1. NHMRC Nausea Studies

2. 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

3. What is working well?
Study 1

4. What is working less well?
Study 2

5. 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

6. 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

7. 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

8. Frequently asked questions

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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)

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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 ) 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.

35. 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

36. 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

37. 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

38. 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

39. 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 ) 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.

40. 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

41. 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