6.2Exclusion Criteria - TransCelerate



Common Protocol Template Patient Library v2.0Section in Common Protocol Template (CPT) V1.0Library Content6.2. Exclusion CriteriaExclusion Criteria8.1 Discontinuation of Study TreatmentLiver Function Stopping Criteria REF _Ref380437237 \h \* MERGEFORMAT QTc Stopping CriteriaAppendix 7: Liver Safety: Suggested Actions and Followup Assessments [and Study Treatment Rechallenge Guidelines]Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines] 6.2Exclusion CriteriaMEDICAL CONDITIONSCriteria below are for molecules that are immune modulators. Delete if not applicable.Symptomatic herpes zoster within 3 months prior to screeningEvidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest x-rays (posterior anterior and lateral), and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON?-TB Gold test. NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made by the investigator according to local licensing and standard of care. The QuantiFERON-TB Gold test can only be used in countries where it is licensed, and the use of this test is dependent on previous treatment(s). This test may not be suitable if previous treatment(s) produced significant immunosuppression.Criteria below are for large molecules that are antibodies. Delete if not applicable.Significant allergies to humanized monoclonal antibodies Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis)Depending on the molecule, some regulatory agencies require exclusion of ANY history of malignancy. Modify the text below as needed.Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 yearsBreast cancer within the past 10 yearsSuggested criteria if CSF is collected. Delete if not applicable.Abnormalities in lumbar spine previously known or determined by a screening lumbar x-ray (if conducted)History of clinically significant back pain, back pathology, and/or back injury (eg, degenerative disease, spinal deformity or spinal surgery) that may predispose participant to complications or technical difficulty with lumbar punctureEvidence or history of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertionAllergy to lidocaine (Xylocaine?) or its derivativesMedical or surgical conditions for which lumbar puncture is contraindicated<Start of common text for Phase I studies>ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)<End of common text for Phase I studies><Start of common text for Phase II studies>ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)<End of common text for Phase II studies><Start of common text for Phase III studies>ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). NOTES: Stable chronic liver disease should be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, and cirrhosis.Chronic stable hepatitis B or C (eg, presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment) is acceptable if the participant otherwise meets entry criteria<End of common text for Phase III studies>For studies of immunosuppressive study treatments, participants with chronic stable hepatitis B and/or hepatitis C (e.g., presence of HBsAg or positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment) should generally be excluded. For potent immunosuppressive agents, participants with the presence of hepatitis B core antibody (HBcAb) should also be excluded. If these participants will be included, then additional screening, anti-viral prophylaxis, monitoring, and follow-up measures may be warranted. For such studies, the relevant sponsor Safety Panel should be consulted for additional guidance. <Start of common text>State the corrected QT interval (QTc) Exclusion Criteria as shown below. These criteria should serve as the general default values for all studies. Due to the different benefit/risk profiles of study treatments as well as the different participant populations, exceptions to these criteria may occur. These should be proposed and agreed upon by all relevant parties within the sponsor organisation<Start of common text for Phase I-IV studies in Patients>[QTc >450 msec for male participants] [or QTc >470 for female participants] or QTc >?480 msec in participants with bundle branch blockNOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read.The specific formula that will be used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulas cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial.<End of common text>The specific QT correction formula(s) that will be used for data analysis should be determined prior to initiation of the study and recorded in the SAP. If a protocol is prescriptive in its choice of QTc correction formula(s) for data analysis, then any study site that does not have available ECG machines pre-programmed with the chosen QT correction formula must have all of the QTc data appropriately calculated using the chosen formula. The bullet points above exist within the standard text of the protocol so that QTc results are not chosen based upon the QT correction formula that presents a more favorable result (i.e., a lower value for QTc).PRIOR/CONCOMITANT THERAPYSummarize the classes of treatments that participants cannot take concomitantly, and cross reference Section 7 Study Treatments for details.[Past or] intended use of over-the-counter or prescription medication [including herbal medications] within [X] days prior to dosing. [Specific medications listed in Section 7.7 may be allowed.]Criteria below are for molecules that are immune modulators. Delete if not applicable.Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study.Criteria below are for large molecules. Delete if not applicable.Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.PRIOR/CONCURRENT CLINICAL TRIAL EXPERIENCEParticipation in the study would result in donation of blood or blood products in excess of [X] mL within [X].Exposure to more than 4 new chemical entities within 12 months prior to the first dosing dayConsider adding the following criteria if participants can only be enrolled once per study.Current enrollment or past participation within the last [X] days before [signing of consent] in [this or] any other clinical study involving an investigational study treatment or any other type of medical researchDIAGNOSTIC ASSESSMENTS Positive HIV antibody test<Start of common text for Phase I or II studies>Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment. For potent immunosuppressive agents, presence of the hepatitis B core antibody (HBcAb) should also lead to exclusion from the study.<End of common text for Phase I or II studies>NOTE: For Phase III studies, hepatitis B and C testing at screening is not suggested unless potent immunosuppressive agents will be administered. Refer to Concurrent Conditions/Medical History section above for additional guidance.OTHER EXCLUSIONSRegular alcohol consumption within [X] months prior to the study defined as: Choose from wording options below or replace with country specific textFor UK sites: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure (25 mL) of spirits. For US sites: An average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces (45 mL) of 80 proof distilled spirits.The following criteria should be considered depending on known metabolic/safety issues of the study treatment or site-specific factors:Sensitivity to heparin or heparin-induced thrombocytopeniaSensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator [or Medical Monitor], contraindicates participation in the study.8.1 Discontinuation of Study Treatment Liver Function Stopping Criteria<Start of common text> Study treatment will be discontinued for a participant if liver function stopping criteria are met.Phase I Liver Function Stopping Algorithm Continue Study Treatment Discontinue Study Treatment *INR value not applicable to participants on anticoagulantsALT ≥ 3xULN NoYes?Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix?Report as an SAE if possible Hy’s Law case: ALT≥3xULN and Bilirubin ≥2xULN (>35% direct) Or INR>1.5, if measured*Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].<End of common text> <Start of common text for Phase II studies>Phase II Liver Function Stopping Criteria and Increased Monitoring AlgorithmLiver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X]. <End of common text for Phase II studies><Start of common text for Phase III-IV studies>Phase III-IV Liver Function Stopping Criteria and Increased Monitoring AlgorithmLiver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X].Phase III-IV Liver Function Increased Monitoring Algorithm with Continued Therapy for Participants with ALT 3xULN but <8xULN Liver Safety: Suggested Actions and Follow-up Assessments can be found in Appendix [X]. <End of common text for Phase III-IV studies>QTc Stopping Criteria<Start of common text for Phase 1-IV studies iin patients> A participant who meets [the OR either] bulleted criterion based on the average of triplicate ECG readings will be withdrawn from the study. QTc >500 msec OR Uncorrected QT >600 msec[Change from baseline of QTc >60 msec]For participants with underlying bundle branch block, follow the discontinuation criteria listed below:Baseline QTc with Bundle Branch BlockDiscontinuation QTc Threshold with Bundle Branch Block< 450 msec> 500 msec450 to 480 msec≥ 530 msec<End of common text for Phase I-IV studies in patients>Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments [and Study Treatment Rechallenge Guidelines]<Start of common text for Phase I studies > Phase I liver function stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase I Liver Function Stopping Criteria and Follow-Up AssessmentsLiver Chemistry Stopping Criteria – Liver Stopping EventALT-absoluteALT≥3xULNIf ALT≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) or INR >1.5, Report as an SAE.1,2See additional Actions and Follow Up Assessments listed belowSuggested Actions and Follow up Assessments following Liver Stopping EventActionsFollow Up AssessmentsImmediately discontinue study treatment. Do not include for single-dose studies.Report the event to the [sponsor] within 24 hoursComplete the liver event CRF, and complete an SAE data collection tool if the event also met the criteria for an SAE.2Perform liver function follow-up assessments. Monitor the participant until liver function test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study treatment unless allowed per protocol and [sponsor] approval is granted. Do not include for single-dose studies.If restart/rechallenge is either not allowed per protocol or not granted, permanently discontinue study treatment. The participant may continue in the study for any protocol-specified follow-up assessments (may include, if applicable, details on suggested follow-up assessments [e.g., follow up for overall survival or disease recurrence or progression]). Do not include for single-dose studies.MONITORING:Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 hrs.Monitor participant twice weekly until liver function test abnormalities resolve, stabilize or return to baseline.A specialist or hepatology consultation is recommended.If ALT ≥3xULN AND bilirubin <2xULN and INR ≤1.5:Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver function abnormalities resolve, stabilize, or return to baseline.Blood sample for pharmacokinetic (PK) analysis obtained [insert time interval recommended by clinical pharmacokinetics representative] after the most recent dose4 Do not include for single-dose studies.Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin ?2xULNComplete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE report formRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications report form.Record alcohol use on the liver event alcohol intake CRFIf ALT≥3xULN AND bilirubin 2xULN or INR >1.5:Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins.Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in the preceding week [James, 2009].) NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerizsed tomography) andor liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRFs.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment if ALT 3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to participants receiving anticoagulants. Includes: Hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody. Do not include for single-dose studies. PK sample may not be required for participants known to be receiving placebo or non-comparator treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the [Study Reference Manual]. References: James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. <End of common text for Phase I studies > <Start of common wording for Phase II studies>Phase II liver function stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase II Liver Function Stopping Criteria and Follow-Up AssessmentsLiver Function Stopping CriteriaALT-absoluteALT 5xULNALT IncreaseALT 3xULN persists for 4 weeksBilirubin1, 2ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)INR2ALT 3xULN and INR >1.5, if INR measuredCannot MonitorALT 3xULN and cannot be monitored weekly for 4 weeksSymptomatic3ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivitySuggested Actions and Follow-up Assessments following ANY Liver Function Event that Requires Study Treatment DiscontinuationActionsFollow-Up AssessmentsImmediately discontinue study treatment. Do not include for single-dose studiesReport the event to the [sponsor] within 24 plete the liver event CRF, and complete an SAE data collection tool if the event also met the criteria for an SAE.2Perform liver function follow-up assessments. Monitor the participant until liver function test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study treatment unless allowed per protocol and [sponsor] Medical Governance approval is granted) Do not include for single-dose studiesIf restart/rechallenge not allowed per protocol or not granted, permanently discontinue study treatment and may continue participant in the study for any protocol specified follow up assessments (may include if applicable details on. Suggested follow up assessments e.g. follow up for overall survival or disease recurrence or progression); Do not include for single-dose studiesMONITORING:For bilirubin or INR criteria: Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 hrs.Monitor participant twice weekly until liver function test abnormalities resolve, stabilize or return to baseline.A specialist or hepatology consultation is recommended.For All other criteria: Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver function abnormalities resolve, stabilize, or return to baseline.Viral hepatitis serology4Blood sample for pharmacokinetic (PK) analysis obtained [insert time interval recommended by clinical pharmacokinetics representative] after the most recent dose5. Do not include for single-dose studies.Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin ?2xULNComplete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE report formRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications report form.Record alcohol use on the liver event alcohol intake CRFFor bilirubin or INR criteria:Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins.Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in the preceding week [James, 2009].)NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRFs.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment if ALT 3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to participants receiving anticoagulants. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).Includes: Hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody. PK sample may not be required for participants known to be receiving placebo or non-comparator treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the [Study Reference Manual]. Do not include for single-dose studies.Phase II Liver Function Increased Monitoring Criteria with Continued TherapyLiver Function Increased Monitoring Criterion and Follow-UpCriteriaActionsALT 3xULN and <5xULN and bilirubin <2xULN, without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 weeksNotify the [sponsor] medical monitor within 24 hours of learning of the abnormality to discuss participant safety. Participant can continue study treatment [this can be deleted for single-dose studies]. Participant must return weekly for repeat liver function tests (ALT, AST, alkaline phosphatase, bilirubin) until the abnormalities resolve, stabilize or return to baseline. If at any time, the participant meets liver function stopping criteria, proceed as described [location].If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor participants twice monthly until liver function tests normalize or return to baseline.ReferencesJames LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.<End of common wording><Start of common wording for Phase III studies>Phase III-IV liver function stopping criteria are designed to assure participant safety and to evaluate liver event etiology.Phase III-IV liver function stopping criteria and Follow-Up assessments Liver Function Stopping CriteriaALT-absoluteALT 8xULNALT IncreaseALT 5xULN but <8xULN persists for 2 weeksALT 3xULN but <5xULN persists for 4 weeksBilirubin1, 2ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) INR2 ALT 3xULN and INR >1.5, if INR measuredCannot MonitorALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeksALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeksSymptomatic3ALT 3xULN associated with symptoms (new or worsening) believed to be related to liver injury or hypersensitivitySuggested Actions and Follow up Assessments following ANY Liver Stopping EventActionsFollow Up AssessmentsImmediately discontinue study treatment. Do not include for single-dose studiesReport the event to the [sponsor] within 24 plete the liver event CRF, and complete an SAE data collection tool if the event also met the criteria for an SAE.2Perform liver function follow-up assessments. Monitor the participant until liver function test abnormalities resolve, stabilize, or return to baseline (see MONITORING).Do not restart/rechallenge participant with study treatment unless allowed per protocol and [sponsor] Medical Governance approval is granted (refer to Appendix [X] ) Do not include for single-dose studiesIf restart/rechallenge not allowed per protocol or not granted, permanently discontinue study treatment and may continue participant in the study for any protocol specified follow up assessments (may include if applicable details on. Suggested follow up assessments e.g. follow up for overall survival or disease recurrence or progression); Do not include for single-dose studiesMONITORING:For bilirubin or INR criteria: Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 hrs.Monitor participant twice weekly until liver function test abnormalities resolve, stabilize or return to baseline.A specialist or hepatology consultation is recommended.For All other criteria: Repeat liver function tests (include ALT, AST, alkaline phosphatase, bilirubin) and perform liver function follow-up assessments within 24 to 72 hours.Monitor participants weekly until liver function abnormalities resolve, stabilize, or return to baseline.Viral hepatitis serology4Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen) quantitative hepatitis B DNA and hepatitis delta antibody5Blood sample for pharmacokinetic (PK) analysis obtained [insert time interval recommended by clinical pharmacokinetics representative] after the most recent dose6 Do not include for single-dose studies.Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)Fractionate bilirubin, if total bilirubin ?2xULNComplete blood count with differential to assess eosinophiliaRecord the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE report formRecord use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-counter medications) on the concomitant medications report form.Record alcohol use on the liver event alcohol intake CRFFor bilirubin or INR criteria:Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins.Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in the preceding week [James, 2009]. NOTE: Not required in China.Liver imaging (ultrasound, magnetic resonance, or computerizsed tomography) andor liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy CRFs.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately available, discontinue study treatment if ALT 3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to participants receiving anticoagulants. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).Includes: Hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody. If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus (where needed) [Le Gal, 2005].PK sample may not be required for participants known to be receiving placebo or non-comparator treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the [Study Reference Manual]. Do not include for single-dose studiesPhase III-IV Liver Function Increased Monitoring Criteria with Continued TherapyLiver Function Increased Monitoring CriteriaCriteriaActionsALT 5xULN and <8xULN and bilirubin <2xULN without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 2 weeks.ORALT 3xULN and <5xULN and bilirubin <2xULN without symptoms believed to be related to liver injury or hypersensitivity, and who can be monitored weekly for 4 weeks.Notify the [sponsor] medical monitor within 24 hours of learning of the abnormality to discuss participant safety. Participant can continue study treatment [this can be deleted for single-dose studies]. Participant must return weekly for repeat liver function tests (ALT, AST, alkaline phosphatase, bilirubin) until the abnormalities resolve, stabilize or return to baseline. If at any time, the participant meets liver function stopping criteria, proceed as described [location].If ALT decreases from ALT 5xULN and <8xULN to ≥3xULN but <5xULN, continue to monitor liver chemistries weekly. If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor particpants twice monthly until liver function tests normalize or return to baseline.ReferencesJames LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol. 2005;43(5):2363–2369. <End of common text for Phase III studies> Liver Safety: Study Treatment Rechallenge Guidelines This part of the appendix is optional and should ONLY be included if study treatment restart/rechallenge will be allowed for participants in the study. If this part of the appendix is not included, then change the title of the appendix accordingly. This section does not apply to single dose studies.This section should ONLY be included if:Study treatment rechallenge is allowed after treatment-related injury in participants has a compelling benefit (i.e., a critical or life-saving medicine for which no alternative therapy is available) and a benefit/risk assessment of continuing study treatment is considered to be favorable (applies to Phase?IIV studies excluding healthy volunteer studies). AND/ORStudy treatment restart is allowed after a participant(s) has a transient and resolved/resolving non-treatment-related liver injury in Phase III-IV studies (available to all studies and particularly suggested for long-term outcome studies). Study treatment restarts are generally limited to Phase III-IV studies, but can be considered in Phase I and II studies if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available, and a benefit/risk assessment of continuing study treatment is considered to be favorable.If this section is included, ensure that the following are utilized:The restart and/or rechallenge informed consent form (ICF). (Note: The restart or rechallenge ICF may be created and reviewed a priori with the main consent form, but is only used after an event has occurred and drug restart or rechallenge is being considered.) The liver CRFs.Pharmacokinetic sample processing and data capture.<Start of common text if study treatment restart/rechallenge is allowed>A participant who met liver function stopping criteria cannot restart study treatment unless all of the following conditions are met:[sponsor] approval is granted (as described below)IRB/IEC approval is obtainedSeparate ICF for treatment restart/rechallenge is signed by the participantIf [sponsor] approval to restart/rechallenge the participant with study treatment is not granted, then the participant must permanently discontinue study treatment and may continue in the study for protocol-specified follow-up assessments (include any applicable details on suggested follow-up assessments [e.g., follow-up for overall survival or disease recurrence or progression]).Rechallenge Following Liver Function Events that are Possibly Related to Study TreatmentFollowing study treatment-induced liver injury, rechallenge is associated with 13% mortality across all study treatments in prospective studies.1 Clinical outcomes vary with nearly 50% fatality with halothane readministered within one month of the initial injury. However, some treatments seldom result in recurrent liver injury or fatality. Risk factors for a fatal rechallenge outcome include:Hypersensitivity with initial liver injury (e.g., fever, rash, eosinophilia) 1 Jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of total)Ongoing severe liver injury defined by ALT 3xULN AND bilirubin 2xULN (direct bilirubin >35% of total), OR INR1.5Serious adverse event or fatality previously observed with rechallenges2,3Evidence of treatment-related preclinical liability (e.g., reactive metabolites, mitochondrial impairment)3Rechallenge refers to resuming study treatment following drug-induced liver injury (DILI). Because of the risks associated with rechallenge after DILI, this should only be considered if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available, and a benefit/risk assessment of rechallenge is considered to be favorable.Approval by the [sponsor] for rechallenge with study treatment can be considered when:The Principal Investigator (PI) requests consideration of rechallenge with study treatment for a participant who is receiving compelling benefit with study treatment that exceeds risk and for whom no effective alternative therapy is available. IRB/IEC approval for rechallenge with study treatment has been obtained.If the rechallenge is approved by the [sponsor] in writing: The participant must be provided with a clear description of the possible benefits and risks of study treatment administration including the possibility of recurrent, more severe liver injury or death. The participant must also provide signed informed consent specifically for the rechallenge with study treatment. Documentation of informed consent must be recorded in the study file. Study treatment must be administered at the dose specified by the [sponsor].Participants approved by the [sponsor] for rechallenge with study treatment must return to the clinic twice a week for liver function tests until stable liver function tests have been demonstrated and then standard laboratory monitoring may resume as per protocol.If the participant meets protocol-defined liver function stopping criteria after study treatment rechallenge, study treatment should be permanently discontinued. The [sponsor] Medical Monitor, and the IRB/IEC, must be informed of the outcome for the participant following study treatment rechallenge. The [sponsor] must be notified of any adverse events, as per Appendix 4. AND/ORRestart Following Transient Resolving Liver Function Events Not Related to Study TreatmentRestart refers to resuming study treatment following liver function events for which there are clear underlying causes (other than DILI) (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be associated with Human Leucocyte antigen (HLA) markers of liver injury.NOTE: Drug restarts are generally limited to Phase III studies, but can be considered in Phase I and II studies if there is compelling evidence of benefit from a critical or life-saving medicine, there is no alternative approved medicine available and a benefit/risk assessment of continuing study treatment is considered to be favorable.Approval by the [sponsor] for study treatment restart can be considered when:The investigator requests consideration for study treatment restart if liver function events have a clear underlying cause (e.g., biliary obstruction, hypotension) and liver function tests have improved to normal or are within 1.5 x baseline and ALT <3xULN.Restart risk factors (e.g., fever, rash, eosinophilia, hypersensitivity, alcoholic hepatitis, possible study treatment-induced liver injury or study treatment has an HLA genetic marker associated with liver injury [e.g. lapatinib, abacavir, amoxicillin/clavulanate]) are reviewed and excluded.IRB/IEC approval of study treatment restart has been obtained.If restart of study treatment is approved by the [sponsor] in writing: The participant must be provided with a clear description of the possible benefits and risks of study treatment administration including the possibility of recurrent, more severe liver injury or death. The participant must also provide signed informed consent specifically for the restart of study treatment. Documentation of informed consent must be recorded in the study file. Study treatment must be administered at the dose specified by the [sponsor].Participants approved by the [sponsor] for restart of study treatment must return to the clinic twice a week for liver function tests until stable liver function tests have been demonstrated and then standard laboratory monitoring may resume as per protocol.If the participant meets protocol-defined liver function stopping criteria after study treatment restart, study treatment should be permanently discontinued. The [sponsor] Medical Monitor, and the IRB/IEC, must be informed of the outcome for the participant following study treatment restart. The [sponsor] must be notified of any adverse events, as per Appendix 4. References:Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM. Drug-induced liver injury following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-2222.<End of common text > ................
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