NHMRC Nausea Studies

A two-stage trial of antiemetic therapy in patients with cancer and nausea not related to anticancer therapy Study 1 A randomised open label study of guideline driven targeted antiemetic therapy versus single agent antiemetic therapy (haloperidol) Study 2 A randomised controlled double blind study of levomepromazine versus placebo with rescue antiemetics (best supportive care (BSC)) in patients with refractory nausea

What is working well? Study 1

What is working less well? Study 2

Recruitment – both studies (up to and including 01/03/2013) Study 1 Study 2 Total Pre-screened 539 138 677 Randomised 128 33 161 Completed 99 16 114 Needed 150 203 As per CRFs/registration faxes received

Study 2 Aim: To compare the effectiveness of parenteral levomepromazine versus placebo and BSC rescue in improving the management of nausea in patients with cancer and refractory nausea not related to anticancer therapy. Treatment schedule: levomepromazine 3.125mg – 9.375mg sc or iv per 24 hours delivered in multiples of 3.125mg/2ml day-tds or placebo (N/Saline) given as 2ml sc or iv day-tds with BSC rescue in all arms

Study 2 population Inclusion criteria Exclusion criteria Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) have refractory nausea despite adequate treatment (as defined above) are able to comply with all trial requirements are able to provide fully informed consent Exclusion criteria Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to study medications or placebo would not be appropriate (e.g. dexamethasone for acutely raised ICP) have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to the study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have received levomepromazine within the last 3 days if on corticosteroids, the dose has changed within 48 hours prior to study have a definite contraindication to levomepromazine (e.g. prior 5HT3 sensitivity, severe hepatic impairment (LFTs > 5 x upper limit of normal*), symptomatic postural hypotension) have had a previous adverse reaction to either of the study medications are pregnant or breastfeeding *this applies to AST, ALT or bilirubin but not to ALP or GGT measurements

Frequently asked questions

If the patient has several possible causes of nausea, which arm? try to determine which is the most likely/dominant cause (it doesn’t matter if you are wrong) it is better to define the most likely cause than put in the cause unknown arm it does not matter if the true cause becomes clear or changes

Clinical practice guidelines for the management of nausea (Modified from the original Glare1 CPGs according to expert consensus) 3 step treatment as determined by cause 1. Glare P et al. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with far advanced cancer. Support Care Cancer 2004; 12:432-40 Code Dominant cause A Central/ CTZ stimulation B CNS disease C Vestibular involvement D Gastric stasis E Ileus F Mechanical obstruction G Gastritis H Cause undetermined (or multifactorial) Refer to detailed handout in registration pack 10

Study 1 – Targeted therapy treatment steps Dominant cause Treatment Step 1 Step 2 Step 3 A: Central/CTZ stimulation Prochlorperazine 5mg tds po or 25mg PR followed by 5mg tds po or 12.5mg bd IM/iv Haloperidol 1.5mg/24hrs po or sc Haloperidol 3mg/24hrs po or sc B: CNS disease Dexamethasone 8mg/24hrs po/sc/iv Dexamethasone 12mg/24hrs po/sc/iv Dexamethasone 16mg/24hrs po/sc/iv C: Vestibular involvement Prochlorperazine 10mg tds po 10mg tds po or 12.5mg tds IM/iv Promethazine 25 mg tds po or 12.5mg sc D: Gastric stasis Metoclopramide 10mg qid po/sc/iv Metoclopramide 10mg Q4h po/sc/iv E: Ileus F: Mechanical obstruction Haloperidol 1.5mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Hyoscine butylbromide 80mg/24hrs sc or Ranitidine 200mg/24hrs sc G: Gastritis PPI min dose PPI max dose H: Cause undetermined (or multifactorial) Clinical practice guidelines for the management of nausea 11

Do I have to wait for results of investigations so I know which arm to put the patient in? No, the patient has nausea that needs treating now the longer you wait, the less likely it is that the patient will start the study if the cause of nausea is unknown, enter it as such do not change course

Study 1 population Inclusion criteria V3.0 Exclusion criteria V3.0 Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) are not currently receiving antiemetics or are already receiving antiemetics but these are inappropriate as defined by the antiemetic guidelines or are at a suboptimal dose are able to comply with all trial requirements are able to provide fully informed consent Exclusion criteria V3.0 Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to haloperidol would not be appropriate (e.g. dexamethasone for acutely raised ICP) if on corticosteroids, the dose has changed within 48 hours prior to study have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation* on most recent ECG, uncontrolled seizures) have had a prior serious adverse event following use of any of the drugs listed in the guidelines (e.g. dystonic reaction, neuroleptic malignant syndrome) are pregnant or breastfeeding * >450msecs in men, >470msecs in women

If a pt has a reversible cause of nausea, are they eligible Yes, in the real world, they will be given antiemetics so it is appropriate to include them Eg nausea from renal impairment that is likely to improve following rehydration Note, these pts were excluded in an earlier version

What if a specific antiemetic is indicated? Eg raised ICP for which dexamethasone is indicated No, not eligible, as they may be randomised to haloperido,l not the targeted treatment (arm B) a clinical decision may have been made for “no increase in dex dose”. The pt is still ineligible as they might be randomised to an increase in dex rather than haloperidol

Study 1 population Inclusion criteria V3.0 Exclusion criteria V3.0 Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) are not currently receiving antiemetics or are already receiving antiemetics but these are inappropriate as defined by the antiemetic guidelines or are at a suboptimal dose are able to comply with all trial requirements are able to provide fully informed consent Exclusion criteria V3.0 Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to haloperidol would not be appropriate (e.g. dexamethasone for acutely raised ICP) if on corticosteroids, the dose has changed within 48 hours prior to study have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation* on most recent ECG, uncontrolled seizures) have had a prior serious adverse event following use of any of the drugs listed in the guidelines (e.g. dystonic reaction, neuroleptic malignant syndrome) are pregnant or breastfeeding * >450msecs in men, >470msecs in women

What constitutes an inappropriate antiemetic? any antiemetic not PBS listed for the treatment of nausea eg cyclizine, levomepromazine, ondansetron (outside specific indications) also remember inappropriate dosing eg maxolon 10mg tds, stemetil prn, haloperidol 0.5 mg prn* * If pt has had 2 doses within a 24 hour period, they are not eligible as GPG dose

Study 1 Definition of appropriate antiemetics If there is a clear aetiology, an appropriate antiemetic is any drug listed in the guidelines for that particular indication at the doses listed, or haloperidol 1-3mg/24hrs The use of agents not listed in the guidelines (e.g. cyclizine, 5HT3 antagonists, levomepromazine) is considered inappropriate when considering study 1 Any antiemetic that is not licensed for the treatment of nausea in this setting must be considered inappropriate

Study 1 – Targeted therapy treatment steps Dominant cause Treatment Step 1 Step 2 Step 3 A: Central/CTZ stimulation Prochlorperazine 5mg tds po or 25mg PR followed by 5mg tds po or 12.5mg bd IM/iv Haloperidol 1.5mg/24hrs po or sc Haloperidol 3mg/24hrs po or sc B: CNS disease Dexamethasone 8mg/24hrs po/sc/iv Dexamethasone 12mg/24hrs po/sc/iv Dexamethasone 16mg/24hrs po/sc/iv C: Vestibular involvement Prochlorperazine 10mg tds po 10mg tds po or 12.5mg tds IM/iv Promethazine 25 mg tds po or 12.5mg sc D: Gastric stasis Metoclopramide 10mg qid po/sc/iv Metoclopramide 10mg Q4h po/sc/iv E: Ileus F: Mechanical obstruction Haloperidol 1.5mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Hyoscine butylbromide 80mg/24hrs sc or Ranitidine 200mg/24hrs sc G: Gastritis PPI min dose PPI max dose H: Cause undetermined (or multifactorial) Clinical practice guidelines for the management of nausea 19

Potential participant with a nausea score <3 on prn antiemetics plus 1.5mg haloperidol nocte for delirium. Is she eligible for study 1? No, score <3 and already on 1.5mg haloperidol (>step1 dose) Also, is she able to consent of delirious? What about study 2? Assuming competence and higher score, only if she has had 3mg haloperidol/24 hrs (or any of the other drugs listed in section 3.1)

My patient is already on dexamethasone, are they eligible? Pts must be on a stable dose for 48 hours or have discontinued steroids 48 hours prior if randomised to Arm F and already on dex, this can get complicated (think about it….) important to have a degree of flexibility with this issue suggest call to discuss, write a file note study is meant to reflect real world practice

Study 1 population Inclusion criteria V3.0 Exclusion criteria V3.0 Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) are not currently receiving antiemetics or are already receiving antiemetics but these are inappropriate as defined by the antiemetic guidelines or are at a suboptimal dose are able to comply with all trial requirements are able to provide fully informed consent Exclusion criteria V3.0 Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to haloperidol would not be appropriate (e.g. dexamethasone for acutely raised ICP) if on corticosteroids, the dose has changed within 48 hours prior to study have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation* on most recent ECG, uncontrolled seizures) have had a prior serious adverse event following use of any of the drugs listed in the guidelines (e.g. dystonic reaction, neuroleptic malignant syndrome) are pregnant or breastfeeding * >450msecs in men, >470msecs in women

What prn medications can I give in study 1 if randomised to haloperidol – maxalon 10mg q4h if randomised to targeted therapy – haloperidol 0.5mg q6h (exc. Arm F) REMEMBER to stop all other regular antiemetics put note in chart to stop out of study prescriptions

The first dose was given at 2. 30pm The first dose was given at 2.30pm. What time do I give the drug if he goes up to a bd dose tomorrow? the first assessment is due 24 hours post the od dose ie at 2.30pm bd doses do not have to be given at 0800 and 2000hrs but whenever is convenient for patient and staff

The first dose was given at 2. 30pm The first dose was given at 2.30pm. What time to I give the drug if he goes up to a bd dose tomorrow? the last dose in a bd or tds regimen must be given at least 6 hours prior to the assessment time (in this case 08.30am) there can be flexibility in dosing times best to chart the daily dose each day following the 24 hour assessment, as the dose may change

What is the definition of response? A two point improvement on an 11 point nausea NRS for average nausea and score <3/10 In the absence of above, a dose increase is indicated

Response assessment See table below (protocol section 11.2) Initial score Maximum score for response 3 1 4 2 5 6 7 8 9 10

Do I have to do an ECG on all pts to check for QTc prolongation? No, it is not standard practice to do ECGs before starting patients on any of the guideline medications If there is an ECG in the notes showing QTc prolongation, suggest repeat if possible, as will then often be within normal limits ?need to refer to cardiology

Study 1 population * >450msecs in men, >470msecs in women Exclusion criteria V3.0 Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to haloperidol would not be appropriate (e.g. dexamethasone for acutely raised ICP) if on corticosteroids, the dose has changed within 48 hours prior to study have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation* on most recent ECG, uncontrolled seizures) have had a prior serious adverse event following use of any of the drugs listed in the guidelines (e.g. dystonic reaction, neuroleptic malignant syndrome) are pregnant or breastfeeding * >450msecs in men, >470msecs in women Inclusion criteria V3.0 Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) are not currently receiving antiemetics or are already receiving antiemetics but these are inappropriate as defined by the antiemetic guidelines or are at a suboptimal dose are able to comply with all trial requirements are able to provide fully informed consent

If a pt is on chemotherapy, are they ever eligible? Study 1, yes. Ondansetron is only indicated for acute N/V ie within the first 5 days. If they have delayed N/V after that time they are eligible as long as they haven’t been given any of the GPG antiemetics at doses listed Note, ondansetron is not indicated for all chemotherapy eg targeted Rx or low dose continuous

If a pt is on chemotherapy, are they ever eligible? Study 2, yes, even more so, as they will almost certainly have had ≥8mg ondansetron the study would have to be completed before the next course of chemo is due however, if they get dex with the chemo

A pt on ondansetron 8mg is now eligible for study1 and study 2? correct, they would be eligible for study 1 because this is an inappropriate antiemetic and they would be eligible for study 2 if they still have N/V >3/10 despite 8mg ondansetron please prioritise study 1 however

Study 2 population Inclusion criteria Exclusion criteria Patients who: are 18 years or over have a clinical diagnosis of cancer have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea) have refractory nausea despite adequate treatment (as defined above) are able to comply with all trial requirements are able to provide fully informed consent Exclusion criteria Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy) have nausea for which a specific antiemetic is indicated and randomisation to study medications or placebo would not be appropriate (e.g. dexamethasone for acutely raised ICP) have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to the study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period have received levomepromazine within the last 3 days if on corticosteroids, the dose has changed within 48 hours prior to study have a definite contraindication to levomepromazine (e.g. prior 5HT3 sensitivity, severe hepatic impairment (LFTs > 5 x upper limit of normal*), symptomatic postural hypotension) have had a previous adverse reaction to either of the study medications are pregnant or breastfeeding *this applies to AST, ALT or bilirubin but not to ALP or GGT measurements

Study 2 Refractory nausea is defined as: nausea rated as ≥3/10 on a NRS for average nausea after completion of study 1; OR nausea rated as ≥3/10 at baseline despite the use of: appropriate antiemetics at sufficient dose (step 3) as specified in the study 1 targeted guideline category (see Appendix 15.1.2) or haloperidol 3mg/24hrs or promethazine 25mg po tds (25mg sc 24 hrly) or metoclopramide 60mg/24hrs or domperidone 20mg qid or cyclizine 100mg/24hrs (75mg/24hrs in the elderly) or ondansetron 8mg/day OR nausea rated as ≥3/10 at baseline if appropriate antiemetics, or any of those listed above, have not been tolerated because of side-effects.  If patients have been on antiemetic combinations, at least one of the agents must have been given at doses as specified above.

What about the other 5HT3 antagonists? the rules that apply to ondansetron apply also to the other drugs in this class eg granisetron and tropisetron dose equivalents are : - ondansetron 8mg - tropisetron 5mg/day for 6 days - granisetron 3mg

Can out-patients do this study? Study 1 yes, we need detailed daily record keeping however for the purposes of monitoring Study 2, yes, if there is the facility for visiting pts at home to give the injections

We have a patient on maxalon 10mg qid who still has nausea We have a patient on maxalon 10mg qid who still has nausea. Can he go straight to step 2 in study 1 No, he is not eligible as already on a GPG dose

Can he go straight to study 2? No, because he needs to have had 60mg maxolon/24 hours (10mg q4h as per step 3) or as per section 3.1 Suggest increase the dose to 10mg q4h or 20mg qid If he still has nausea, he can go to study 2 Remember to count b’thru doses into the total daily dose

Study 2 Refractory nausea is defined as: nausea rated as ≥3/10 on a NRS for average nausea after completion of study 1; OR nausea rated as ≥3/10 at baseline despite the use of: appropriate antiemetics at sufficient dose (step 3) as specified in the study 1 targeted guideline category (see Appendix 15.1.2) or haloperidol 3mg/24hrs or promethazine 25mg po tds (25mg sc 24 hrly) or metoclopramide 60mg/24hrs or domperidone 20mg qid or cyclizine 100mg/24hrs (75mg/24hrs in the elderly) or ondansetron 8mg/day OR nausea rated as ≥3/10 at baseline if appropriate antiemetics, or any of those listed above, have not been tolerated because of side-effects.  If patients have been on antiemetic combinations, at least one of the agents must have been given at doses as specified above.

What prn meds can I give pts on study 2? maxalon prochlorperazine haloperidol promethazine no dose or time restriction stated NOT ondansetron, cyclizine, levomepromazine this is best supportive care

Study 1 – Targeted therapy treatment steps Dominant cause Treatment Step 1 Step 2 Step 3 A: Central/CTZ stimulation Prochlorperazine 5mg tds po or 25mg PR followed by 5mg tds po or 12.5mg bd IM/iv Haloperidol 1.5mg/24hrs po or sc Haloperidol 3mg/24hrs po or sc B: CNS disease Dexamethasone 8mg/24hrs po/sc/iv Dexamethasone 12mg/24hrs po/sc/iv Dexamethasone 16mg/24hrs po/sc/iv C: Vestibular involvement Prochlorperazine 10mg tds po 10mg tds po or 12.5mg tds IM/iv Promethazine 25 mg tds po or 12.5mg sc D: Gastric stasis Metoclopramide 10mg qid po/sc/iv Metoclopramide 10mg Q4h po/sc/iv E: Ileus F: Mechanical obstruction Haloperidol 1.5mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Haloperidol 3mg/24hrs po/sc Hyoscine butylbromide 80mg/24hrs sc or Ranitidine 200mg/24hrs sc G: Gastritis PPI min dose PPI max dose H: Cause undetermined (or multifactorial) Clinical practice guidelines for the management of nausea 41