Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000832976
Ethics application status
Approved
Date submitted
27/05/2020
Date registered
21/08/2020
Date last updated
21/08/2020
Date data sharing statement initially provided
21/08/2020
Date results information initially provided
21/08/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Exploring the effects of obesity-related inflammation on activity of chemotherapy metabolising liver proteins in breast cancer patients during treatment
Scientific title
An exploratory study assessing effects of the circulating levels of obesity-related inflammatory cytokines on in vivo activity of cytochrome P450 enzymes in women receiving chemotherapy for breast cancer.
Secondary ID [1] 301377 0
None
Universal Trial Number (UTN)
U1111-1185-0771
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer 317631 0
Obesity 317802 0
Condition category
Condition code
Cancer 315714 315714 0 0
Breast
Inflammatory and Immune System 316367 316367 0 0
Other inflammatory or immune system disorders
Diet and Nutrition 316368 316368 0 0
Obesity

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The Inje probe drug cocktail was used in this study to measure in vivo activity of 5 different cytochrome P450 enzymes in all of the recruited study participants, regardless of whether they were non-obese or obese (according to their BMI). Though, the differences in response to Inje probe cocktail will be compared between these two groups. The Inje probe drug cocktail components were: 100 mg caffeine tablet (Key Pharmaceuticals, Pty Ltd, Port Macquarie, NSW, Australia; Batch: P60064); 25 mg losartan tablet (Actavis, NJ, USA; Batch: GXM016002); 20 mg omeprazole tablet (Mylan, PA, USA; Batch: ZC16064B); 30 mg of dextromethorphan syrup (Pfizer, Sydney, NSW, Australia; Batch: 17RDX10A); and 1 mg of midazolam syrup (Claris Injectables Ltd, Ahmedabad, India; Batch: B5A0219). The probe drug cocktail will be administered prior to beginning chemotherapy (following diagnosis for neoadjuvant chemotherapy patients, and following diagnosis and surgery for adjuavnt chemotherapy patients) and again following dose 6 of Pacliatxel chemotherapy (of which there are a total of 12 doses given once weekly for 12 weeks). Paclitaxel chemotherapy will be administered immediately after the last cycle of AC chemotherapy (of which there are a total of 4 cycles given every three weeks).

Physical activity levels (daily step counts) will be assessed in the participants for 3 weeks (21 days) following cycle one of AC chemotherapy, for 1 week (7 days) following dose one of Paclitaxel, and for 1 week (7 days) following dose six of Paclitaxel. The average daily step counts will be passively assessed using FitBit One devices; this is not an exercise intervention as patients are not required to perform any physical activity, other than what they choose to do themselves. FitBit devices will be given to patients prior to each of the three measuring periods (described above here) and collected at the end of each of measuring period for data upload and charging.
Intervention code [1] 317790 0
Diagnosis / Prognosis
Comparator / control treatment
Comparison between non-obese (BMI ranging from 18.5-29.9 kg/m2) and obese (BMI greater than or equal to 30 kg/m2) participants will be carried out.
Control group
Active

Outcomes
Primary outcome [1] 323925 0
Changes in in vivo CYP1A2 activity as a measure of chemotherapy drug metabolism. Changes in in vivo CYP1A2 was assessed by administering the inje probe drug cocktail (5 component cocktail administered at the same time; described in detail in the intervention/exposure section), and by collecting serum post-administration.
Timepoint [1] 323925 0
CYP1A2 activity was determined by collecting serum samples at baseline (0 hour timepoint) and again 4 hours after probe drug cocktail administration. Probe drug cocktails are given to participants at baseline (0-7 days prior to beginning chemotherapy) and again following dose six of paclitaxel chemotherapy (towards the end of treatment, approximately 18 weeks after baseline) for comparative purposes.
Primary outcome [2] 323926 0
Change in the serum concentration of inflammatory cytokine concentrations during chemotherapy were assessed using a cytokine protein array in order to measure the relative expression differences of 105 different inflammatory cytokines.
Timepoint [2] 323926 0
Inflammatory cytokines were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Primary outcome [3] 324264 0
Changes in in vivo CYP2C9 activity as a measure of chemotherapy drug metabolism. Changes in in vivo CYP2C9 activity during chemotherapy were assessed by administering the inje probe drug cocktail (5 component cocktail administered simultaneously; described in detail in the intervention/exposure section), and by collecting urine post-administration.
Timepoint [3] 324264 0
CYP2C9 activity was determined by collecting urine at baseline (0 hour timepoint) and for 0-8 hours after probe drug cocktail administration. Total urine excreted by the participant for the entire 8 hour duration is collected in a 24 hour urine collection container- the sample may be a combination of multiple excretions. Probe drug cocktails are given to participants at baseline (0-7 days prior to beginning chemotherapy) and again following dose six of paclitaxel chemotherapy (towards the end of treatment, approximately 18 weeks after baseline) for comparative purposes.
Secondary outcome [1] 383349 0
Changes in body composition during chemotherapy will be assessed by measuring waist-to-hip ratio (WHR; determined using a tape measure).
Timepoint [1] 383349 0
WHR was determined once prior to beginning chemotherapy (baseline) and once following dose six of paclitaxel (approximately 18 weeks after baseline). Changes in WHR were determined by comparing baseline to post-paclitaxel dose six measures.

Secondary outcome [2] 383350 0
Levels of routine physical activity carried out during chemotherapy as measured using using step count data recorded by FitBit One devices worn by each participant at specified timepoints throughout the study period
Timepoint [2] 383350 0
Physical activity was measured using step count data recorded by FitBit One devices worn by each participant. FitBits were worn for 3 consecutive weeks following Cycle one of AC chemotherapy (21 days), for 1 week following Dose 1 of paclitaxel chemotherapy (7 days) and for 1 week following dose six of paclitaxel chemotherapy (7 days). Step counts were measured for a total of 5 weeks (35 days). There was no exercise intervention, only passive number of steps were recorded.
Secondary outcome [3] 384202 0
Changes in body composition during chemotherapy will be assessed by measuring BMI (height determined by stadiometer and weight determined using the Tanita body composition scale).
Timepoint [3] 384202 0
BMI was determined once prior to beginning chemotherapy (baseline) and once following dose six of paclitaxel (approximately 18 weeks after baseline). Changes in BMI were determined by comparing baseline to post-paclitaxel dose six measures.
Secondary outcome [4] 384203 0
Changes in body composition during chemotherapy will be assessed by measuring body fat percentages (determined fusing the Tanita body composition scale).
Timepoint [4] 384203 0
Body fat percentage were determined once prior to beginning chemotherapy (baseline) and once following dose six of paclitaxel (approximately 18 weeks after baseline). Changes in body fat percentages measured were determined by comparing baseline to post-paclitaxel dose six measures.
Secondary outcome [5] 384204 0
This is a primary outcome. Changes in in vivo CYP2C19 activity as a measure of chemotherapy drug metabolism. Changes in in vivo CYP2C19 activity during chemotherapy were assessed by administering the inje probe drug cocktail (5 component cocktail administered simultaneously; described in detail in the intervention/exposure section), and by collecting serum post-administration.
Timepoint [5] 384204 0
CYP2C19 activity was determined by collecting serum samples at baseline (0 hour timepoint) and again 4 hours after probe drug cocktail administration. Probe drug cocktails are given to participants at baseline (0-7 days prior to beginning chemotherapy) and again following dose six of paclitaxel chemotherapy (towards the end of treatment, approximately 18 weeks after baseline) for comparative purposes.
Secondary outcome [6] 384205 0
This is a primary outcome. Changes in in vivo CYP2D6 activity as a measure of chemotherapy drug metabolism. Changes in in vivo CYP2D6 activity during chemotherapy were assessed by administering the inje probe drug cocktail (5 component cocktail administered simultaneously; described in detail in the intervention/exposure section), and by collecting urine post-administration.
Timepoint [6] 384205 0
CYP2D6 activity was determined by collecting urine at baseline (0 hour timepoint) and for 0-8 hours after probe drug cocktail administration. Total urine excreted by the participant for the entire 8 hour duration is collected in a 24 hour urine collection container- the sample may be a combination of multiple excretions. Probe drug cocktails are given to participants at baseline (0-7 days prior to beginning chemotherapy) and again following dose six of paclitaxel chemotherapy (towards the end of treatment, approximately 18 weeks after baseline) for comparative purposes.
Secondary outcome [7] 384206 0
This is a primary outcome. Changes in in vivo CYP3A4 activity as a measure of chemotherapy drug metabolism. Changes in in vivo CYP3A4 activity during chemotherapy were assessed by administering the inje probe drug cocktail (5 component cocktail administered simultaneously; described in detail in the intervention/exposure section), and by collecting serum post-administration.
Timepoint [7] 384206 0
CYP3A4 activity was determined by collecting serum samples at baseline (0 hour timepoint) and again 4 hours after probe drug cocktail administration. Probe drug cocktails are given to participants at baseline (0-7 days prior to beginning chemotherapy) and again following dose six of paclitaxel chemotherapy (towards the end of treatment, approximately 18 weeks after baseline) for comparative purposes.
Secondary outcome [8] 384207 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine ANG2, during chemotherapy, was assessed using an ELISA.
Timepoint [8] 384207 0
ANG2 concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Secondary outcome [9] 384208 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine BAFF, during chemotherapy, was assessed using an ELISA.
Timepoint [9] 384208 0
BAFF concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Secondary outcome [10] 384209 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine CRP, during chemotherapy, was assessed using an ELISA.
Timepoint [10] 384209 0
CRP concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Secondary outcome [11] 384210 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine GDF-15, during chemotherapy, was assessed using an ELISA.
Timepoint [11] 384210 0
GDF-15 concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Secondary outcome [12] 384211 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine IL-10, during chemotherapy, was assessed using an ELISA.
Timepoint [12] 384211 0
IL-10 concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.
Secondary outcome [13] 384212 0
This is a primary outcome. Change in the serum concentration of inflammatory cytokine MCP-1, during chemotherapy, was assessed using an ELISA.
Timepoint [13] 384212 0
MCP-1 concentrations were assessed in serum samples collected once prior to beginning chemotherapy (baseline; 0-7 days before first cycle of AC chemotherapy eg. whenever the participant was in the clinic for the pre-chemotherapy education session with the oncologist) and once following dose six of paclitaxel (1-7 days following dose 6 of paclitaxel, but prior to receiving dose 7 of paclitaxel; approximately 18 weeks after baseline)- changes in concentrations were calculated by comparing these measures.

Eligibility
Key inclusion criteria
• Women of age 18 or older.
• Obese (BMI greater than or equal to 30 kg/m2) or normal weight (BMI ranging from 18.5-24.9 kg/m2) at diagnosis, according to BMI scoring.
• Ability to understand and give written informed consent.
• Ability to take oral medications.
• Clinically defined stage II or III breast cancer.
• Planned neoadjuvant or adjuvant chemotherapy with AC-T (cyclophosphamide, doxorubicin, paclitaxel).
• Willing to wear FitBit One® throughout the selected cycles/doses of chemotherapy.
• Willing to take probe drug cocktail and provide subsequent blood/urine samples.
• No known sensitivity or contraindications to any of the cocktail components, including: midazolam, losartan, caffeine, omeprazole and dextromethorphan.
• Have adequate end-organ function, as measured by:
Creatinine less than or equal to 2x Upper Limit of Normal (ULN)
Haemoglobin greater than 90 g/L
Systolic Blood Pressure greater than 90 mmHg
AST less than or equal to 3x ULN
ALT less than or equal to 3x ULN
Bilirubin less than or equal to 2x ULN
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Enrollment in any conflicting clinical trials.
• Uncontrolled intercurrent illness including, but not limited to, on-going or active infection and psychiatric illness/social situations that would limit compliance with study requirements.
• Patients that suffer from ongoing urinary incontinence and/or current use of a urinary catheter.
• Cirrhosis as documented by liver biopsy, fibroscan, or a clinical history laboratory findings consistent with cirrhosis.
• Impaired mobility due to disability or medical illness. For example:
o Amputation of either or both lower extremities
o Restricted to a wheelchair
• Are known to have active infection with a viral hepatitis (e.g. Hepatitis B or C).
• Unwilling to comply with requirements for recording times when the FitBit One® is not worn.
• Any abnormal laboratory value or medical condition that would, in the investigators’ judgement, make the patient a poor candidate for the study.
• Use of concurrent medications known to be inhibitors or inducers of the cytochrome P450 enzymes being studied. Weak inducers or inhibitors will be acceptable for inclusion.

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Non-normal distribution data was assumed based on the inherent variability associated with clinical data, and thus, non-parametric testing was performed. Statistical significance was considered as a p-value < 0.05. Median values were calculated for patient study data. Statistical significance between paired data was determined by Wilcoxon matched-pairs signed rank testing. Mann Whitney U testing was used for the comparison of unpaired data. Serum cytokine concentrations throughout chemotherapy were compared to baseline using the Kruskal-Wallis test. Correlational data was evaluated using the Spearman’s correlation coefficient.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
11/05/2017
Date of last participant enrolment
Anticipated
Actual
5/09/2018
Date of last data collection
Anticipated
Actual
18/01/2019
Sample size
Target
40
Accrual to date
Final
12
Recruitment outside Australia
Country [1] 22575 0
New Zealand
State/province [1] 22575 0
Christchurch

Funding & Sponsors
Funding source category [1] 305816 0
Charities/Societies/Foundations
Name [1] 305816 0
Canterbury Medical Research Foundation
Country [1] 305816 0
New Zealand
Primary sponsor type
Hospital
Name
Canterbury District Health Board Research Office
Address
2 Riccarton Avenue, Christchurch Central City, Christchurch 8011
Country
New Zealand
Secondary sponsor category [1] 306262 0
None
Name [1] 306262 0
Address [1] 306262 0
Country [1] 306262 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306085 0
Central Health and Disability Ethics Committees (HDECS)
Ethics committee address [1] 306085 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 306085 0
New Zealand
Date submitted for ethics approval [1] 306085 0
11/08/2016
Approval date [1] 306085 0
02/09/2016
Ethics approval number [1] 306085 0
16/CEN/116

Summary
Brief summary
This study involves women receiving chemotherapy for breast cancer. During chemotherapy this study will measure changes in body composition, physical activity levels, changes in the body’s level of inflammation, and changes in the function of liver processes involved in breaking down the chemotherapy. Inflammation is your body’s response to stress or injury. Swelling of an ankle, or a fever, is a common sign of inflammation. People that are obese (body mass index > 30) have been shown to have higher levels of markers of inflammation in their bloodstream. The level of inflammation recorded in blood samples from overweight subjects is still lower than the levels of inflammation experienced in an acute response. However, this type of low level inflammation is sustained over prolonged periods of time and may impact the body’s ability to process medications. Many medications are processed in the body by enzymes in the liver. The chemical messengers in the body that cause inflammation can change the function of these liver enzymes and decrease the ability of the body to process medications. It is not known at this time whether physical activity during chemotherapy affects inflammation or the function of these liver enzymes. This study is seeking to determine if breast cancer patients undergoing chemotherapy have differences in the function of liver enzymes, and if the amount of blood inflammation or physical activity impacts this function.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102650 0
Dr Matthew Strother
Address 102650 0
University of Otago Christchurch and Christchurch District Health Board
2 Riccarton Avenue, Christchurch City, Christchurch, 8011
Country 102650 0
New Zealand
Phone 102650 0
+64 3 3640230
Fax 102650 0
Email 102650 0
[email protected]
Contact person for public queries
Name 102651 0
Miss Rebekah Crake
Address 102651 0
University of Otago Christchurch
2 Riccarton Avenue, Christchurch City, Christchurch, 8011
Country 102651 0
New Zealand
Phone 102651 0
+64 3 3640544
Fax 102651 0
Email 102651 0
[email protected]
Contact person for scientific queries
Name 102652 0
A/Prof Margaret Currie
Address 102652 0
University of Otago Christchurch
2 Riccarton Avenue, Christchurch City, Christchurch, 8011
Country 102652 0
New Zealand
Phone 102652 0
+64 3 3640544
Fax 102652 0
Email 102652 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It was stated in the ethics and consent form that data of this kind will be kept confidential.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8095Study protocol  [email protected]
8096Informed consent form  [email protected]
8097Ethical approval  [email protected] 379898-(Uploaded-27-05-2020-08-37-20)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseInfluence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study.2021https://dx.doi.org/10.1038/s41598-021-85048-1
N.B. These documents automatically identified may not have been verified by the study sponsor.