: We built a Markov cohort model that uses individual-level data from the TEAR trial, published literature, and supplemental clinical data. Costs were in US dollars, benefits in quality-adjusted life years (QALYs), perspective was societal, and the time horizon was 5 years. RESULTS: The immediate strategies were more efficacious than step-up strategies. SE and IE were more costly than ST and IT, primarily due to treatment cost differences. In addition, IT was the least expensive and most effective strategy when the time horizon was 1 and 2 years. When the time horizon was 5 years, IE was marginally more effective than IT (3.483 versus 3.476 QALYs), but IE was substantially more expensive than IT ($148,800 versus $52,600), producing an incremental cost-effectiveness ratio of $12.5 million per QALY. These results were robust to both one-way deterministic and joint probabilistic sensitivity analyses. CONCLUSION: IT was highly cost-effective in the majority of scenarios. Although IE was more effective in 5 years, a substantial reduction in the cost of biologic agents was required in order for IE to become cost-effective in early aggressive RA under willingness-to-pay thresholds that most health care settings may find acceptable.

Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial.

OBJECTIVE: To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. METHODS: In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1 year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3-4 months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27,487 vs €10,364; adjusted mean difference €16,956 (95% CI 14,647 to 19,162)), while productivity losses did not differ (€33,804 vs €29,220; €3961 (95% CI -3986 to 11,850)), resulting in higher societal cost compared to the conventional group (€61,291 vs €39,584; €20,916 (95% CI 12,800 to 28,660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI -0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2,404,197/QALY from the societal perspective and €1,948,919/QALY from the healthcare perspective. CONCLUSIONS: In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. TRIAL REGISTRATION NUMBER: NCT00764725.

Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial.

BACKGROUND: Osteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain. METHODS/DESIGN: HERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis. DISCUSSION: The HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a new treatment for OA, which could be of particular use in the primary care setting. TRIAL REGISTRATION: ISRCTN91859104.

[Financial cost of early rheumatoid arthritis in the first year of medical attention: three clinical scenarios in a third-tier university hospital in Colombia]. / Costos directos de la artritis reumatoide temprana en el primer año de atención: simulación de tres situaciones clínicas en un hospital universitario de tercer nivel en Colombia.

INTRODUCTION: In Colombia, the cost burden of chronic diseases is not well known, either globally or in localized areas of the health system. Rheumatoid arthritis is one of most common chronic diseases, and represents a high cost for the health system. OBJECTIVE: The direct medical costs were estimated for rheumatoid arthritis patients in the in the first year of diagnosis at a level 3 university hospital in Colombia. MATERIALS AND METHODS: Three therapy settings for early rheumatoid arthritis patients were established in the first year of diagnosis according to national and international guidelines. Each setting included treatment with disease-modifying anti-rheumatic drugs or biologic therapy based on disease severity as measured by Disease Activity Score 28. All direct medical costs were included: specialized medical care, diagnostic tests and drugs. Cost information was obtained from the Central Military Hospital finance department in Bogotá and the national manual of drug prices based on the "Farmaprecios" 2007 guide, a reference in general use by health institutions. Results. The average of cost of medical care in patients with mild, moderate and severe disease was US $1689, $1805 and $23,441 respectively. The recommended retail prices of the medicines published in "Farmaprecios" was US $1418, $1821 and $31,931. When the charges levied by several major health institutions were compared, substantial increases were noted, US $4936, $7716 and $123,661, respectively. Drug costs represented 86% of total cost, laboratory costs were 10% and medical attention was only 4%. CONCLUSIONS: Drugs costs were the principal component of the total direct medical cost, and it increased 40 times when a biological therapy is used. Complete economic evaluation studies are necesary to estimate the viability and clinical relevance of biological therapy for early rheumatoid arthritis.

Physician treatment preferences in rheumatoid arthritis of differing disease severity and activity: the impact of cost on first-line therapy.

OBJECTIVE: To conduct a pilot study to identify rheumatologists' treatment preferences for first-line rheumatoid arthritis (RA) therapy and determine whether pharmacoeconomic variables modify physician choice(s). METHODS: A questionnaire describing 3 different RA scenarios was mailed to American College of Rheumatology members within 4 geographic regions of the US. Physicians were asked to identify their choice(s) of first-line therapy for each of the cases, first taking cost into consideration, second without considering the influence of cost, and third identifying the therapy that would be chosen for either themselves or a family member. RESULTS: Three hundred seventy-five questionnaires out of a total of 994 (37.7%) were returned between 3/12/00 and 4/25/00. Hydroxychloroquine was the most commonly cited medication for a mild disease activity/severity presentation, and methotrexate for a moderate-to-severe disease activity/severity presentation. For the severe disease activity/severity presentation, when cost was not considered, 217 (65%) rheumatologists included new disease-modifying antirheumatic drugs (leflunomide, etanercept, and infliximab) in their choice of first-line agents; this number decreased to 47 (14%) when cost was a consideration. CONCLUSION: Pharmacoeconomics appear to play a dominant role in rheumatologists' choice of treatment regimens, at times contrary to the physician's perception of the effectiveness of a drug. Future studies should address physician preferences in more depth with respect to cost and its various components.

Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1.

Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed. We treated 22 patients who were infected with HIV-1 (viral load < 100000 copies/mL and CD4 count >150 cells/microL) with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily. Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1 3 log, and CD4 count was maintained (percentage increase; 2 9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated.

The total costs of drug therapy for rheumatoid arthritis. A model based on costs of drug, monitoring, and toxicity.

OBJECTIVE: We created a model to estimate the total medication costs of treating patients with rheumatoid arthritis with 6 second-line agents for the first 6 months of treatment. METHODS: Drug costs were obtained from a survey of pharmacies; monitoring costs were calculated from utilization information obtained in a survey of rheumatologists; toxicity costs were obtained using decision trees to represent the evaluation and treatment of potential toxicities. Monitoring and toxicity costs were estimated using costs from the Boston University Medical Center or, for hospitalizations, using appropriate diagnosis-related group categories. The sum of the 3 components determined the total medication costs. RESULTS: The least expensive medication was penicillamine, at $10.62/week, and the most expensive was injectable gold, at $30.89/week. In terms of monitoring costs, methotrexate had the highest costs associated with necessary laboratory tests and office visits. Hydroxychloroquine had the lowest monitoring costs for office visits, and oral gold had the lowest for laboratory costs. Hematologic toxicities were the largest component of toxicity costs for all 6 medications, and renal toxicities were costly for patients taking oral gold, penicillamine, and injectable gold. Total medication costs revealed oral gold as the least expensive medication and injectable gold as the most expensive. The combination of monitoring and toxicity costs accounted for more than 60% of the total costs for all medications except injectable gold. In all cases, the cost of treating toxicities was the smallest of the 3 components. CONCLUSION: When calculating the costs of drug therapy, it is important to consider not only the price of the drug, but also the costs of monitoring and treating the toxicities that might occur. Failure to do so will result in underestimating the true costs of treatment with these medications.