Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia: a double-blind, randomised, placebo-controlled trial.

RATIONALE: Pulse glucocorticoid therapy is used in hyperinflammation related to coronavirus disease 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with COVID-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for three consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need for supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival. RESULTS: Overall, 112 (75.4%) out of 151 patients in the pulse methylprednisolone arm and 111 (75.2%) of 150 in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups (15 days, 95% CI 13.0-17.0 days and 16 days, 95% CI 13.8-18.2 days, respectively; hazard ratio (HR) 0.92, 95% CI 0.71-1.20; p=0.528). No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to intensive care unit with orotracheal intubation or death (20.0% versus 16.1%; HR 1.26, 95% CI 0.74-2.16; p=0.176) or overall mortality (10.0% versus 12.2%; HR 0.83, 95% CI 0.42-1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups. CONCLUSIONS: Methylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial.

BACKGROUND: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. METHODS: A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. RESULTS: In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P = 0.52) and 22.4% (97.5% CI: 17.2-28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. CONCLUSIONS: Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

Short-term and long-term effects of tibolone in postmenopausal women.

BACKGROUND: Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. OBJECTIVES: To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. SEARCH METHODS: In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. MAIN RESULTS: We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I2 = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I2 = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I2 = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I2 = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I2 = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I2 = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women). AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.

[Novel oral anticoagulants: more opportunities or more risks? And for which patients?]. / I nuovi anticoagulanti orali nella prevenzione del cardioembolismo nei pazienti con fibrillazione atriale non valvolare: più opportunità o più rischi? E per chi?

Novel direct oral anticoagulants (NAO) represent an innovative and potentially relevant option for the prevention of cardiac embolism in patients with atrial fibrillation. Their recent introduction has been followed by a wide debate on their appropriate use, considering that they do not require regular monitoring of INR values as Vitamin K Antagonists (VKA) do, but that are much less tested in everyday clinical practice and much more expensive than VKA. Starting from the quite favourable results of the available RCTs - showing that NAO are at least non-inferior to VKA and that may be even better for some outcomes - this article discusses the clinical relevance of these results, their transferability into clinical practice looking at the methods of those RCTs and potential risks related to their widespread introduction. Final considerations on possible strategies for their appropriate and progressive introduction are also provided, using the experience developing in the Emilia-Romagna region.

Short and long term effects of tibolone in postmenopausal women.

BACKGROUND: Tibolone is an option available for the treatment of menopausal symptoms, based on short-term data on its efficacy. However, there is a need to consider the balance between the benefits and risks of tibolone as there are concerns about breast and endometrial cancer as well as stroke. OBJECTIVES: To evaluate the effectiveness and safety of tibolone in treating postmenopausal women. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register (19 April 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, 2nd Quarter), MEDLINE (from inception to 19 April 2011), EMBASE (1980 to week 3 April 2011), PsycINFO (1806 to week 3 April 2011), Clinical Trials.gov (30 April 2011). Individual researchers and the current manufacturer of tibolone were contacted to identify unpublished and ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared tibolone versus placebo, estrogens or combined hormone replacement therapy (HT) by assessing the percentage of women with menopausal symptoms, the severity of those symptoms and the occurrence of safety outcomes in postmenopausal women. DATA COLLECTION AND ANALYSIS: Four review authors independently extracted information from the articles, resolving discrepancies by consensus. All outcomes studied were dichotomous. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random-effects model. Heterogeneity of studies was taken into account before deciding to combine the data. MAIN RESULTS: When compared to placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 847; OR 0.42, 95% CI 0.25 to 0.69), although only the 2.5 mg/day dose of tibolone was significantly better than placebo; but with increased vaginal bleeding (seven RCTs, n = 7462; OR 2.75, 95% CI 1.99 to 3.80). When compared to equipotent doses of combined HT, tibolone reduced vaginal bleeding (15 RCTs, n = 6342; OR 0.32, 95% CI 0.24 to 0.42) but was less effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 545; OR 4.16, 95% CI 1.50 to 11.58).As for long term safety, two major RCTs of tibolone versus placebo provided the most relevant data. An RCT of 3098 women with breast cancer and menopausal symptoms was halted after 3.1 years because of increased tumour recurrence (OR 1.50; 95% CI 1.21 to 1.85). However, in another RCT that selected osteoporotic women with negative mammograms (n = 4506) tibolone was associated with a reduction in breast cancer compared to placebo after 2.8 years (OR 0.32, 95% CI 0.13 to 0.79) although the trial was not specifically designed to assess that outcome and the number of overall events was low. In the same RCT, an excess risk of stroke was observed (OR 2.18, 95% CI 1.12 to 4.21). There was no clear evidence of a tibolone effect on endometrial cancer compared with placebo given the low number of events (seven RCTs, n = 8152; OR 1.98, 95% CI 0.73 to 5.32).There was no evidence of a difference in long term safety between tibolone and combined HT. AUTHORS' CONCLUSIONS: Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms.

[Early access programs and managed entry agreements for medicines in Italy: results of a Focus Group (Early Access Programs and Managed Entry Agreement).] / Programmi di early access dei farmaci e managed entry agreement in Italia: i risultati di un Focus Group (programmi di early access e managed entry agreement).

BACKGROUND: Early access of medicines occurs with an uncertainty in the evidence even higher than the one experienced when price and reimbursement status is negotiated. Our aim is discussing the role of managed entry agreements (MEA) within early access programs (EAP) in Italy. METHODS: The discussion relied on a Focus Group, participated by twelve experts, including clinicians and representatives of regulatory authorities, regional and local pharmaceutical departments, pharmaceutical companies, and an association advocating for active citizenship. RESULTS: The Focus Group emphasised that the topic under discussion should be embedded into a more general reform of EAP in Italy. The 648 List mostly includes mature products and indications that are rarely launched into the market afterwards. The 5% Fund is affected by an important administrative burden uncertainty of the timing of reimbursement. CONCLUSIONS: Starting from the discussion on MEA and EAP, the Focus Group recommended a new legislation better regulating EAP, that early access concerns specific classes of medicines selected on the grounds of the need to guarantee a rapid access and to collect real world data, that early access can be accompanied by outcome-based and population-based MEA, and that MEA are embedded into the subsequent price and reimbursement negotiation.

Susceptibility to COVID-19 in Patients Treated With Antimalarials: A Population-Based Study in Emilia-Romagna, Northern Italy.

OBJECTIVE: To evaluate the susceptibility to coronavirus disease 2019 (COVID-19) in patients with autoimmune conditions treated with antimalarials in a population-based study. METHODS: All residents treated with chloroquine (CQ)/hydroxychloroquine (HCQ) from July through December 2019 and living in 3 provinces of Regione Emilia-Romagna were identified by drug prescription registries and matched with the registry containing all residents living in the same areas who have had swabs and tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: A total of 4,408 patients were identified. The prevalence of patients receiving antimalarials was 0.85 per 1,000 men and 3.3 per 1,000 women. The cumulative incidence of testing during the study period was 2.7% in the general population and 3.8% among those receiving CQ or HCQ, while the cumulative incidence of testing positive was 0.55% in the general population and 0.70% among those receiving CQ/HCQ. Multivariate models showed that those receiving CQ/HCQ had a slightly higher probability of being tested compared to the general population (OR 1.09 [95% CI 0.94-1.28]), the same probability of being diagnosed as having COVID-19 (OR 0.94 [95% CI 0.66-1.34]), and a slightly lower probability of being positive once tested (OR 0.83 [95% CI 0.56-1.23]). None of the differences were significant. CONCLUSION: Our findings do not support the use of antimalarials as a prophylactic treatment of COVID-19.

Social marketing: should it be used to promote evidence-based health information?

The implementation of public health knowledge is a complex process; researchers focus on organizational barriers but generally give little attention to the format and validity of relevant information. Primary and secondary papers and practice guidelines should represent valid and relevant sources of knowledge for clinicians and others involved in public health. However, this information is usually targeted at researchers rather than practitioners; it is often not completely intelligible, does not explain what it really adds to existing knowledge or which clinical/organizational context to place it in, and often lacks 'appeal' for those who are less informed. Moreover, this information is sometimes founded on biased research, shaped by sponsors to give scientific plausibility to market-driven messages. A "social marketing" approach can help public health researchers make evidence-based information clear and appealing. The validity and relevance of this information can be explained to target readers in light of their own knowledge levels and in terms of how this information could help their practice. In this paper we analyse the barriers to knowledge transfer that are often inherent in the format of the information, and propose a more user-friendly, enriched and non-research-article format.

Randomised controlled trials for evaluating the prescribing impact of information meetings led by pharmacists and of new information formats, in General Practice in Italy.

BACKGROUND: Suboptimal translation of valid and relevant information in clinical practice is a problem for all health systems. Lack of information independent from commercial influences, limited efforts to actively implement evidence-based information and its limited comprehensibility are important determinants of this gap and may influence an excessive variability in physicians' prescriptions. This is quite noticeable in Italy, where the philosophy and methods of Evidence-Based Medicine still enjoy limited diffusion among practitioners. Academic detailing and pharmacist outreach visits are interventions of proven efficacy to make independent and evidence-based information available to physicians; this approach and its feasibility have not yet been tested on a large scale and, moreover, they have never been formally tested in Italy. METHODS/DESIGN: Two RCTs are planned:1) a two-arm cluster RCT, carried out in Emilia-Romagna and Friuli Venezia Giulia, will evaluate the effectiveness of small group meetings, randomising about 150 Primary Care Groups (corresponding to about 2000 GPs) to pharmacist outreach visits on two different topics. Physicians' prescriptions (expressed as DDD per 1000 inhabitants/day), knowledge and attitudes (evaluated through the answers to a specific questionnaire) will be compared for target drugs in the two groups (receiving/not receiving each topic).2) A three-arm RCT, carried out in Sardinia, will evaluate both the effectiveness of one-to-one meetings (one pharmacist visiting one physician per time) and of a 'new' information format (compared to information already available) on changing physicians' prescription of specific drugs. About 900 single GPs will be randomised into three groups: physicians receiving a visit supported by "traditional" information material, those receiving a visit with "new" information material on the same topic and those not receiving any visit/material. DISCUSSION: The two proposed RCTs aim to evaluate the organisational feasibility and barriers to the implementation of independent information programs led by NHS pharmacists. The objective to assess a 10 or 15% decreases in the prescription of the targeted drugs is quite ambitious in such 'natural' settings, which will be minimally altered by the interventions themselves; this in spite of the quite large sample sizes used comparing to other studies of these kind. Complex interventions like these are not easy to evaluate, given the many different variables into play. Anyway, the pragmatic nature of the two RCTs appears to be also one of their major strengths, helping to provide a deeper insight on what is possible to achieve - in terms of independent information - in a National Health System, with special reference to Italy. TRIAL REGISTRATION: ISRCTN05866587 (cluster RCT) and ISRCTN28525676 (single GPs RCT).

[Considerations on limits and profits of registries]. / Riflessioni e confronti sui limiti e i vantaggi dei registri.

The article collects the summary of the discussion occurred in the setting of PRIER II, in the session dedicated to the taxonomy of registries. Shown below, some specific contributions by health professionals working at the regional departments, which deal with registries, as well as the contribution on the same subject by specialists working at some pharmaceutical companies. In particular, after the presentation summarized in the article by prof. Giuseppe Costa1, the contributions, respectively by a representative of the Emilia-Romagna Region, of a health and hospital service and by the PRIER II workgroup, are following. Finally, a collective work with all participants to the working group took place to focus on all the issues considered to be crucial in defining clinical registries. At the same discussion table, institutional representatives of the regulatory national and regional branch were also invited to take into consideration the points of view of all public and private registry users, in particular in their benefits, limits and purposes. Going through the discussion on a specific check list and deepening a number of statements identified by the working group, a list of key points, essential to characterize each clinical registry, was produced.

Long term effectiveness on prescribing of two multifaceted educational interventions: results of two large scale randomized cluster trials.

INTRODUCTION: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. OBJECTIVES: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. METHODS: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach--TEA, with information materials on osteoporosis or prostatic hyperplasia--and a single drug oriented approach--SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. RESULTS: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. INTERPRETATION: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN05866587.

Feasibility and effectiveness of a low cost campaign on antibiotic prescribing in Italy: community level, controlled, non-randomised trial.

OBJECTIVES: To test the hypothesis that a multifaceted, local public campaign could be feasible and influence antibiotic prescribing for outpatients. DESIGN: Community level, controlled, non-randomised trial. SETTING: Provinces of Modena and Parma in Emilia-Romagna, northern Italy, November 2011 to February 2012. POPULATION: 1,150,000 residents of Modena and Parma (intervention group) and 3,250,000 residents in provinces in the same region but where no campaign had been implemented (control group). INTERVENTIONS: Campaign materials (mainly posters, brochures, and advertisements on local media, plus a newsletter on local antibiotic resistance targeted at doctors and pharmacists). General practitioners and paediatricians in the intervention area participated in designing the campaign messages. MAIN OUTCOMES MEASURES: Primary outcome was the average change in prescribing rates of antibiotics for outpatient in five months, measured as defined daily doses per 1000 inhabitants/day, using health districts as the unit of analysis. RESULTS: Antibiotic prescribing was reduced in the intervention area compared with control area (-4.3%, 95% confidence interval -7.1% to -1.5%). This result was robust to "sensitivity analysis" modifying the baseline period from two months (main analysis) to one month. A higher decrease was observed for penicillins resistant to ß lactamase and a lower decrease for penicillins susceptible to ß lactamase, consistent with the content of the newsletter on antibiotic resistance directed at health professionals. The decrease in expenditure on antibiotics was not statistically significant in a district level analysis with a two month baseline period (main analysis), but was statistically significant in sensitivity analyses using either a one month baseline period or a more powered doctor level analysis. Knowledge and attitudes of the target population about the correct use of antibiotics did not differ between the intervention and control areas. CONCLUSIONS: A local low cost information campaign targeted at citizens, combined with a newsletter on local antibiotic resistance targeted at doctors and pharmacists, was associated with significantly decreased total rates of antibiotic prescribing but did not affect the population's knowledge and attitudes about antibiotic resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT01604096.