None listed
Conditions
Brief summary
Nausea in advanced cancer is a multifaceted problem. Recent systematic reviews have concluded that aetiology based guidelines may be effective in reducing nausea, but no rigorously controlled studies have been undertaken to trial this approach. Moreover, evidence to support the implementation of guidelines in practice is limited and contradictory, and a number of barriers to the implementation of the guidelines have been identified. This is a randomised open label study to compare the effectiveness of aetiology based antiemetic guideline therapy (targeted) versus haloperidol (single agent therapy) in improving the management of nausea not related to anticancer therapy in patients with advanced cancer. The hypothesis is that for advanced cancer patients with nausea not related to treatment, there is no difference in response to targeted aetiology-based antiemetic guideline treatment compared to using haloperidol alone, after 72 hours of treatment. Response to treatment is defined as a minimum two point improvement from baseline and end score <3 on an 11 point (0-10) numeric rating scale for average nausea for the previous 24 hours, measured 72 hours after the first study antiemetic administered Participants will be randomised into one of two study arms. In Arm 1, guideline driven antiemetic therapy is given orally or parenterally (subcutaneous or intravenous) according to the presumed cause of nausea using freely available PBS listed antiemetics in a 3 step dose escalation schedule. In Arm 2, Haloperidol is administered in a 3 step dose escalation schedule from 1mg/24 hours to 3mg/24hours orally or parenterally (subcutaneously). The active comparator is standard guideline treatment.
Interventions
This is a multi-centre, open label randomised parallel arm trial to determine whether guideline driven (targeted) aetiology based antiemetic therapy is more effective than single agent therapy with haloperidol in patients with cancer and nausea not related to anticancer therapy.
Participants will be randomised to active treatment arms 1 or 2.
In each trial arm, the duration of each step is 24 hours and the overall duration of treatment is 72 hours (3 days) after administration of the first stu
This is a multi-centre, open label randomised parallel arm trial to determine whether guideline driven (targeted) aetiology based antiemetic therapy is more effective than single agent therapy with haloperidol in patients with cancer and nausea not related to anticancer therapy. Participants will be randomised to active treatment arms 1 or 2. In each trial arm, the duration of each step is 24 hours and the overall duration of treatment is 72 hours (3 days) after administration of the first study antiemetic. The mode of administration will be a clinician decision based on patient characteristics. Abbreviations: subcutaneous (sc), po (orally), bd (twice daily), iv (intravenously), tds (three dimes/day), qid (four times /day), Q4/6h (every 4/6 hours), prn (as required). Rescue medication for all patients will be metoclopramide (10mg po, sc, iv, prn q4h). If this dose is already delivered in the standard treatment (Arm 1), haloperidol (0.5mg po, sc, prn to q6h) will be administered. Patients will have access to laxatives according to clinician practice. Arm 1 Clinical Practice Guideline (CPG) driven antiemetic therapy, given orally or parenterally (subcutaneous or intravenous), according to the presumed cause of nausea, using freely available Pharmaceutical Benefits Scheme (PBS) listed antiemetics, in a 3 step dose escalation schedule. The duration of each step is 24 hours. Overall duration of treatment is 72 hours. Treatment drugs are prochlorperazine, haloperidol, dexamethasone, promethazine, metoclopramide, hyoscine butylbromide, ranitidine. CPG dosing schedule and drug selection by cause: If there are multiple causes, the most likely cause is chosen from the following schedule. Note: sc drug delivery can be in a 24hr infusion, except for Dexamethasone which is not given as an infusion. Dominant Cause A: Central/Chemoreceptive Trigger Zone (CTZ) stimulation Step 1 Prochlorperazine 5mg tds po or 25mg PR followed by 5mg tds po or 12.5mg bd iv Step 2: Haloperidol 1.5mg/24hrs po or sc Step 3: Haloperidol 3mg/24hrs po or sc Dominant Cause B: Central Nervous System (CNS) disease Step 1 Dexamethasone 8mg/24hrs po/sc/iv Step 2 Dexamethasone 12mg/24hrs po/sc/iv Step 3 Dexamethasone 16mg/24hrs po/sc/iv Dominant Cause C: Vestibular involvement (nausea related to abnormalities of the middle ear or motion and/or positional nausea) Step 1 Prochlorperazine 5mg tds po or 25mg per rectum (PR) followed by 5mg tds po or 12.5mg bd iv Step 2 Prochlorperazine 10mg tds po or 25mg PR followed by 10mg tds po or 12.5mg tds iv Step 3 Promethazine 25 mg tds po or 12.5mg sc followed by 10mg tds po Dominant Cause D: Gastric stasis Step 1 Metoclopramide 10mg qid po/sc/iv Step 2 Metoclopramide 10mg Q4h po/sc/iv (patients must receive at least 5 doses of 4 hourly metoclopramide/24hours) Step 3 Metoclopramide 10mg Q4h po/sc/iv, Dexamethasone 8mg/24hrs po/sc/iv Dominant Cause E: Ileus Step 1 Metoclopramide 10mg qid po/sc/iv Step 2 Metoclopramide 10mg Q4h po/sc/iv Step 3 Metoclopramide 10mg Q4h po/sc/iv, Dexamethasone 8mg/24hrs po/sc/iv Dominant Cause F: Mechanical obstruction Step 1 Haloperidol 1.5mg/24hrs po/sc, Dexamethasone 8mg/24hrs Step 2 Haloperidol 3mg/24hrs po/sc, Dexamethasone 8mg/24hrs Step 3 Haloperidol 3mg/24hrs po/sc, Dexamethasone 8mg/24hrs po/sc/iv, Hyoscine butlybromide 80mg/24hrs sc or Ranitidine 200mg/24hrs sc (in patients where there is a realistic chance of bowel obstruction). Dominant Cause G: Gastritis Step 1 Metoclopramide10mg qid po/sc/iv, Proton Pump Inhibitors (PPI) min dose Step 2 Metoclopramide 10mg qid po/sc/iv, PPI max dose Step 3 Metoclopramide 10mg Q4h po/sc/iv, PPI max dose (PPI choice according to local policy) Dominant Cause H: Cause undetermined (or multifactorial) Step 1 Metoclopramide 10mg qid po/sc/iv Step 2 Metoclopramide 10mg qid po/sc/iv, Haloperidol 1.5mg/24hrs po/sc Step 3 Metoclopramide 10mg Q4h po/sc/iv, Haloperidol 3mg/24hrs sc Arm 2 Haloperidol, in a 3 step dose escalation schedule from 1mg/24 hours to 3mg/24 hours orally or parenterally (subcutaneously). Participants with intolerable nausea despite maximum breakthrough doses can proceed to Study 2 prior to the next 24 hour assessment. Participants already on Step 3 should be considered for Study 2. Treatment after the 72 hour trial period should be at the clinicians’ discretion if the patient does not continue to study 2. For all study participants, secondary outcomes and collection of data for safety will occur until the end of 4 weeks after the primary endpoint, unless consent is withdrawn.
Sponsors
Professor Patsy Yates
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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), 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
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), 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, if on corticosteroids, the dose has changed within 48 hours prior to study, have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation on most recent ECG (>450msecs in men, >470msecs in women), 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
Outcome results
None listed