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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]

Nil

Universal Trial Number (UTN)

Trial acronym

APEC

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Breast Cancer

Gastrointestinal Cancer

colorectal cancer

Condition category

Condition code

Cancer

Breast

Cancer

Bowel - Back passage (rectum) or large bowel (colon)

Cancer

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]

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]

Area Under the Curve AUC(0-8) of 5”DFUR (Blood and urine sample)

Timepoint [1]

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]

Area Under the Curve AUC(0-8) of 5-FU (blood and urine sample)

Timepoint [2]

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]

AUC(0-8) of Capecitabine (blood and urine)

Timepoint [1]

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]

Time to maximum concentration (Tmax) of capecitabine. (Blood test)

Timepoint [2]

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]

Maximum concentration (Cmax) of capecitabine (blood test)

Timepoint [3]

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]

AUC(0-8) of 5'DFCR (blood and urine)

Timepoint [4]

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]

AUC(0-8) of FBAL (blood and urine)

Timepoint [5]

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]

Time to maximum concentration (Tmax) of 5'DFCR. (Blood test)

Timepoint [6]

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]

Time to maximum concentration (Tmax) of FBAL (Blood test)

Timepoint [7]

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]

Time to maximum concentration (Tmax) of 5FU. (Blood test)

Timepoint [8]

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]

Time to maximum concentration (Tmax) of 5'DFUR. (Blood test)

Timepoint [9]

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]

Maximum concentration (Cmax) of 5FU (blood test)

Timepoint [10]

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]

Maximum concentration (Cmax) of 5'DFCR (blood test)

Timepoint [11]

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]

Maximum concentration (Cmax) of 5'DFUR (blood test)

Timepoint [12]

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]

Maximum concentration (Cmax) of FBAL (blood test)

Timepoint [13]

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]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Gut Cancer Foundation New Zealand

Address [1]

Level 5, Tower One, 205 Queen Street, Auckland CBD, Auckland 1010

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committees (HDECs)

Ethics committee address [1]

133 Molesworth Street
 Thorndon
 Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

10/11/2020

Approval date [1]

17/11/2020

Ethics approval number [1]

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

Dr Edmond Ang

Address

Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023

Country

New Zealand

Phone

+64275236584

Fax

Email

[email protected]

Contact person for public queries

Name

Edmond Ang

Address

Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023

Country

New Zealand

Phone

+64275236584

Fax

Email

[email protected]

Contact person for scientific queries

Name

Edmond Ang

Address

Cancer and Blood Research, Auckland City Hospital
2, Park Road, Grafton,
Auckland 1023

Country

New Zealand

Phone

+64275236584

Fax

Email

[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

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.