国国立卫生研究院NIH过敏和传染病研究所NIAID临床评价分级标准

1、DIVISION OF MICROBIOLOGY AND INFECTIOUSDISEASES (DMID) ADULT TOXICITY TABLENOVEMBER 2007DRAFTNote: The following toxicity table is a DRAFT and designed to provide general guidanee on parameters for monitoring safety in elinieal trials. This toxicity table is not eomprehensive and should not be appli

2、ed directly to all trials.When selecting a toxicity table, the following are some of the items that must be taken into eon siderati on: The populati on being studied o Does the eli ni cal trial evaluate healthy subjects, subjects with a particular disease or eon diti on?* The stage of test article d

3、evelopme nto Is the elinieal trial a Phase I, II, III or IV?* The type of test articleo Does the eli ni cal trial evaluate a drug, device, vace ine or other biologic age nt?* The prior huma n and preeli ni cal experie nee with the test articleo Are there any specific findings that require adjustme n

4、t of the toxicity table?Sin gle site eli nieal trials evaluat ing healthy subjects should con form to the laboratory no rmal values at the si ngle site. Multi-ce nter eli ni cal trials should rec on cile among their laboratory no rmal values whe n evaluat ing a healthy volu nteer populati on.Please

5、confer with the DMID protocol team and DMIDs Office of Cli nieal Research Affairs whe n select ing or develop ing a toxicity table for a DMID-sp on sored trial.ULN = Upper Limit of Normal Rx = TherapyMod = ModerateADL = Activities of Daily Livi ngLLN = Lower Limit of NormalReq = RequiredIV = In trav

6、e nousDec = DecreasedABBREVIATIONS:Abbreviations utilized in the Table:ESTIMATING SEVERITY GRADEFor abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate grade of severity:GRADE 1MildTran sie nt or mild discomfortGRADE 2GRADE 3GRADE 4( 48 hours); no medical in terv

7、e nti on /therapy required ModerateMild to moderate limitationinactivity - some assista ncemay be n eeded; no or mini mal medical in terve nti on /therapy requiredSevereMarked limitation in activity, someassista nee usually required; medical in terve nti on /therapy required, hospitalizati ons possi

8、bleLife-threatening Extreme limitatio n in activity, significant assistanee required; significant medical in terve nti on /therapy required, hospitalizati on or hospice care probableSERIOUS OR LIFE-THREATENING AEsANY cli nical eve nt deemed by the clin icia n to be serious or life-threate ning shoul

9、d be con sidered a grade 4 eve nt. Cli nical eve nts con sidered to be serious or life-threate ning include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depressi on.COMMENTS REGAR

10、DING THE USE OF THESE TABLES?Standardized and commonly used toxicity tables (Division of AIDS, NCIsCom mon Toxicity Criteria (CTC), and World Health Orga ni zation (WHO) have been adapted for use by the Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the needs of

11、participants in DMID trials.? For parameters not in cluded in the followi ng Toxicity Tables, sites should refer to the “ Guide For Estimati ng Severity Grade” located above.Criteria are gen erally grouped by body system.Some protocols may have additional protocol specific grading criteria, which wi

12、ll supercede the use of these tables for specified criteria.HEMATOLOGYGrade 1Grade 2Grade 3Grade 4Hemoglob in9.5 - 10.5 gm/dL8.0 - 9.4gm/dL6.5 - 7.9 gm/dL 6.5 gm/dLAbsolute Neutrophil Cou nt31000-1500/mm3750-999/mm3500-749/mm3500/mmPlatelets75,000-399,999/mm50,000-374,999/mm320,000-49,999/mm330,000

13、or3 80%90 -95%95%Abno rmalFibri nogenLow:100-200 mg/dLHigh:400-600 mg/dLLow:600 mg/dLLow: 60 mcg/mlProthrombi nTime (PT)1.01 - 1.25 x ULN1.26-1.5 x ULN1.51 -3.0 x ULN3 x ULNActivated PartialThromboplastin (APPT)1.01-1.66 x ULN1.67 - 2.33 xULN2.34 - 3 x ULN 3 x ULNMethemoglob in5.0 - 9.9 %10.0 - 14.9

14、 %15.0 - 19.9% 20.0 %CHEMISTRIESGrade 1Grade 2Grade 3Grade 4Hyp on atremia130-135 mEq/L123-129mEq/L116-122 mEq/L 165 mEq/L or abno rmal sodium with men tal status cha nges or seizuresHypokalemia3.0 - 3.4 mEq/L2.5 - 2.9 mEq/L2.0 - 2.4 mEq/L or inten sive replaceme nt therapy or hospitalizati on requi

15、red 7.0 mEq/L or abno rmal potassium with life-threate ning arrhythmiaHypoglycemia55-64 mg/dL40-54 mg/dL30-39 mg/dL 500 mg/dL or abno rmal glucose with ketoacidosis or seizuresHypocalcemia (corrected for album in)8.4 - 7.8 mg/dL7.7 - 7.0 mg/dL6.9 - 6.1 mg/dL 13.5 mg/dL or abno rmal calcium with life

16、 threate ning arrhythmiaHypomag nesemia1.4 - 1.2 mEq/L1.1 - 0.9 mEq/L0.8 - 0.6 mEq/L 0.6 mEq/L or abno rmal magn esium with life-threate ning arrhythmiaHypophosphatemia2.0 - 2.4 mg/dL1.5 -1.9 mg/dL or replaceme nt Rx required1.0 -1.4 mg/dL inten sive therapy or hospitalizati on required 1.0 mg/dL or

17、 abno rmal phosphate with life-threate ning arrhythmiaHyperbilirubi nemia (whe n accompa nied by any in crease in other liver fun cti on test)1.1 - 1.25 x ULN1.25 - 1.75 x ULNHyperbilirubi nemia (whe n other liver fun cti on are in the no rmal ran ge)1.1 - 1.5 x ULN1.5 - 3.0 x ULNBUN1.25 - 2.5 x ULN

18、2.6 - 5 x ULN5.1 - 10 x ULN 10 x ULNHyperuricemia (uric acid)7.5 -10.0 mg/dL10.1 -12.0 mg/dL12.1 -15.0 mg/dL15.0 mg/dLCreati nine1.1 - 1.5 x ULN1.6 - 3.0 x ULN3.1 - 6 x ULN 6 x ULN or dialysis requiredDIVISION OF MICROBIOLOGY AND INFECTIOUSDISEASES (DMID) ADULT TOXICITY TABLENOVEMBER 2007DRAFTENZYME

19、SGrade 1Grade 2Grade 3Grade 4AST (SGOT)1.1 - 2.0 x ULN2.0 - 8 x ULNALT (SGPT)1.1 - 2.0 x ULN2.0 - 8 x ULNGGT1.1 - 2.0 x ULN2.0 - 8 x ULNAlkali ne Phosphatase1.1 - 2.0 x ULN2.0 - 8 x ULNAmylase1.1 - 1.5 x ULN1.6 - 2.0 x ULN2.1 - 5.0 x ULN 5.1 x ULNLipase1.1 - 1.5 x ULN1.6 - 2.0 x ULN2.1 - 5.0 x ULN 5

20、.1 x ULNURINALYSISGrade 1Grade 2Grade 3Grade 4Protei nuria1 +or200 mg - 1 gm loss/day2-3+ or1- 2 gm loss/day4+or2-3.5 gm loss/dayn ephrotic syn drome or 3.5 gm loss/dayHematuriamicroscopic only 10 rbc/hpfgross, with or without clots, OR red blood cell castsobstructive or required tran sfusi onCARDIO

21、VASCULARGrade 1Grade 2Grade 3Grade 4Cardiac Rhythmasymptomatic, transient sig ns, noRx requiredrecurre nt/persiste nt; symptomatic Rx requiredun stable dysrythmia; hospitalizati on and treatme nt requiredHyperte nsiontran sie nt in crease 20 mm/Hg; no treatme ntrecurre nt, chr onic in crease 20mm/Hg

22、. /treatme nt requiredacute treatme nt required; outpatie nt treatme nt or hospitalizati on possibleend orga n damage or hospitalizati on requiredHypote nsiontran sie nt orthostatic hypote nsion with heart rate in creased by 20 beat/m in or decreased by 10 mm Hg systolic BP, No treatme nt requiredsy

23、mptoms due to orthostatic hypote nsion or BP decreased by 20 mm Hg systolic; correctable with oral fluid treatme ntrequires IV fluids; no hospitalizati on requiredmean arterial pressure 3 un its tran sfusedRESPIRATORYGrade 1Grade 2Grade 3Grade 4Coughtran sie nt- no treatme ntpersiste nt cough; treat

24、me nt resp on siveParoxysmal cough; uncon trolled with treatme ntBron chospasm. Acutetran sie nt; no treatme nt;70% - 80% FEV 1 of peak flowrequires treatme nt; no rmalizes with bron chodilator; FEV1 50% - 70% (of peak flow)no no rmalizati on withbron chodilator; FEV1 25% - 50% of peak flow; or retr

25、acti ons prese ntcyano sis: FEV 16 episodes in 24 hours or n eedi ng IV fluidsphysiologic consequences requiri ng hospitalizati on or requiri ng pare nteral n utriti onCon stipati onrequiri ng stool softe ner or dietary modificati onrequiri ng laxativesobstipati on requiri ng man ual evacuati on or

26、en emaobstructi on or toxic megaco lonDiarrheamild or tra nsie nt;3-4 loose stools/day or mild diarrhea last 1 week7 loose stools/day or bloody diarrhea; or orthostatic hypote nsion or electrolyte imbala nee or 2L IV fluids requiredhypote nsive shock or physiologic consequences requiri ng hospitaliz

27、ati onOral Discomfort/Dysphagiamild discomfort; no difficulty swallowi ngsome limits on eati ng/dr inkingeat in g/talk ing very limited; un able to swallow solid foodsun able to drink fluids; requires IV fluidsNEUROLOGICALGrade 1Grade 2Grade 3Grade 4Neuro-Cerebellarslightin coord in ati on dysdiadoc

28、hok in esisinten ti on tremor, dysmetria, slurred speech; n ystagmuslocomotor ataxiain capacitatedPsychiatricmild an xiety or depressi onmoderate an xiety or depressi on; therapy required; cha nge in no rmal rout inesevere mood cha nges requir ing therapy; or suicidal ideati on; or aggressive ideati

29、 onacute psychosis requiri ng hospitalizati on; or suicidal gesture/attempt or halluc in ati onsMuscle Stre ngthsubjective weakness no objective symptoms/ sig nsmild objective sig ns/symptoms no decrease in fun cti onobjective weak ness fun cti on limitedparalysisParesthesia (bur ning, tin gli ng, e

30、tc.)mild discomfort; no treatme nt requiredmoderate discomfort; non-n arcotic an algesia requiredsevere discomfort; or n arcotic an algesia required with symptomatic improveme ntin capacitat ing; or not resp on sive to n arcotic an algesiaNeuro-se nsorymild impairment in sen sati on (decreased sen s

31、ati on, e.g., vibratory, pin prick, hot/cold in great toes) in focal area or symmetrical distribution; or cha nge in taste, smell, visio n an d/or heari ngmoderate impairme nt (mod decreased sen sati on, e.g., vibratory, pin prick, hot/cold to an kles) an d/or joint positi on or mild impairment that

32、 is not symmetricalsevere impairme nt (decreased or loss of sen sati on to kn ees or wrists) or loss of sen sati on of at least mod degree in multiple differe nt body areas (i.e., upper and lower extremities)sen sory loss in volves limbs and trunk; paralysis; or seizuresMUSCULOSKELATELGrade 1Grade 2

33、Grade 3Grade 4Arthralgia (joint pain)mild pai n not in terferi ng with fun cti onmoderate pain, an algesics an d/or pain in terferi ng with fun cti on but not with activities of daily liv ingsevere pain; pain an d/or an algesics in terferi ng with activities of daily livi ngdisabli ng painArthritism

34、ild pai n with in flammati on, erythema or joi nt swelling -but not in terferi ng with fun cti onmoderate pain with in flammati on, erythema or joi nt swelli ng - in terferi ng with fun cti on, but not with activities of daily livi ngsevere pain with in flammati on, erythema or joi nt swelling -and in terferi ng with activities of daily livi ngperma nent an d/or disabli ng joint distructio nMyalgiamyalgia with no limitation of activitymuscle tendern ess (at other tha n injection site) or with moderate impairme nt of activitysevere muscle