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Trial registered on ANZCTR


Registration number
ACTRN12615000889550
Ethics application status
Approved
Date submitted
6/08/2015
Date registered
25/08/2015
Date last updated
6/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II randomized study of perioperative beta-blocker vs placebo on gene expression in newly diagnosed breast cancer
Scientific title
Investigating whether, in patients receiving breast cancer surgery, pre-operative Propranolol compared with placebo, changes the cancer's gene expression.
Secondary ID [1] 287237 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer 295843 0
Condition category
Condition code
Cancer 296097 296097 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1:Propranolol

Trade/Product/Code Name
Deralin (Unregistered Trademark)

Dosage form
Tablet

Presentation
40 mg tablet (red, film coated, marked PP/40, G on reverse)

Route of administration
Oral

Formulation
Propranolol hydrochloride

Participants in the study will be given 7 days of pre-operative Propranolol (or placebo equivalent) prior to and including the day of surgery and then will be titrated off Propranolol over two days in the postoperative period.

Day AM dose PM dose
-7 40mg 40mg
-6 40mg 40mg
-5 40mg 40mg
-4* 80mg 80mg
-3 80mg 80mg
-2 80mg 80mg
-1 80mg 80mg
0 80mg 40mg
+1 40mg 40mg
+2 40mg 40mg
(0 = Day of surgery)

Arm 2:
Matched Placebo

Compliance:
Assessed through
i) Second daily phone calls
ii) Assessed pill return
iii) Pill diary (for participants to self administer)
iv) Quantification of propranolol dosing on day of surgery
Intervention code [1] 292522 0
Treatment: Drugs
Comparator / control treatment
- Study medication (placebo and propranolol) will be packaged in an identical capsule.
- The capsule will contain lactose (used to pack around the propranolol tablets in the active capsules) and to fill the placebo capsules.
- The lactose is Lactose BP powder packed by Medisca Inc.
- The propranolol tablets will be packed (not crushed) with lactose into a capsule.
- Placebo capsules will be matching capsules packed with lactose alone.
Control group
Placebo

Outcomes
Primary outcome [1] 295770 0
Primary tumour gene expression (quantitative level: i.e. mRNA concentration within the cell sample) for each of 20,000 genes at baseline and at surgical resection.
Timepoint [1] 295770 0
Day of surgery procurement of tumour. Compare with biopsy (pre-treatment) sample where available.
Secondary outcome [1] 316479 0
Tumour markers of inflammation at baseline and at time of surgery: CD68, CD163 (M2) macrophage markers, neutrophil elastase, T cell markers (CD3, CD4, CD8), CD31 and VEGF angiogenesis markers, and D2-40 lymphangiogenesis marker.
Timepoint [1] 316479 0
Procurement of tumour on day of surgery. Compare with biopsy (pre-treatment) sample where available.
Secondary outcome [2] 316480 0
Leukocyte gene expression (specifically conserved transcriptional response to adversity profile) at baseline and at surgery.

Assessment:
Total RNA will be extracted from the whole blood samples and then subjected to quality assurance assays to test suitable mass (by spectroscopy) and integrity (by Agilent Bioanalyzer RNA Integrity Score) for analysis, and subjected to microarray target synthesis and hybridization. This will be done in collaboration with the UCLA Neuroscience Genomics Core Laboratory using standard Illumina assay equipment and protocols.

Timepoint [2] 316480 0
Comparison of baseline and day of surgery blood sample
Secondary outcome [3] 316481 0
Inflammation-relevant cytokines (IL-1beta, IL-2, IL-6, IL-10, IFN-gamma, TNFalpha) and gene expression of cytokines at baseline and at surgery.

Assessment:
An interleukin arrays kit (multiplex ELISA) will be used to measure the stated plasma interleukins to compare baseline and day of surgery blood samples.
Timepoint [3] 316481 0
Baseline, and at day of surgery (beginning and end of surgery)
Secondary outcome [4] 316482 0
Beck Anxiety Inventory at baseline and on the day of surgery

Rather than a composite outcome, the Beck Anxiety Inventory is a questionnaire that provides a validated level of 'anxiety' through a scored questionnaire: 21 questions, each scored with 0, 1, 2 or 3 points. The scores within a patient at a particular time are summed, to be a total score ranging from 0 to 63. A score of 0-7 indicates minimal, 8-15 mild, 16-25 moderate and 26-63 severe anxiety. ANOVA will be used to assess whether there are differences in Beck Anxiety Inventory between groups, with p-values reported.


Timepoint [4] 316482 0
Baseline and day of surgery.
Secondary outcome [5] 316483 0
To assess the effect of beta blockade on:
* Hypotension (Systolic blood pressure < 100mmHg)

Assessment:
Sphygmomanometer either at PMCC or a home blood pressure/heart rate monitoring device.
Timepoint [5] 316483 0
Assessed pre–surgery (while on study drug) and day of surgery. This will be assessed every day while the patient is medicated with the study medication and recorded in the patient's own blood pressure chart (at home). If the patient is in hospital while on the study medication, blood pressure will be measured using the hospital's sphygmomanometer and recorded.
Secondary outcome [6] 316664 0
To assess the effect of beta blockade on:
* Perioperative labile blood pressure (Perceived by treating anaesthetist).
Timepoint [6] 316664 0
Assessed on day of surgery.
Secondary outcome [7] 316665 0
To assess the effect of beta blockade on:
* Symptoms of bronchial hyper-reactivity. Specifically the report of wheezing, dry cough or sensation of shortness of breath.
Timepoint [7] 316665 0
Assessed pre–surgery (while on study drug) and day of surgery.
This will be assessed every day while the patient is medicated with the study medication and recorded in the patient's own symptom chart (at home). If the patient is in hospital while on the study medication, they will be asked about the experience of these symptoms.
Secondary outcome [8] 316666 0
To assess the effect of beta blockade on:
* Bradycardia (Heart Rate < 50bpm)

This will be assessed using the patient's home blood pressure/heart rate monitoring device supplied to the patient. While in hospital, this will be measured using the hospital's pulse oximeter.
Timepoint [8] 316666 0
Assessed pre–surgery (while on study drug) and day of surgery.
This will be assessed every day while the patient is medicated with the study medication and recorded in the patient's own heart rate chart (at home). If the patient is in hospital while on the study medication, heart rate will be measured using the hospital's oximeter device and recorded.

Eligibility
Key inclusion criteria
- Written, informed consent;
- Female subjects with histologically-confirmed breast cancer, who will undergo surgical excision at PMCC at least 7 days after enrollment;
- Age 18-80 years old;
- World Health Organization ECOG performance status 0 or 1;
Minimum age
18 Years
Maximum age
80 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Women who are pregnant or breast feeding;

- Women with absolute or relative contraindications to Propranolol:
Sick sinus syndrome.
Sinus bradycardia (less than 60 beats/minute).
First, Second or third degree atrioventricular block.
Resting blood pressure less than 100/60mmHg.
Untreated phaeochromocytoma
Untreated thyroid disorder
Patients receiving dihydropyridine or non-dihydropyridine Calcium Channel Blocking agents (eg diltiazem, verapamil, nifedipine, amlodipine)
Severe peripheral vascular disease (intermittent claudication)
Patients receiving anti-arrhythmic agents (eg amiodarone, sotalol, digoxin)
Patients with renal impairment (defined as Creatinine greater than 0.15mmol/L)
Patients with liver impairment: AST or ALT or ALP > 2.5 x upper limit of normal range (ULN), bilirubin > 1.5 x ULN, ALP > 2.5.
Patients receiving Clonidine, Digoxin, Rizatriptan, Cimetidine, Hydralazine, Guanethidine or Ergotamine
Episodes of major depression

- Breast resection within 6 months of study entry;

- Women who have received neoadjuvant chemotherapy prior to the planned breast cancer resection;

- Women with histologically demonstrated ductal carcinoma in situ;

- Non-English speaking women;

- Women using regular (daily) pre-operative anti-inflammatory agents eg NSAIDs and aspirin >100mg/day;

- Women using regular anxiolytics (eg benzodiazepines), alpha-receptor adrenergic agonists (eg Clonidine);

- Use of selective or non-selective beta-adrenergic inhibitors in the last three months (examples include Propranolol, Metoprolol, Atenolol, Sotalol);

- Past history of stroke;

- Women with moderate or severe asthma, as defined by previous Intensive Care Unit admission or oral steroid-requiring asthma;

- Other medical conditions considered prohibitive by the treating physician (including frailty).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients diagnosed with breast carcinoma have an initial consultation with a breast surgeon to determine suitability for surgical resection. If surgery is the initial management, patients will be screened for suitability for enrollment. A study investigator will subsequently discuss the study and obtain written informed consent from the patient.

Allocation to the Propranolol or placebo arms will occur on the day of recruitment and registration. The Department of Pharmacy has pre-prepared a random sequence pre-determining patient registration number and group allocation (Propranolol or placebo). The random sequence has been generated by Ms Carol Rice (Clinical Trials Pharmacist) using Microsoft Excel Software in accordance with standard policy.

Once recruited, each patient will be assigned a study number. The study number will correspond to the pre-prepared (numbered) dispensary bottles.

As such, the Department of Pharmacy (Ms Rice) alone will be aware of patient allocation. No investigator (or patient) will be aware of treatment allocation until the completion of recruitment and sample analyses.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (Microsoft Excel).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analyses for primary endpoint I and secondary endpoint II will be conducted by collaborator SC. All other patient outcome data will be analysed by the study’s statistician.

Baseline patient characteristics will be summarised for the whole sample and by treatment arm using descriptive statistics and will be reported for continuous variables as number of patients, mean, median, standard deviation, minimum and maximum; and for categorical variables as counts and percentages. Patients who achieve 80% compliance with the pre-surgery dosing schedule will be included and analysed per protocol.

For each of the continuous primary and secondary endpoints, the mean difference between the treatment arms will be calculated with a corresponding 95% confidence interval (95% CI). Hypothesis testing will be performed for each endpoint at each time point separately using the appropriate statistical test based on the distribution of data (e.g., mixed effect linear models for the a priori gene expression composite outcomes). For single-value outcomes, an independent two-sample t-test will be used if data are normally distributed or if an appropriate transformation can be found, otherwise a non-parametric Mann-Whitney U test will be performed. Given the exploratory nature of this pilot study, no adjustments for multiple comparisons will be made. We will generate both simple estimates of effect size as well as adjusted estimates, controlling for any accidental confounding that may occur despite randomization.

Specifically, secondary endpoint 2 (CTRA signature) will be analysed using the following approach. Effects of drug treatment on a priori-defined gene expression composites (53 CTRA genes in whole blood samples) will be analyzed using mixed effect linear models treating experimental condition as the primary variable of interest and treating the multiple target genes as repeated measures (with covariance matrices estimated to control for potential correlations in gene expression across participants). In cross-sectional analyses at one time point, analyses will examine the effect of experimental Group on average level of transcript expression across all a priori indicator genes. In analyses of change over time, a similar mixed effect linear models will use a Group x Time factorial design. In both cases, expression values will be quantile normalized across subjects, log2-transformed to stabilize variance, and centered to mean = 0 to facilitate estimation algorithms. Any factors that are found to be potentially confounded (e.g., p < .10 for association with experimental group) will be included as covariates in subsequent mixed effect linear model analyses.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6303 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 13838 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 291804 0
Charities/Societies/Foundations
Name [1] 291804 0
Australian New Zealand College of Anaesthetists
Address [1] 291804 0
ANZCA House
630 St Kilda road
Melbourne 3004
Victoria
Country [1] 291804 0
Australia
Funding source category [2] 294163 0
Government body
Name [2] 294163 0
National Cancer Institute Biobehavioural Network (Leidos)
Address [2] 294163 0
Frederick National Laboratory for Cancer Research
PO Box B
Frederick, MD 21702
Country [2] 294163 0
United States of America
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan street
Melbourne, 3000
Victoria
Country
Australia
Secondary sponsor category [1] 290464 0
None
Name [1] 290464 0
Nil
Address [1] 290464 0
Nil
Country [1] 290464 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293322 0
Peter MacCallum Cancer Centre
Ethics committee address [1] 293322 0
Locked Bag 1, A'Beckett Street
East Melbourne Vic 8006
Australia
Ethics committee country [1] 293322 0
Australia
Date submitted for ethics approval [1] 293322 0
Approval date [1] 293322 0
29/07/2015
Ethics approval number [1] 293322 0
14/139

Summary
Brief summary
This study will investigate whether, in patients receiving breast cancer surgery, pre-operative Propranolol compared with placebo, changes the cancer's gene expression.
Who is it for? You may be eligible to join this study if you are a female aged 18-70 years old, have histologically-confirmed breast cancer and will undergo breast cancer surgery at Peter MacCallum Cancer Centre.
Study details Participants will be randomly allocated (by chance) to one of two treatment groups. Patients in one group will receive Propranolol for 7 days prior to their scheduled breast cancer surgery while patients in the other group will receive a placebo tablet over the same period. Tablets will be taken two times a day. To determine the results of the study, the researchers will compare blood tests and tumour samples (biopsy and excision samples) obtained before and after administration of the study medication (at the time of surgery). In the samples, the investigators will be looking for the behaviour of specific ‘anti-cancer’ immune cells in the blood and in the tissue surrounding and controlling the tumour. The investigators will also be analysing the immune cells to understand the biological effects of the ‘stress’ that a patient may be experiencing. The information from this study will be presented to clinicians and researchers and will provide very useful information to guide a larger study examining the role of propranolol in all patients receiving breast surgery or in those patients where breast cancer has spread.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59378 0
Dr Jonathan Hiller
Address 59378 0
Peter MacCallum Cancer Centre
305 Grattan street
Melbourne, 3000
Victoria
Country 59378 0
Australia
Phone 59378 0
+ 61 3 8559 5000
Fax 59378 0
+ 61 3 8559 7379
Email 59378 0
jonathan.hiller@petermac.org
Contact person for public queries
Name 59379 0
Dr Jonathan Hiller
Address 59379 0
Peter MacCallum Cancer Centre
305 Grattan street
Melbourne, 3000
Victoria
Country 59379 0
Australia
Phone 59379 0
+ 61 3 8559 5000
Fax 59379 0
+ 61 3 8559 7379
Email 59379 0
jonathan.hiller@petermac.org
Contact person for scientific queries
Name 59380 0
Dr Jonathan Hiller
Address 59380 0
Peter MacCallum Cancer Centre
305 Grattan street
Melbourne, 3000
Victoria
Country 59380 0
Australia
Phone 59380 0
+ 61 3 8559 5000
Fax 59380 0
+ 61 3 8559 7379
Email 59380 0
jonathan.hiller@petermac.org

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary