TITLE: Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis: A Review of Clinical Effectiveness and Guidelines

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1 TITLE: Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis: A Review of Clinical Effectiveness and Guidelines DATE: 27 May 2016 CONTEXT AND POLICY ISSUES Invasive fungal infections (IFI) are opportunistic infections and a major threat to critically ill patients. IFIs remain a significant cause of illness and death in patients with compromised immune systems. 1 Two IFIs in particular, aspergillosis and candidiasis, have a reported mortality of 40 to 50% in patients with neutropenia who have hematologic cancers. 1 Aspergillosis is an infection caused by common mould of the genus Aspergillus. There are many types of aspergillosis, but one of the most serious types is invasive aspergillosis, 2 a serious infection that affects people with compromised immune systems. It usually affects the lungs, but can spread to other vital organs in the body. 2 Candidiasis is a fungal infection caused by over 20 species of Candida yeasts. 3 When Candida species give rise to invasive candidiasis, the pathogen enters the bloodstream and spreads throughout the body. 3 Invasive candidiasis is a serious infection that can affect major organs in the body including the blood, heart, brain, eyes, and bones. Antifungal drugs provide treatment for acute, chronic, and recurrent IFIs, including aspergillosis and candidiasis. 4 Antifungal prophylaxis can also be used to reduce morbidity and mortality among patients with a weakened immune system. Despite the availability of newer secondgeneration antifungals, reported mortality is still high among patients at risk of IFIs. 5 Firstgeneration azoles, fluconazole, and itraconazole, are most frequently used as prophylaxis and treatment in critically ill patients. 6 Fluconazole and itraconazole are antifungals that have proven to be effective in reducing morbidity and mortality among patients at risk of an IFI; however, their lack of activity against moulds and toxicity levels limit their effectiveness. 5,6 Secondgeneration azoles, like posaconazole, may be an effective alternative as they exhibit a more favourable toxicity profile, while significantly reducing IFI occurrence and related mortality. 5,6 Posaconazole (brand name Posanol ) is a triazole antifungal agent that is used to treat or prevent fungal infections. It is mainly used as a prophylaxis to prevent serious fungal infections in people with a compromised immune system or to treat yeast infections that cannot be successfully treated with another medication. 7 Posaconazole can be taken as an oral suspension, injection, or in tablet form and works by slowing the growth of the fungi that cause infection. 7 Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH) could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a w eb site, redistributed by or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the ow ners ow n terms and conditions.

2 The purpose of this Rapid Response report is to review the clinical effectiveness and evidencebased guidelines regarding the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis. RESEARCH QUESTIONS 1. What is the clinical effectiveness of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis? 2. What are the evidence-based guidelines associated with posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis? KEY FINDINGS Eight systematic reviews, one randomized controlled trial, and one evidence-based guideline were identified regarding the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis. The studies were favourable to the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis. The results, however, must be interpreted with caution, as there were many limitations with the included studies. The evidencebased guideline provided recommendations on the use of posaconazole in children over the age of 13. METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Medline, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 01, 2011 and April 28, Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 2

3 Population Intervention Comparator Outcomes Study Designs Patients (aged 13 years of age) with, or at risk of developing, fungal infections (either aspergillosis or candidiasis) with or without Human Immunodeficiency Virus (HIV) Posaconazole (for treatment or prophylaxis) in injection, suspension, or tablet form Other antifungals Placebo Clinical effectiveness (including safety) Guidelines Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, evidence-based guidelines Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to Critical Appraisal of Individual Studies The included systematic reviews (SRs) were critically appraised using the AMSTAR checklist, 8 randomized studies were critically appraised using Downs and Black, 9 and guidelines were assessed with the AGREE II 10 instrument. Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 95 citations were identified in the literature search. Following screening of titles and abstracts, 81 citations were excluded and 14 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, six publications were excluded for various reasons, while 10 publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 5. Summary of Study Characteristics A detailed summary of the characteristics of the included SRs, randomized controlled trial (RCT), and evidence-based guideline is presented in Appendix 2. Study Design Eight SRs 4,6,11-16 regarding the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis were identified. One SR 11 examined 21 RCTs, but did not specify which RCT(s) reported on the use of posaconazole as a prophylaxis. One SR 12 analyzed five RCTs, and one of these RCTs examined the clinical effectiveness of posaconazole as a prophylaxis. Another SR 13 reviewed four RCTs and 34 non-randomized studies (NRS); one of the NRS measured the clinical effectiveness of posaconazole as a treatment. One SR 14 Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 3

4 examined 25 RCTs, and one of these RCTs examined the clinical effectiveness of posaconazole as a prophylaxis. Another SR 15 reviewed 20 RCTs, and one of these RCTs reported on the clinical effectiveness of posaconazole as a prophylaxis. One SR 6 analyzed four RCTs, and two of these RCTs measured the clinical effectiveness of posaconazole as a prophylaxis. Another SR 16 examined 17 clinical trials; three studies reported the clinical effectiveness of posaconazole as a prophylaxis. One SR 4 reviewed 47 RCTs, and one of these RCTs reported the clinical effectiveness posaconazole as a treatment. One RCT 5 regarding the use of posaconazole for the treatment of aspergillosis or candidiasis with fluconazole as the comparator was identified. One evidence-based guideline 17 was identified on the use of posaconazole in treating children with cancer and undergoing hematopoietic stem cell transplantation. Country of Origin Two SRs and were conducted in Canada. 12,14 One SR 11 was conducted in Singapore, and another SR 13 was conducted in Portugal. Two SRs 6,16 and one RCT 5 were conducted in China. One SR 15 was conducted in the United States of America, and another SR 4 was conducted in the United Kingdom. The evidence-based guideline was conducted in Canada. 17 Patient Population Six SRs 6,11,12,14-16 and one RCT 5 examined antifungals for the prophylaxis for invasive fungal infections, including aspergillosis and candidiasis, in patients with hematological malignancies, patients undergoing hematopoietic cell transplantation (HSCT), or patients expected to develop neutropenia. One SR 13 examined the treatment of aspergillosis in asthmatic and cystic fibrosis patients. Another SR 4 examined the treatment and prophylaxis of candidiasis in patients who were undergoing treatments that cause immunosuppression, infants and children, people with dentures, and people infected with the human immunodeficiency virus (HIV); nevertheless, this SR examined posaconazole as a treatment in the patients with HIV. The evidence-base guideline 17 is intended for healthcare professionals who are treating children with cancer and undergoing HSCT. Interventions and Comparators All of the SRs 4,6,11-16 examined posaconazole as an intervention in at least one of the included studies. The RCT 5 used posaconazole as an intervention, and five of the studies 4-6,12,16 indicated posaconazole was administered in oral form. Most of the studies 4-6,11,12,14-16 used fluconazole as one of the comparators. Other comparators included itraconazole, voriconazole, ketoconazole, natamycin, nystatin, amphotericin B, micafungin, caspofungin, and anidulafungin. Outcomes Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 4

5 Seven SRs 6,11-16 and one RCT 5 examined the incidence of proven and probable IFIs as a primary clinical outcome. A proven IFI occurs when a direct observation by microscopic staining or culture from diseased tissue, and a probable IFI is based on pathologic or clinical features, or the presence of fungi in non-diseased tissue or site. Many of the studies 4-6,11,12,14,15 also reported mortality as a primary clinical outcome. One SR 13 examined lung function, biomarkers, exacerbations, and quality of life as major clinical outcomes. Summary of Critical Appraisal A detailed summary of the critical appraisal of the included SRs, RCT, and evidence-based guideline is presented in Appendix 3. All of the SRs 4,6,11-16 used an a priori design. The study selection and data extraction were done in duplicate in seven of the SRs. 6,11-16 A comprehensive literature search was performed in all of the SRs. 4,6,11-16 Seven of the SRs 6,11-16 reported the characteristics of the included studies. The quality of the included studies was assessed and documented in six of the SRs. 4,6,11,13-15 Two of the SRs 12,16 did not did not indicate if a quality appraisal of the included studies was completed. Publication bias was assessed in two of the SRs. 13,16 Six of the SRs 4,6,11,12,14,15 did not provide any evidence that publication bias was assessed. The methods used to combine the findings were appropriate in all of the SRs. 4,6,11-16 Conflicts of interest were declared in three of the SRs. 11,12,14 These conflicts, therefore, may have impacted the results. No conflicts of interest were declared by the authors in three of the SRs, 6,13,15 and potential conflicts of interest were not mentioned in two of the SRs. 4,16 The RCT 5 had several strengths. Patient characteristics were tabulated and evaluated for significant differences. The study had a sample size of 252 patients from 15 sites in China. A statistical power calculation was completed to determine the sample size, and the statistical methods were described. The study explicitly defined patient eligibility, intervention, and outcomes measured. As well, the methods used to assess adverse events were described. The authors declared no conflict of interest. The study also had a few limitations. There was no discussion on the study limitations, and the methods used to randomize patients were not described in detail. Moreover, the study was open-label, and blinding or allocation concealment was not reported. The evidence-based guideline 10 described the objectives, health questions, and target populations addressed in the recommendations. The guideline was developed by individuals from all relevant professional groups; target population input was sought and target users were described. The guideline was externally reviewed by experts prior to its publication. Systematic search methods were used, evidence selection criteria were described, and appraisals on the quality of included evidence were provided. Recommendations were unambiguous, specific for different types of conditions or issues, and easily identifiable. Facilitators and barriers to implementing the guideline were described. The guideline did not provide links to tools and resources, as well as any monitoring or auditing criteria. Funding sources were disclosed, and the authors did not report any conflicts of interest. Summary of Findings Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 5

6 A detailed summary of the findings of the included SRs, RCT, and evidence-based guideline is presented in Appendix What is the clinical effectiveness of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis infections? Posaconazole as a Treatment Treatment of Invasive Fungal Infections One SR 13 reported posaconazole was more effective than voriconazole in the treatment of IFIs. Posaconazole as a Treatment in Patients with HIV One SR 4 concluded that posaconazole, ketoconazole, and fluconazole may be equally effective at increasing cure rates for IFIs in patients infected with HIV. The proportion of people with clinical cure using posaconazole was 97% (139/143) compared with 96% (130/135) for fluconazole. Adverse Events In one SR, 13 adverse events were reported in 22% of patients who took posaconazole compared with in 40% of patients who took voriconazole. Posaconazole as a Prophylaxis Incidence of Invasive Fungal Infections One SR 12 found that posaconazole may be preferable for protection against invasive aspergillosis compared with fluconazole, but itraconazole was more preferable to use against invasive candidiasis. Another SR 14 concluded that posaconazole was the most effective antifungal for prophylaxis against IFIs in neutropenic patients. Another SR 15 included a single RCT that stated that newer antifungals, such as posaconazole, may outperform older azoles and amphotericin B for prophylaxis. One SR 6 conducted a meta-analysis and concluded that antifungal prophylaxis with second-generation azoles (voriconazole and posaconazole) may significantly reduce the incidence of IFI with no increase in adverse events. Another SR 16 reported that antifungal prophylaxis with newer agents, including posaconazole, reduces the incidence of IFIs. One RCT 5 concluded that prophylaxis with posaconazole showed significant advantage compared with fluconazole in reducing the incidence of IFIs in patients undergoing chemotherapy. All-Cause Mortality One SR 11 reported that posaconazole was more effective than fluconazole and itraconazole at reducing invasive fungal infections and all-cause deaths among patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation Adverse Events Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 6

7 One SR 16 reported the results of a meta-analysis of adverse events, specifically liver function. The authors reported that 13/304 for patients who took posaconazole experiences adverse events compares with 3/240 for patients who took fluconazole. The SR 16 also reported a metaanalysis in adverse reactions to stop use: posaconazole (267/605) versus fluconazole (257/539) and posaconazole (164/336) versus itraconazole (37/74). One RCT 5 reported serious adverse events in 5.6% of patients who took posaconazole (7/124), compared to 8.3% of patients who took fluconazole (10/121). 2. What are the evidence-based guidelines associated with posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis infections? The evidence-based guideline 17 suggested using posaconazole as an alternative to fluconazole in children 13 years of age or older with acute myeloid leukemia or myelodysplastic syndrome. The guideline also suggested using posaconazole in children 13 years of age or older undergoing allogeneic hematopoietic stem cell transplantation with acute grade II-IV or chronic extensive graft-versus-host disease. No recommendation was found regarding the use of posaconazole for treating IFIs. Limitations There were several limitations identified from the literature. One SR 13 included mainly lowquality studies including case series and case reports. Another SR 12 also included studies that were of low quality most of the studies were NRS. Some of the studies 13,15 had sample sizes ranging from 21 to 40 patients. These sample sizes, therefore, may impact the external validity of the findings, meaning they may not be a representative sample of the general population. In addition, most of the SRs 4,11-16 included literature published before 2000, so the relevance of these studies may be uncertain due to scientific advancements in treatment and prophylaxis. One SR 12 did not provide any evidence of quality appraisal. The same study 12 was also funded by a pharmaceutical company, which may have introduced significant bias into the study findings. Another SR 11 did not specify how many RCTs included in the review examined posaconazole as an intervention. One of the SRs 6 had significant heterogeneity among some of the subgroup analyses, making it difficult to derive any firm conclusions from the included studies. Most of the included studies 4-6,11,13,15,16 in this report were conducted outside of Canada. Because these studies, therefore, were not conducted in a Canadian context, the applicability of their findings may be reduced. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Eight systematic reviews, one RCT, and one evidence-based guideline regarding the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis were identified. The studies 4-6,11-16 in this report were favourable to the use of posaconazole for the treatment or prophylaxis of aspergillosis or candidiasis. Three of the included studies 5,11,14 found posaconazole to be superior to other antifungals at reducing incidence of IFIs or mortality in patients with compromised immune systems. Three SRs 6,12,16 concluded that posaconazole and voriconazole may be the preferred antifungals for invasive aspergillosis or candidiasis. One SR 15 reported that newer drugs, such as posaconazole, may be more clinically effective than Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 7

8 older azoles for prophylaxis. Another SR 13 examined one case series comparing voriconazole to posaconazole, and posaconazole was found to be more effective. The evidence-based guideline 17 recommended using posaconazole in children 13 years of age or older undergoing allogeneic hematopoietic stem cell transplantation with acute grade II-IV or chronic extensive graft-versus-host disease. The guidelines also recommended using posaconazole as an alternative to fluconazole in children 13 years of age or older with acute myeloid leukemia or myelodysplastic syndrome. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 8

9 References: 1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med Jan 25;356(4): Aspergillosis [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2016 Jan 21. [cited 2016 May 17]. Available from: 3. Candidiasis [Internet]. Atlanta (GA): Centers for Disease Control and Prevention; 2015 Jun 12. [cited 2016 May 16]. Available from: 4. Pankhurst CL. Candidiasis (oropharyngeal). Clin Evid (Online) [Internet] [cited 2016 May 4];2013:1304. Available from: 5. Shen Y, Huang XJ, Wang JX, Jin J, Hu JD, Yu K, et al. Posaconazole vs. fluconazole as invasive fungal infection prophylaxis in China: a multicenter, randomized, open-label study. Int J Clin Pharmacol Ther Sep;51(9): Ping B, Zhu Y, Gao Y, Yue C, Wu B. Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis. Ann Hematol Jun;92(6): Posaconazole Apr 15 [cited 2016 May 17]. In: MedlinePlus [Internet]. 27 Sep Bethesda: National Library of Medicine; Available from: 8. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2016 May 26];7:10. Available from: 9. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet] Jun [cited 2016 May 26];52(6): Available from: Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet] Dec [cited 2016 May 26];182(18):E839-E842. Available from: Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 9

10 11. Zhao YJ, Khoo AL, Tan G, Teng M, Tee C, Tan BH, et al. Network meta-analysis and pharmacoeconomic evaluation of fluconazole, itraconazole, posaconazole, and voriconazole in invasive fungal infection prophylaxis. Antimicrob Agents Chemother Jan;60(1): Bow EJ, Vanness DJ, Slavin M, Cordonnier C, Cornely OA, Marks DI, et al. Systematic review and mixed treatment comparison meta-analysis of randomized clinical trials of primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients. BMC Infect Dis [Internet] [cited 2016 May 4];15:128. Available from: Moreira AS, Silva D, Ferreira AR, Delgado L. Antifungal treatment in allergic bronchopulmonary aspergillosis with and without cystic fibrosis: a systematic review. Clin Exp Allergy Oct;44(10): Pechlivanoglou P, Le HH, Daenen S, Snowden JA, Postma MJ. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother [Internet] Jan [cited 2016 May 4];69(1):1-11. Available from: Ziakas PD, Kourbeti IS, Mylonakis E. Systemic antifungal prophylaxis after hematopoietic stem cell transplantation: a meta-analysis. Clin Ther Feb 1;36(2): Xu SX, Shen JL, Tang XF, Feng B. Newer antifungal agents for fungal infection prevention during hematopoietic cell transplantation: a meta-analysis. Transplant Proc Jan;45(1): Science M, Robinson PD, MacDonald T, Rassekh SR, Dupuis LL, Sung L. Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients. Pediatr Blood Cancer Mar;61(3): Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 10

11 APPENDIX 1: Selection of Included Studies 95 citations identified from electronic literature search and screened 81 citations excluded 14 potentially relevant articles retrieved for scrutiny (full text, if available) 2 potentially relevant reports retrieved from other sources (grey literature, hand search) 16 potentially relevant reports 6 reports excluded: -irrelevant intervention (2) -irrelevant comparator (1) -irrelevant study design (2) -already included in at least one of the selected systematic reviews (1) 10 reports included in review Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 11

12 APPENDIX 2: Characteristics of Included Publications First Author, Publication Year, Country Zhao, 2016, Singapore 11 Bow, 2015, Canada 12 Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses Types and numbers Population Intervention Comparator(s) Clinical Outcomes of primary studies Characteristics included 21 RCTs published until November 2014 Number of RCTs that examined posaconazole as a prophylaxis was not reported. 5 RCTs published between 2003 and RCT examined posconazole as a prophylaxis Moreira, 2014, 4 RCTs and 34 Portugal 13 observational studies (21 case reports, 11 case series, on cohort study, and 1 uncontrolled clinical trial) 1 NRS used posconazole as an intervention 5,505 patients with hematological malignancies or stem cell transplants who were at risk of developing IFIs Number of patients who used posconazole as a prophylaxis: n = NR 2,147 patients using primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplantation recipients post-transplant Number of patients in 1 RCT: n = asthmatics and 110 cystic fibrosis patients Number of patients in 1 NRS: n = 21 Posaconazole Posaconazole Posaconazole Fluconazole, itraconazole, voriconazole Fluconazole, itraconazole, voriconazole Voriconazole, itraconazole, ketoconazole, natamycin, nystatin, amphotericin B Incidence of proven/probable IFIs, all-cause mortality Incidence of proven/probable IFIs, all-cause mortality Lung function (measured by spirometry), biomarkers (measured by inflammatory biomarkers), exacerbations (measured by an acute episode or relapse after the drug the need for antibiotics, or hospital admission), quality of life (measured by qualitative symptom description and respiratory symptom by severity and frequency) Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 12

13 First Author, Publication Year, Country Pechlivanoglo u, 2014, Canada 14 Ziakas, 2014, USA 15 Ping, 2013, China 6 Xu, 2013, China 16 Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses Types and numbers Population Intervention Comparator(s) Clinical Outcomes of primary studies Characteristics included 25 RCTs published until April RCT examined posaconazole as a prophylaxis 20 RCTs published between 1991 and RCT examined posaconazole as a prophylaxis 4 RCTs published between 2002 and of these RCTs used posaconazole as a prophylaxis 17 randomized, clinical trials published between 1987 and of these studies used posconazole as a prophylaxis 7,062 patients who were undergoing hematopoietic cell transplantation or bone marrow transportation Number of patients in 1 RCT: n = 602 4,823 hematopoietic stem transplant recipients who were at risk of developing IFIs Number of patients in 1 RCT: n = 40 2,267 hematology patients Number of patients in 1 RCT: n = 1,202 5,122 transplanted hematologic patients Number of patients in 4 RCTs: n = 1,341 Posaconazole Posaconazole Posaconazole Posaconazole Fluconazole, itraconazole, amphotericin, voriconazole, micafungin, Fluconazole, itraconazole, voriconazole, micafungin, caspofungin, anidulafungin, amphotericin Fluconazole, itraconazole, voriconazole Fluconazole, itraconazole, micafungin, voriconazole Incidence of proven/probable IFIs, all-cause mortality Proven/probable IFIs, invasive candidiasis, invasive aspergillosis, all mold IFIs, withdrawals related to adverse events, need for empirical antifungal therapy, overall mortality, mortality attributed to IFIs Incidence of proven/probable IFIs, receipt of empirical antifungal therapy, overall mortality, withdrawal from the studies due to the development of adverse events Incidence of proven/probable IFIs Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 13

14 First Author, Publication Year, Country Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses Types and numbers Population Intervention Comparator(s) Clinical Outcomes of primary studies Characteristics included Pankhurst, 47 RCTs or 2013, UK 4 systematic reviews of RCTs published until July RCT examined posaconazole vs fluconazole as an intervention Patients who were undergoing treatments that cause immunosuppression, infants and children, people with dentures, and people infected with HIV Number of patients in 1 RCT: n = 278 Posaconazole Fluconazole, miconazole, itraconazole, other antifungals HIV = Human immunodeficiency virus; IFI = Invasive fungal infections; NR= not reported; NRS = Non-randomized studies; RCT = Randomized controlled trial Prevention of oral candidiasis (measured by rate of occurrence or recurrence), treatment success (measured by cure, clinical cure, resolutions of symptoms), adverse effects, mortality, druginduced resistance to treatment First Author, Publication Year, Country Table A2: Characteristics of Included Randomized Controlled Trials Study Design Patient Characteristics Intervention Comparator(s) Clinical Outcomes Shen, 2013, China 5 Randomized, openlabel study 252 patients who either had persistent neutropenia or were expected to develop neutropenia in 3-5 days Posaconazole Fluconazole Incidence of proven/probable IFIs, all-cause mortality IFI = Invasive fungal infections Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 14

15 Intended users/ Target population Objectives Intervention and Practice Considered Table A3: Characteristics of Included Evidence-Based Guidelines Methodology Major Evidence collection, Evidence Quality Recommendations Outcomes Selection and and Strength development and Considered Synthesis Evaluation Guideline Validation Science, C 17 Antifungal Prophylaxis Panel The guideline is intended for healthcare professionals who are treating children with cancer and undergoing HSCT Prophylaxis treatment for the prevention of invasive fungal infections Appropriate strategies for antifungal prophylaxis, all-cause mortality, proven or probable IFI, fungal-related mortality and adverse events Systematic search of literature published until 2012 Selection of studies based on inclusion/exclusion criteria Grading of included recommendations, using categorization HSCT = Hematopoietic stem cell transplantation; IFI = Invasive fungal infections The quality of evidence and strength of each recommendation was determined using GRADE Recommendations were developed by a committee, consisting of a panel of experts The guideline underwent a twostage external review Stage 1: The guideline was reviewed by an international, interprofressional panel of 11 experts in relevant areas Stage 2: The guideline was sent to representatives from Canadian pediatric hematology/oncology tertiary hospitals for stakeholder review Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 15

16 APPENDIX 3: Critical Appraisal of Included Publications Table A4: Strengths and Limitations of Included Systematic Reviews and Meta-Analyses using AMSTAR checklist 8 Strengths Limitations Zhao 11 An a priori design was used. The likelihood of publication bias not assessed. Study selection and data extraction was done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. Bow 12 An a priori design was used. Study selection and data extraction were done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. The methods used to combine the findings of studies were appropriate. Moreira 13 An a priori design was used. Study selection and data extraction were done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. The likelihood of publication bias assessed. A list of the included studies was provided. The characteristics of the included studies were provided. A list of excluded studies was provided. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. A list of excluded studies was not provided. Conflicts of interest were declared by the author; these conflicts, therefore, may have impacted the results of the study. A list of excluded studies was not provided. The likelihood of publication bias was not assessed. There was no evidence that the quality of the included studies was assessed and documented. Therefore, the scientific quality of the included studies was not used in formulating conclusions. Conflicts of interest were declared by the author; however, these conflicts may have impacted the results of the study. No limitations identified. Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 16

17 Table A4: Strengths and Limitations of Included Systematic Reviews and Meta-Analyses using AMSTAR checklist 8 Strengths Limitations The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. No conflicts of interest were declared by the authors. Pechlivanoglou 14 An a priori design was used. There is no evidence that the likelihood of Study selection and data extraction were done publication bias was assessed. in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. Ziakas 15 An a priori design was used. Study selection and data extraction was done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. No conflicts of interest were declared by the authors. Ping 6 An a priori design was used. Study selection and data extraction was done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed A list of excluded studies was not provided. Conflicts of interest were declared by the author; however, these conflicts may have impacted the results of the study. There is no evidence that the likelihood of publication bias was assessed. A list of excluded studies was not provided. There is no evidence that the likelihood of publication bias was assessed. A list of excluded studies was not provided. Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 17

18 Table A4: Strengths and Limitations of Included Systematic Reviews and Meta-Analyses using AMSTAR checklist 8 Strengths Limitations search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. No conflicts of interest were declared by the authors. Xu 16 An a priori design was used. Study selection and data extraction were done in duplicate. A comprehensive literature search was performed, including grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies was provided. The characteristics of the included studies were provided. Publication bias was assessed. The methods used to combine the findings of studies were appropriate. Pankhurst 4 An a priori design was used. A comprehensive literature search was performed, including grey literature. The quality of the included studies was assessed and documented; the results of the quality assessment were reported. The results of the quality assessment were considered when formulating conclusions. The methods used to combine the findings of studies were appropriate. A list of excluded studies was not provided. There was no evidence that the quality of the included studies was assessed and documented. Conflicts of interest were not mentioned in the article. Study selection and data extraction were not done in duplicate. A flow diagram for the search results was not provided. A list of the included studies was not provided. The characteristics of the included studies were not provided. There is no evidence that the likelihood of publication bias was assessed. A list of excluded studies was not provided. Conflicts of interest were not mentioned in the article. Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 18

19 Table A5: Strengths and Limitations of Included Randomized Controlled Trials using Downs and Black 9 Strengths Limitations Shen 5 The patient characteristics were tabulated. There were no discussions on study limitations. Patient recruitment data were included. The study was open-label - no blinding or Patient characteristics were evaluated for allocation concealment was used. significant differences. The study had a sample size of 250 patients, who were derived from multiple centres in China (15 sites). A statistical power calculation was completed to determine sample size. The statistical methods were described. The study explicitly defined patient eligibility. The study explicitly defined intervention. The study explicitly defined outcomes. Any adverse events were quantified. The authors declared no conflict of interest. The methodology used to randomize patients was not well described. Table A6: Strengths and Limitations of Included Evidence-Based Guidelines using AGREE II 10 Strengths Limitations Science 17 Scope and Purpose Applicability Objectives were described. The guideline did not provide links to tools and Health questions were described. resources including a summary document. Target populations were described. It is unclear if the guideline provided monitoring Stakeholder Involvement and/or auditing criteria. The guideline was developed by individuals from all relevant professional groups. Target population input was sought. Targets users were described. Rigour of Development Systematic search methods were used. Evidence selection criteria were described. Appraisals on the quality of included evidence were provided. Methods for formulating recommendations were described. Recommendations considered benefits, harms, costs, and quality of evidence, and their links to supporting evidence tables were explicit. The guideline was externally reviewed by experts prior to its publication. A procedure for updating the guideline was described. Clarity of Presentation Recommendations were unambiguous, specific for different types of conditions or issues, and easily identifiable. Applicability Facilitators and barriers to implementing the Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 19

20 Table A6: Strengths and Limitations of Included Evidence-Based Guidelines using AGREE II 10 Strengths Limitations guideline were described. The guideline considered resource implications. Editorial Independence Funding sources were disclosed. The authors did not report any conflicts of interest. Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 20

21 APPENDIX 4: Main Study Findings and Author s Conclusions Table A7: Summary of Findings of Included Systematic Reviews and Meta-Analyses Main Study Findings Author s Conclusions Zhao, In preventing invasive fungal infections, posaconazole was found: posaconazole was associated with the greatest benefits in terms of numbers of o Significantly better than fluconazole (OR 0.35 [95%CI 0.16 to 0.73]) invasive fungal infections avoided and life years saved." page 383 o Significantly better than intraconazole capsule (OR 0.25 [95%CI 0.06 to 0.97]) Overall, posaconazole was superior to reducing invasive fungal infections and allcause deaths among patients receiving o Not as effective as voriconazole (OR 1.31 [95%CI 0.43 to 4.01] chemotherapy or undergoing hematopoietic stem cell transplantation. In preventing aspergillus infections, posaconazole was found significantly more effective than: page 383 o Placebo (OR 0.12 [95%CI 0.02 to 0.61]) o Fluconazole (OR 0.07 [95%CI 0.01 to 0.29]) o Intraconazole (OR 0.10 [95%CI 0.02 to 0.47]) o Vorizonacole* (OR 6.46 [95%CI 1.22 to 34.04]) *The treatment effects of posaconazole vs voriconazole were generated through indirect evidence and needs to be interpreted with caution Posaconazole was associated with significant reductions in all-cause mortality compared with: o Placebo (OR 0.49 [95%CI 0.38 to 0.85]) o Fluconazole (OR 0.54 [95%CI 0.33 to 0.88]) o Itraconazole solution (OR 0.49 [95%CI 0.28 to 0.83]) Fewer patients receiving posaconazole prophylaxis required empirical therapies compared with: o Fluconazole (OR 0.35 [95%CI 0.15 to 0.80]) o Itraconazole capsule (OR 0.33 [95%CI 0.12 to 0.95]) o Intraconazole solution (OR 0.37 [95%CI 0.15 to 0.91]) The SUCRA values for five treatments against invasive fungal infections were calculated (a value of 1 indicates the treatment is certain to be the best and a value of 0 indicates the treatment is certain to be the worst): o Posaconazole 0.92 o Voriconazole 0.80 o Itraconazole solution 0.63 o Fluconazole 0.36 o Itraconavole capsule 0.27 Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 21

22 Table A7: Summary of Findings of Included Systematic Reviews and Meta-Analyses Main Study Findings Author s Conclusions Bow, One RCT (n= 600) by Ullmann et al. was reported using posaconavole and fluconazole: o All-cause mortality: Posaconazole:19% (58/301) Fluconazole: 20% (59/299) o o o o Moreira, Incidence of proven/probable invasive fungal infections overall: Posaconazole: 5% (16/301) Fluconazole: 9% (27/299) Incidence of proven/probable invasive aspergillosis: Posaconazole: 2% (7/301) Fluconazole: 7% (21/299) Incidence of invasive candidiasis: Posaconazole: 1% (4/301) Fluconazole: 1% (2/299) Incidence of other licensed antifungal therapy: Posaconazole: 11% (31/291) Fluconazole: 10% (29/288) One case series (n=21) by Chishimba et al. was reported using voriconzaole ( mg/day) and posaconazole (800 mg/day): o Symptoms improved by 78% with posaconazole and 69% with voriconazole o Radiological infiltrates improved in 50% with posaconazole and 57% in voriconazole o Adverse events were reported in 22% with posaconazole and 40% voriconazole o Quality of life improved by 78% in posaconazole and 58% voriconazole Pechlivanoglou, One RCT (n=602) examined the use of posaconazole as a prophylaxis: o Posaconazole was more effective than no prophylaxis/placebo in reducing all-cause mortality (RR 0.56 [95%CI ]) o The risk of developing an invasive fungal infection was lower when taking voriconazole or posaconazole (RR 0.38 [95%CI ], RR 0.34 [95%CI ]) as a prophylaxis than using fluconazole or itraconazole tablets (RR 0.22 [95%CI ], RR 0.20 [95%CI ]) Ziakas, One RCT (n=40) by Chaftari et al. was reported using posaconazole and amphotericin: o Posaconazole was slightly better than posaconazole and voriconazole may be preferable for protection from invasive aspergillosis, intraconazole for protect from invasive candidiasis, and voriconazole for reducing other licensed antifungal therapy use, based on the respective relatively high posterior probabilities. page 9 This systematic review showed that antifungal treatment in [allergic bronchopulmonary aspergillosis] improves patient- and disease-oriented outcomes. page 1225 due to the small number of controlled studies analysed, the heterogeneity between studies and the potential bias associated with observational studies, the recommendation to use antifungal agents in [allergic bronchopulmonary aspergillosis] is weak. page 1225 The analysis has additionally supported posaconazole as potentially the most effective antifungal agent for prophylaxis against invasive fungal infections in neutropenic patients, especially those undergoing chemotherapy page 8 A single study comparing posaconazole to amphotericin B indicated that newer drugs (such as posaconazole) might outperform Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 22

23 Table A7: Summary of Findings of Included Systematic Reviews and Meta-Analyses Main Study Findings Author s Conclusions amphotericin regarding effects from withdrawal (data not reported) older azoles and amphotericin B. page 301 o Posaconazole and amphotericin were similar in other comparisons o Unable to draw firm conclusions based on a sample size of 40 patients. Ping, Incidence of proven/probable invasive fungal infection: The second-generation azoles, including voriconazole and posaconazole, had been o Posaconazole: OR=0.40 (95%CI , p=0.02) investigated in several phase III studies and were shown to be more effective than o Voriconazole: OR=0.56 (95%CI , p=0.06) early-generation oral azole agents for antifungal prophylaxis. page 836 There were significantly fewer cases of invasive aspergillosis for: In conclusion, this meta-analysis demonstrated that antifungal prophylaxis o Posaconazole: OR=0.20 (95%CI , p=0.008) with second-generation azoles (voriconazole, posaconazole) can o Voriconazole: OR=0.45 (95%CI , p=0.04) significantly reduce the incidence of invasive fungal infections and invasive Overall mortality: aspergillosis but with no risk of increase in o Posaconazole: OR=0.77 adverse event. page 839 (95%CI , p=0.06) o Voriconazole: OR=0.90 (95%CI , p=0.61) Using second-generation azoles (posaconazole and voriconazole) resulted in significantly fewer: o Proven or probably fungal infections: OR=0.35 (95%CI , p=0.02) o Cases of invasive aspergillosis: OR=0.11 (95%CI , p=0.0008) Xu, Meta-analysis of proven infection: Posaconazole was well tolerated; its o Posaconazole (24/639) vs Fluconazole (49/595) overall safety profile was comparable with that of fluconazole page 413 (OR=0.44, 95%CI , p=0.001) Our analysis revealed a reduction in o Posaconazole (7/337) vs Itraconazole (8/74) (OR=0.17: 95%CI , p=0.001) invasive fungal infections with micafungin, voriconazole and posaconazole for prophylaxis. page 413 Meta-analysis of mortality: o Posaconazole (55/638) vs Fluconazole/Itraconazole (86/613) (OR=0.33, 95%CI , p=0.04) Meta-analysis of adverse events (liver function): o Posaconazole (13/304) vs Fluconazole (3/240) (OR=3.53, 95%CI , p=0.05) Meta-analysis of adverse reactions to stop use: o Posaconazole (267/605) vs Fluconazole (257/539) (OR=0.82, 95%CI , p=0.11) o Posaconazole (164/336) vs In conclusion, systematic review and randomized, controlled trials have demonstrated that antifungal prophylaxis with newer agents* reduces the incidence of invasive infections page 413 *posaconazole is one of the newer agents described Posaconazole for the Treatment or Prophylaxis of Aspergillosis or Candidiasis 23