Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001317987
Ethics application status
Approved
Date submitted
3/11/2020
Date registered
7/12/2020
Date last updated
7/12/2020
Date data sharing statement initially provided
7/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to assess if pantoprazole affects the absorption of capecitabine in patients with breast and gastrointestinal cancers.
Scientific title
Does the Concomitant Administration of Proton Pump Inhibitors Effect Capecitabine Pharmacokinetics? – A Prospective, Single-Centre, Two-Arm, Randomised, Unblinded, Cross-Over Bioequivalence Study of Capecitabine With or Without Concomitant Pantoprazole.
Secondary ID [1] 302680 0
Nil
Universal Trial Number (UTN)
Trial acronym
APEC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 319600 0
Gastrointestinal Cancer 319601 0
colorectal cancer 319933 0
Condition category
Condition code
Cancer 317540 317540 0 0
Breast
Cancer 317541 317541 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 317871 317871 0 0
Bowel - Small bowel (duodenum and ileum)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Consented participants who are scheduled for capecitabine monotherapy for breast or gastrointestinal cancer will be randomly allocated to receive concomitant oral pantoprazole 40mg daily, 4 days prior to and on the first day (total 5 doses) of either the first (group A) or second (Group B) cycle of capecitabine. Pharmacokinetic blood and urine sampling for capecitabine will be performed over eight hours on both cycle1 day 1 and cycle 2 day 1 to determine if PK parameters are different with pantoprazole. Participants will be contacted by phone a day before their course of pantoprazole begins and will receive a daily text reminder on the subsequent 4 days. A medication diary will be kept. The washout period is 21 days (in between cycle 1 day 1 and cycle 2 day 1)
Intervention code [1] 318965 0
Treatment: Drugs
Comparator / control treatment
This is a cross-over study. Each patient will serve as their own control. The control is capecitabine monotherapy WITHOUT pantoprazole 4 days before and on the first day of a capecitabine cycle
Control group
Active

Outcomes
Primary outcome [1] 325583 0
Area Under the Curve AUC(0-8) of 5”DFUR (Blood and urine sample)
Timepoint [1] 325583 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Primary outcome [2] 325584 0
Area Under the Curve AUC(0-8) of 5-FU (blood and urine sample)
Timepoint [2] 325584 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [1] 388452 0
AUC(0-8) of Capecitabine (blood and urine)

Timepoint [1] 388452 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [2] 388453 0
Time to maximum concentration (Tmax) of capecitabine. (Blood test)
Timepoint [2] 388453 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [3] 388454 0
Maximum concentration (Cmax) of capecitabine (blood test)
Timepoint [3] 388454 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [4] 389435 0
AUC(0-8) of 5'DFCR (blood and urine)
Timepoint [4] 389435 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [5] 389436 0
AUC(0-8) of FBAL (blood and urine)
Timepoint [5] 389436 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [6] 389437 0
Time to maximum concentration (Tmax) of 5'DFCR. (Blood test)
Timepoint [6] 389437 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [7] 389438 0
Time to maximum concentration (Tmax) of FBAL (Blood test)
Timepoint [7] 389438 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [8] 389439 0
Time to maximum concentration (Tmax) of 5FU. (Blood test)
Timepoint [8] 389439 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [9] 389440 0
Time to maximum concentration (Tmax) of 5'DFUR. (Blood test)
Timepoint [9] 389440 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [10] 389441 0
Maximum concentration (Cmax) of 5FU (blood test)
Timepoint [10] 389441 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [11] 389442 0
Maximum concentration (Cmax) of 5'DFCR (blood test)
Timepoint [11] 389442 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [12] 389443 0
Maximum concentration (Cmax) of 5'DFUR (blood test)
Timepoint [12] 389443 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole
Secondary outcome [13] 389444 0
Maximum concentration (Cmax) of FBAL (blood test)
Timepoint [13] 389444 0
Cycle 1 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole, Cycle 2 Day 1: pre-dose, 0.25, 0,5, 1, 1.5, 2, 3, 4, 6, 8 hours post-ingestion of pantoprazole

Eligibility
Key inclusion criteria
adults (18+ years) with histologically confirmed GI or breast cancer, receiving adjuvant or palliative capecitabine monotherapy within the Regional Cancer and Blood Services, Auckland District Health Board. Adequate functional status (ECOG 2 or less) and organ function as defined as (i) Neutrophil>1.5, Hb>9g, Platelet>100,000, (ii) Bilirubin<1.5x ULN, ALT, AST <2.0 ULN, (iii) Creatinine clearance calculated by Cockcroft Gault >50ml/min within 14 days of cycle 1.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Previous capecitabine use, recent Proton pump inhibitors (PPI), /H2 Receptor Blocker or antacid use, pre-existing gastritis/ gastro-oesophageal reflux necessitating treatment, previous intolerance to PPI and any condition deemed by study investigators to significantly affect normal gastrointestinal tract function (e.g. upper gastrointestinal tract surgery/ radiation/ pre-existing condition)

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation (using random lengths 4 / 6)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis
Statistical approach applied in bioequivalence study will be employed with the use of 90% confidence intervals. The geometric mean and 90%CI of the AUC(0-8) ratios will be estimated and compared to the internationally accepted bio-equivalence margin of 0.80- 1.25. The pharmacokinetic parameters will be considered to not differ after the addition of pantoprazole, if the 90% CI lies entirely within that boundary. The two AUC estimates will be computed for each individual. The estimates will be logged and differences obtained (corresponding to the ratio of the two AUCs). A linear model will be used adjusting for period and treatment order. The adjusted mean difference can be compared to (-0.2231,0.2231) or exponentiated to compare with (0.80, 1.25).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/12/2020
Actual
Date of last participant enrolment
Anticipated
7/01/2022
Actual
Date of last data collection
Anticipated
1/03/2022
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment outside Australia
Country [1] 23085 0
New Zealand
State/province [1] 23085 0
Auckland

Funding & Sponsors
Funding source category [1] 307119 0
Charities/Societies/Foundations
Name [1] 307119 0
Gut Cancer Foundation New Zealand
Country [1] 307119 0
New Zealand
Primary sponsor type
Hospital
Name
Auckland District Health Board
Address
Research Office ADHB
Level 14, Support Building, Auckland City Hospital
Private Bag 92024, 1023, Auckland, New Zealand
Country
New Zealand
Secondary sponsor category [1] 307691 0
None
Name [1] 307691 0
Address [1] 307691 0
Country [1] 307691 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307231 0
Health and Disability Ethics Committees (HDECs)
Ethics committee address [1] 307231 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 307231 0
New Zealand
Date submitted for ethics approval [1] 307231 0
10/11/2020
Approval date [1] 307231 0
17/11/2020
Ethics approval number [1] 307231 0
20/NTB/289

Summary
Brief summary
Proton pump inhibitors (PPIs) are very common medications used for managing gastritis and reflux. Patients on chemotherapy tend to have more problems with gastritis and reflux and approximately 20-55% patients on chemotherapy are reported to be on PPIs. Capecitabine is a tablet form of chemotherapy widely used to treat cancer and has to be absorbed in the gut to be effective. Recent studies have raised concerns that individuals on capecitabine who are also prescribed with PPIs may have poorer cancer survival outcomes compared to those who are not on PPIs. One suggestion is that changes in the pH of the stomach from PPI use, affects the dissolution of the tablet and decreases how much capecitabine enters the body.In late 2019, the NZ regulatory body MEDSAFE advised NZ oncologists that there may be a possible interaction between PPI drugs and capecitabine, but fell short of making any specific recommendations due to the paucity of good quality data.

To address this very real and relevant concern, we plan to conduct a study that will help us determine whether pantoprazole, an approved PPI, affects capecitabine absorption. The study will be conducted in Auckland City Hospital and will involve 20 patients who are scheduled to receive capecitabine for their bowel or breast cancer treatment. The study will span the first 2 cycles (6 weeks) of their capecitabine treatment. Each participant will receive a short course of pantoprazole either before their first or second cycle of capecitabine (cross over design). Whether they receive pantoprazole before the first or second cycle will be randomly assigned (randomization). On the first day of both cycles of capecitabine, blood and urine samples will be collected over an 8 hour period. The samples will be analysed to determine how much capecitabine was absorbed and processed in each participant (pharmacokinetic study). This will allow us to compare if the short course of pantoprazole had any effects on capecitabine.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106490 0
Dr Edmond Ang
Address 106490 0
Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023
Country 106490 0
New Zealand
Phone 106490 0
+64275236584
Fax 106490 0
Email 106490 0
eang@adhb.govt.nz
Contact person for public queries
Name 106491 0
Dr Edmond Ang
Address 106491 0
Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023
Country 106491 0
New Zealand
Phone 106491 0
+64275236584
Fax 106491 0
Email 106491 0
eang@adhb.govt.nz
Contact person for scientific queries
Name 106492 0
Dr Edmond Ang
Address 106492 0
Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023
Country 106492 0
New Zealand
Phone 106492 0
+64275236584
Fax 106492 0
Email 106492 0
eang@adhb.govt.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not applicable/ PK study.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.