Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:

2 Supplement to: Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia Methods Definition of the Study Population Details on the Inclusion Criteria 1. Basic demographics: Subjects greater than or equal to 13 years of age (weighing greater than 34 kg), of either sex and of any race. 2. Disease definition: a. Anticipated or documented prolonged neutropenia (ANC<500/mm 3 [0.5x10 9 /L]) at Baseline or likely to develop within 3 to 5 days and lasting for at least 7 days due to: i. Intensive induction-remission chemotherapy for a new diagnosis of acute leukemia receiving standard anthracycline based chemotherapy ii. Reinduction of acute leukemia after primary relapse iii. Myelodysplastic syndromes requiring induction (myelosuppressive) chemotherapy b. Eastern Cooperative Oncology Group (ECOG) performance score of less than 3.

3 3. Subjects' clinical laboratory safety tests (blood chemistries) must be within normal limits or clinically acceptable to the investigator/sponsor (ie, show no Grade 4/life threatening abnormalities). 4. Subjects must be free of any clinically significant disease (other than the primary hematologic disease) that would interfere with the study evaluations. 5. Subjects (and/or parent/guardian for subjects under 18 years of age) must be willing to give written informed consent and able to adhere to dosing, study visit schedule, and mandatory procedures (as long as local regulations are met). 6. Female subjects of childbearing age must be using a medically accepted method of birth control a before beginning study-drug treatment and agree to continue its use during the study or be surgically sterilized (eg, hysterectomy or tubal ligation). Female subjects of childbearing potential should be counseled in the appropriate use of birth control while in this study. Female subjects who are not currently sexually active must agree and consent to use one of the above-mentioned methods should they become sexually active while participating in the study. 7. Female subjects of childbearing potential must have a negative serum pregnancy test (beta-human chorionic gonadotrophin) at Baseline or within 72 hours before the start of study drug. a Oral or injectable hormonal contraceptive, medically prescribed intra-uterine device or barrier method (eg, condom in combination with spermicide). Vasectomy of the partner and tubal ligation should each be considered effective methods of birth control.

4 Details on the Exclusion Criteria 1. Female subjects who are pregnant, intend to become pregnant, or are nursing. 2. Excluded prior treatments: Subjects previously treated with amphotericin B, fluconazole, or itracaonazole for proven or probable invasive fungal infection within 30 days of enrollment. 3. Excluded treatments prior to specific study phases: Subjects who have taken the following drugs: a. those known to interact with azoles and that may lead to life-threatening side effects (terfenadine, cisapride, and ebastine at entry or within 24 hours before entry, or astemizole at entry or within 10 days before entry); b. those known to lower the serum concentration/efficacy of azole antifungal agents: cimetidine, rifampin, carbamazepine, phenytoin, rifabutin, barbiturates, and isoniazid at entry or within 24 hours before entry; c. and those receiving vinca alkaloids, or anthracyclines with evidence of cardiotoxicity. 4. Subjects who are in a situation or have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study, ie, any condition requiring the use of prohibited drugs or unstable medical conditions other than the hematological disorder such as cardiac or neurologic disorder or impairment expected to be unstable or progressive during the course of this study (eg, seizures or demyelinating syndromes, acute myocardial infarction, myocardial ischemia, or unstable congestive heart failure). 5. Subjects who have used any investigational drugs or biologic agents other than their chemotherapy regimens within 30 days of study entry.

5 6. Subjects who are participating in any other blinded clinical study within 30 days of study entry. 7. Subjects who are part of the staff personnel directly involved with this study. 8. Subjects who are a family member of the investigational study staff. 9. Prior enrollment in this study, or other posaconazole studies. 10. Subjects with a history of hypersensitivity or idiosyncratic reactions to azole agents. 11. Subjects with ECOG performance score of 3 or Subjects with known or suspected invasive or systemic fungal infection at Baseline (randomization). 13. Subjects with renal insufficiency (estimated creatinine clearance less than 20 ml/minute at Baseline or likely to require dialysis during the study). 14. Subjects having an electrocardiogram with a prolonged QTc interval by manual reading: QTc greater than 450 msec for men and greater than 470 msec for women. 15. Subjects with moderate or severe liver dysfunction at Baseline, defined as aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase levels greater than 5 times the upper limit of normal (ULN), or a total bilirubin level greater than 3 times the ULN.

6 Results Post hoc analysis of posaconazole versus fluconazole only A post hoc analysis limited to centers where fluconazole was the comparator confirmed the superiority of posaconazole: incidence of proven and probable invasive fungal infections during the treatment period was 4 (2 percent) of 239 posaconazole patients and 19 (8 percent) of 240 fluconazole patients (95 percent confidence interval, percent to -2.4 percent, P = 0.001). At 100 days, 8 (3 percent) of 239 posaconazole patients and 26 (11 percent) of 240 fluconazole patients had a proven or probable fungal infection (95 percent confidence interval, percent to -2.9 percent, P = 0.001). Post hoc analysis of posaconazole versus itraconazole only The same post hoc analysis limited to centers where itraconazole was the comparator did not show a difference between the study groups: incidence of proven and probable invasive fungal infections during the treatment period was 3 (5 percent) of 65 posaconazole patients and 6 (10 percent) of 58 itraconazole patients (95 percent confidence interval, -0.2 percent to 0.04 percent, P = 0.22). At 100 days, 6 (9 percent) of 65 posaconazole patients and 7 (12 percent) of 58 itraconazole patients had a proven or probable fungal infection (95 percent confidence interval, -0.1 percent to 0.1 percent, P = 0.61). However, it must be noted that sub-analysis of this type may reduce the statistical power of the overall results despite a favorable numeric response.

7 Fungal Colonization Throat and stool surveillance cultures were collected once weekly during treatment and repeated during suspected infection episodes. The reduction in the incidence of fungal colonization after prophylaxis was similar for the three study drugs. There was no difference in the emergence of Candida species between the two treatment arms. There was no change in the minimum inhibitory concentration (90th percentile) of more than 2 tube dilutions for all yeast species in any azole group when in vitro testing of colonizing isolates evaluated changes in susceptibility from baseline to end of treatment.

8 Table A. Treatment-emergent Serious Adverse Events* Fluconazole and Itraconazole Posaconazole Fluconazole/ Fluconazole Itraconazole Itraconazole Serious Adverse Event Pooled No. (%) of patients (n=304) (n=298) (n=240) (n=58) Any event 159 (52) 175 (59) 143 (60) 32 (55) Thrombocytopenia 46 (15) 52 (17) 43 (18) 9 (16) Febrile neutropenia 29 (10) 36 (12) 32 (13) 4 (7) Anemia 25 (8) 15 (5) 11 (5) 4 (7) Fever 23 (8) 31 (10) 22 (9) 9 (16) Neutropenia 22 (7) 23 (8) 18 (8) 5 (9) Bacteremia 16 (5) 22 (7) 18 (8) 4 (7) Sepsis 15 (5) 25 (8) 20 (8) 5 (9) Septic shock 14 (5) 17 (6) 12 (5) 5 (9) Acute myelogenous leukemia aggravated 11 (4) 12 (4) 10 (4) 2 (3) Hypotension 10 (3) 21 (7) 17 (7) 4 (7) Vaginal hemorrhage 4 (3) 1 (1) 1 (1) 0 Gastrointestinal hemorrhage 8 (3) 3 (1) 2 (1) 1 (2) Leukemia 8 (3) 3 (1) 3 (1) 0 Respiratory insufficiency 8 (3) 18 (6) 16 (7) 2 (3)

9 Bilirubinemia 7 (2) 5 (2) 4 (2) 1 (2) Pulmonary edema 7 (2) 8 (3) 7 (3) 1 (2) Pulmonary hemorrhage 7 (2) 1 (<1) 1 (<1) 0 Acute myelogenous leukemia 6 (2) 7 (2) 7 (3) 0 Acute respiratory failure 6 (2) 1 (<1) 1 (<1) 0 Cardiac failure 6 (2) 3 (1) 3 (1) 0 Cerebral hemorrhage 6 (2) 4 (1) 4 (2) 0 Leukopenia 6 (2) 8 (3) 6 (3) 2 (3) Multiple organ failure 6 (2) 6 (2) 4 (2) 2 (3) Pneumonia 6 (2) 14 (5) 12 (5) 2 (3) Cardiac arrest 4 (1) 6 (2) 5 (2) 1 (2) Cardio-respiratory arrest 4 (1) 5 (2) 4 (2) 1 (2) Dyspnea 4 (1) 6 (2) 3 (1) 3 (5) Hypoxia 4 (1) 8 (3) 4 (2) 4 (7) Fungal pneumonia (not otherwise specified) 4 (1) 7 (2) 5 (2) 2 (3) Abdominal pain 3 (1) 6 (2) 4 (2) 2 (3) Loss of consciousness 3 (1) 5 (2) 4 (2) 1 (2) Aspergillosis (not otherwise specified) 2 (1) 8 (3) 6 (3) 2 (3) Atrial fibrillation 2 (1) 6 (2) 5 (2) 1 (2) Catheter-related infection 1 (<1) 6 (2) 3 (1) 3 (5) Intracranial hemorrhage 1 (<1) 7 (2) 7 (3) 0

10 Renal failure 1 (<1) 5 (2) 5 (2) 0 Acute respiratory distress syndrome 0 6 (2) 5 (2) 1 (2) * With 2% incidence or more in posaconazole group or pooled fluconazole/itraconazole group. Numbers for subentries may not sum to the total numbers because patients could have more than 1 event. Percentage based on number of female patients.

11 Table B. Possibly or Probably Treatment-related Serious Adverse Events Fluconazole and Itraconazole Posaconazole Fluconazole/ Fluconazole Itraconazole Itraconazole Serious Adverse Event Pooled No. (%) of patients (n=304) (n=298) (n=240) (n=58) Any event* 19 (6) 6 (2) 4 (2) 2 (3) Bilirubinemia 5 (2) 3 (1) 2 (1) 1 (2) Hepatic enzymes increased 3 (1) 1 (<1) 1 (<1) 0 Syncope 2 (1) Abdominal pain 1 (<1) Allergic reaction 1 (<1) Alanine amino transferase increased 1 (<1) 1 (<1) 0 1 (2) Anemia 1 (<1) Aplasia bone marrow 1 (<1) Atrial fibrillation 1 (<1) Diarrhea 1 (<1) Drug interaction 1 (<1) Dysphagia 1 (<1) Ejection fraction decreased 1 (<1) 0 0 0

12 Encephalopathy 1 (<1) Fall 1 (<1) Glossitis 1 (<1) Hemorrhagic gastritis 1 (<1) Hepatic failure 1 (<1) Hepatitis 1 (<1) Hepatocellular damage 1 (<1) Inflammation, nonspecific 1 (<1) Interstitial pneumonia 1 (<1) Jaundice 1 (<1) Melena 1 (<1) Pneumonitis 1 (<1) QT/QTc prolongation 1 (<1) Torsades de pointes 1 (<1) Diplopia 0 1 (<1) 1 (<1) 0 * Numbers for subentries may not sum to the total numbers because patients could have more than 1 event. 95 percent confidence interval on the difference in rates between the posaconazole group and the pooled fluconazole/itraconazole group, 1.1 percent to 7.4 percent, P= >450 msec for males and >470 msec for females.

13 Table C. Possibly or Probably Treatment-related Adverse Events, including Serious Adverse Events* Fluconazole and Itraconazole Posaconazole Fluconazole/ Fluconazole Itraconazole Itraconazole Adverse event Pooled No. (%) of patients (n=304) (n=298) (n=240) (n=58) Any event 102 (34) 101 (34) 71 (30) 30 (52) Nausea 22 (7) 25 (8) 17 (7) 8 (14) Diarrhea 20 (7) 21 (7) 12 (5) 9 (16) Vomiting 14 (5) 20 (7) 14 (6) 6 (10) QT/QTc prolongation 12 (4) 9 (3) 5 (2) 4 (7) Abdominal pain 9 (3) 9 (3) 8 (3) 1 (2) Hypokalemia 9 (3) 6 (2) 5 (2) 1 (2) Rash 9 (3) 11 (4) 10 (4) 1 (2) Mucositis, not otherwise specified 7 (2) Bilirubinemia 7 (2) 8 (3) 5 (2) 3 (5) Hepatic enzymes increased Alanine amino transferase increased 7 (2) 3 (1) 3 (1) 0 7 (2) 5 (2) 4 (2) 1 (2) Aspartate amino 6 (2) 5 (2) 4 (2) 1 (2)

14 transferase increased Gamma-glutamyl transferase increased 5 (2) 2 (1) 1 (<1) 1 (2) Headache 5 (2) 1 (<1) 0 1 (2) Dyspepsia 5 (2) 3 (1) 3 (1) 0 Constipation 3 (1) 7 (2) 7 (3) 0 * With 2% incidence or more in posaconazole group or pooled fluconazole/itraconazole group. Numbers for subentries may not sum to the total numbers because patients could have more than 1 event. >450 msec for males and >470 msec for females.

15 CONSORT Flowchart Assessed for eligibility (n=666) Excluded (n=64) Not meeting inclusion criteria (n= 64) Randomized (n=602) All analyses were performed in this population Posaconazole arm Allocated to intervention (n=304) Received allocated intervention (n=297) Did not receive allocated intervention (n=7) Standard azole arm Allocated to intervention (n=298) Received allocated intervention (n=292) Did not receive allocated intervention (n=6) Allocation and Treatment Completed treatment phase (n=159) Discontinued treatment (n=145) Treatment failure (n=80) Adverse event (n=40) Did not wish to continue (n=14) Noncompliance (n=6) Did not meet protocol eligibility (n=3) Lost to follow-up (n=1) Administrative (n=1) Completed treatment phase (n=125) Discontinued treatment (n=173) Treatment failure (n=117) Adverse event (n=37) Did not wish to continue (n=12) Noncompliance (n=4) Did not meet protocol eligibility (n=3) Lost to follow-up (n=0) Administrative (n=0) Entered Follow-up (n=281) Completed Follow-up (n=237) Discontinued Follow-up (n=44) Adverse event (n=32) Treatment failure (n=5) Did not wish to continue (n=4) Lost to follow-up (n=1) Noncompliance (n=2) Never entered Follow-up (n=23) Follow up Entered Follow-up (n=275) Completed Follow-up (n=220) Discontinued Follow-up (n=55) Adverse event (n=28) Treatment failure (n=17) Did not wish to continue (n=6) Lost to follow-up (n=3) Noncompliance (n=1) Never entered Follow-up (n=23) Analyzed (n=304) Analysis Analyzed (n=298)