Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001254684
Ethics application status
Approved
Date submitted
24/08/2023
Date registered
4/12/2023
Date last updated
4/12/2023
Date data sharing statement initially provided
4/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Nutritional response to chyme reinfusion therapy in intestinal failure – a pilot study
Scientific title
Investigation into the nutritional response to chyme reinfusion therapy in patients with type 2 intestinal failure – a pilot study
Secondary ID [1] 310453 0
Nill known
Universal Trial Number (UTN)
U1111-1297-0712
Trial acronym
RESTORE (nutRitional rEsponSe TO chyme Reinfusion thErapy) study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Intestinal failure 331239 0
Malabsorption 331240 0
Malnutrition 331400 0
Condition category
Condition code
Diet and Nutrition 327998 327998 0 0
Other diet and nutrition disorders
Oral and Gastrointestinal 327999 327999 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Main aim is to determine the protein absorption and net balance, as well as the change in colonic fibre fermentation after undergoing to Chyme Reinfusion Therapy by using stable isotope tracer techniques. Further to explore the impact on body composition and primary systemic mineral and vitamin status.

Condition observed:
Adult patients with type 2 intestinal failure and suitability for chyme reinfusion therapy (CRT) (double enterostomy, entero-atmospheric fistula (EAF) or proximal ileostomy with an accessible distal limb), and younger than 70 years.
Healthy subjects, matched for gender and age as a reference group.

Measurements of protein and fibre metabolism will take place in one time point for healthy control participants and in two time points for T2IF participants:
Healthy Participants - As suits the clinic/ team schedule and the participant following recruitment - one visit only at the Human Nutrition Research centre at Massey University Albany Campus, Auckland, New Zealand. In total, 8 hours of participant's time will be required.
T2IF Participants - First: Before starting CRT, after surgery and in a general ward following safe commencement of drinking fluids.
- Second: After the initiation of CRT for at least 21 days either in hospital or at the Human Nutrition Research Centre at Massey University. On each of the two days (the days before and after establishment of CRT) of investigation (8 hours per day), the data collection will start in the early morning after overnight fasting. In total, 16 hours of participant's time across these two time points will be required. Participants will not receive PN during this period to prevent interference, and missed nutrition will be compensated afterwards.

For all participants:
Day 1 of investigation for protein absorption, whole body protein and fibre metabolism will involve:
• Having a peripheral catheter placed in a superficial vein of the lower arm or access will be from a peripheral venous line already in place for clinical care for stable isotope infusion
• A second peripheral catheter will be placed for arterialised venous blood sampling in a superficial dorsal vein of the contralateral hand. The hand will be placed in a thermostatically controlled heated box, a technique to mimic direct arterial sampling.
• Having a blood sample taken via their peripheral line to measure natural background isotope enrichments of phenylalanine (Phe) and tyrosine (Tyr) and three SCFA (acetate, propionate and butyrate) in their body prior to infusion. Methods are adapted from Jonker et al (Jonker, Deutz, Schols, et al., 2019).
• Next, a primed, constant intravenous infusion of L-[ring-13C6]-Phe ([13C6]-Phe: prime = 270 µmol; infusion = 270 µmol x h-1) and L-[U-13C9, 15N]-Tyr ([U-13C9, 15N]-Tyr: prime = 8.5 µmol; infusion = 8.5 µmol x h-1) will be infused to assess net whole-body protein balance (protein synthesis minus protein breakdown) (Jonker, Deutz, Schols, et al., 2019).
• At the same time, a one-off pulse IV solution containing 89.0 mmol/L acetate [1,2-13C2], 13.1 mmol/L propionate [1-13C], and 10.9 mmol/L butyrate [1-13C] will also be given. Methods are adapted from Kirschner et al (Kirschner et al., 2023).
• Over the next 30 mins, four blood samples will be taken at 4, 8, 15 and 30 minutes to determine whole body SCFA production (Kirschner et al., 2023).
• After two hours of priming:

1. the participant will start sipping a spirulina-flavoured stable isotope tracer-enriched oral nutritional supplement (ONS) drink e.g. Fresubin Energy, every 30 minutes for the next five hours. The ONS dosage for each participant will be determined as one-third of their total daily protein needs, estimated using Dietary Recommended Intakes (DRI). If the participants in the patient group are unable to drink this, they will receive it enterally through a feeding tube (when feeding tube is present). The ONS drinks are tracer-enriched with 3.14 mg/kg body weight free L-[1-13C]-Phe and 1861 mg intrinsically-labelled 15N-spirulina containing 51 mg L-[1-15N] Phe for the purpose of measuring net protein absorption. Methods are adapted from Engelen et al (Engelen et al., 2014).

2. six blood samples will be taken in 60-minute intervals to measure the amounts of Phe and Tyr.

• In the T2IF patient group, CRT will be performed using the InsidesTM System (Registered Class 2b device with CE marking, The Insides Company, Auckland, NZ) every 60 min or as required. Four chyme samples will be collected from the patient's stoma bag throughout the day: one at the start, one at the end (after 8 hours) and two in between that must be at least 120 minutes apart (to determine isotope content).

Day 2 of investigation at the end of the study will be a repeat procedure for the T2IF patients only.

Arterialised venous blood samples will be collected by a certified phlebotomist or research nurse. Isotope infusion will be conducted by the research nurse or trained researcher (physiologist).
The Insides System is part of the CRT that is prescribed by the hospital.
Patients will receive CRT regardless of their participation in this study.

The following data will also be collected during the study:
- Body composition.
- Weighed diet record x 3 – before, during and after receiving CRT.
- Dietary diversity and quality questionnaires x 3 - before, during and after receiving CRT.
- Micronutrient status – blood sampling (Vitamin B12, Folate, selenium, Vitamin D, Copper, Zinc, Iron).
- Patient experience assessment – short patient interview in person or via videoconference call.
- Clinician perceptions regarding CRT – short interview in person or videoconference call.
References used:
Jonker, R., Deutz, N. E. P., Ligthart-Melis, G. C., Zachria, A. J., Veley, E. A., Harrykissoon, R., & Engelen, M. (2019). Preserved anabolic threshold and capacity as estimated by a novel stable tracer approach suggests no anabolic resistance or increased requirements in weight stable COPD patients. Clin Nutr, 38(4), 1833-1843. https://doi.org/10.1016/j.clnu.2018.07.018

Kirschner, S. K., Ghane, P., Park, J. K., Simbo, S. Y., Ivanov, I., Braga-Neto, U. M., Ten Have, G. A. M., Thaden, J. J., Engelen, M., & Deutz, N. E. P. (2023). Short-chain fatty acid production in accessible and inaccessible body pools as assessed by novel stable tracer pulse approach is reduced by aging independent of presence of COPD. Metabolism, 141, 155399. https://doi.org/10.1016/j.metabol.2023.155399

Engelen, M. P., Com, G., Anderson, P. J., & Deutz, N. E. (2014). New stable isotope method to measure protein digestibility and response to pancreatic enzyme intake in cystic fibrosis. Clin Nutr, 33(6), 1024-1032. https://doi.org/10.1016/j.clnu.2013.11.004
Intervention code [1] 326851 0
Not applicable
Comparator / control treatment
Healthy subjects, matched for gender and age as a reference group.
Measurements of protein and fibre metabolism will take place in one time point for healthy control participants:
Healthy Participants - As suits the clinic/ team schedule and the participant following recruitment - one visit only at the Human Nutrition Research centre at Massey University Albany Campus, Auckland, New Zealand. In total, 8 hours of participant's time will be required.
Control group
Active

Outcomes
Primary outcome [1] 335863 0
Quantify relative dietary protein digestibility relative to basal state and healthy people using stable isotope tracer technique.
Timepoint [1] 335863 0
Healthy participants - during one-off visit,
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Primary outcome [2] 335864 0
Investigate the change in whole-body short chain fatty acid (SCFA) production (derived from colonic) relative to basal state and healthy people using stable isotope tracer technique.
Timepoint [2] 335864 0
Healthy participants - during one-off visit,
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Primary outcome [3] 335865 0
Explore the patient experience of CRT and stable isotope tracer protocol qualitatively before, during and after treatment of T2IF using semi-structured interviews.
Timepoint [3] 335865 0
Three times - Before commencing CRT, during the study after Day 1 of Investigation and 3 weeks after receiving CRT.
Secondary outcome [1] 425921 0
Vitamin D concentrations measured using serum assays.
Timepoint [1] 425921 0
Twice - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [2] 425922 0
Nutrient intake using diet records and a validated semi-quantitative food frequency.
Timepoint [2] 425922 0
Three times - immediately before receiving CRT, during (2 weeks after receiving CRT) and 3 weeks after receiving CRT,
Secondary outcome [3] 425923 0
Explore clinician perspectives of CRT in the treatment of T2IF using semi-structured interviews and a study-specific survey,
Timepoint [3] 425923 0
Once-off during the first week following the completion of CRT.
Secondary outcome [4] 427078 0
New Primary Outcome - Quantify relative dietary protein absorption relative to basal state and healthy people using stable isotope tracer technique.
Timepoint [4] 427078 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [5] 427079 0
New Primary Outcome - Quantify relative net whole-body protein balance relative to basal state and healthy people using stable isotope tracer technique.
Timepoint [5] 427079 0

Healthy participants - during one-off visit.
T2IF Participants -immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [6] 427080 0
Vitamin B12 concentrations measured using serum assays.
Timepoint [6] 427080 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT
Secondary outcome [7] 427081 0
Folate concentrations measured using serum assays.
Timepoint [7] 427081 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [8] 427082 0
Iron concentrations measured using serum assays.
Timepoint [8] 427082 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT
Secondary outcome [9] 427083 0
Copper concentrations measured using serum assays
Timepoint [9] 427083 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [10] 427084 0
Zinc concentrations measured using serum assays
Timepoint [10] 427084 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [11] 427085 0
Selenium concentrations measured using serum assays.
Timepoint [11] 427085 0
Healthy participants - during one-off visit.
T2IF Participants - immediately before receiving CRT and 3 weeks after receiving CRT.
Secondary outcome [12] 427086 0
Dietary patterns using a validated semi-quantitative food frequency and dietary diversity questionnaires.
Timepoint [12] 427086 0
Healthy participants - during one-off visit.
T2IF Participants - three times; immediately before receiving CRT, during (2 weeks after receiving CRT) and 3 weeks after receiving CRT,

Eligibility
Key inclusion criteria
Adult patients with type 2 intestinal failure and suitability for chyme reinfusion therapy (CRT) (double enterostomy, entero-atmospheric fistula (EAF) or proximal ileostomy with an accessible distal limb), and younger than 70 years.
Minimum age
18 Years
Maximum age
69 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who have an anastomotic leak or bowel obstruction, or are pregnant, immunocompromised, or unable to understand risks and benefits.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
We aim to recruit nine adult patients that comply with inclusion and exclusion criteria and three healthy subjects over a period of 12-15 months. Sample size in this proof-of-principle pilot study was calculated from error rates in the study by Kirschner et al, 2022 comparing protein absorption using the 15N-spirulina method in patients with congestive heart failure compared to controls and by consideration of likely number of patents available in the 12-month tenure of funding available (Kirschner et al., 2022). In Kirschner et al, the within-subject SD/typical error was a protein absorption ratio of 0.12. The mean effect size between groups was 0.236, p=0.001. We are expecting a similar or larger sample size with effect size of 0.2 yielding n=11 in the patent group with the normal error rates of 5% type-1 and 90% type-2 error containment.
The healthy reference group (three participants) is a single observation only and being used as a reference to effect size in the healthy gut only.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/12/2023
Actual
Date of last participant enrolment
Anticipated
10/03/2025
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment outside Australia
Country [1] 25725 0
New Zealand
State/province [1] 25725 0

Funding & Sponsors
Funding source category [1] 314661 0
University
Name [1] 314661 0
Massey University Strategic Research Excellence Fund
Country [1] 314661 0
New Zealand
Primary sponsor type
University
Name
Massey University
Address
Massey University, Albany express highway (SH17), Albany, Auckland 0632, NZ
Country
New Zealand
Secondary sponsor category [1] 316625 0
Hospital
Name [1] 316625 0
Te Whatu Ora Te Toka Tumai Auckland
Address [1] 316625 0
Nutrition Services, Level 8, Support Building, Auckland City Hospital, 2 Park road, Grafton, Auckland, 1023
Country [1] 316625 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313680 0
Health and Disability Ethics Committee - Northern B
Ethics committee address [1] 313680 0
Ethics committee country [1] 313680 0
New Zealand
Date submitted for ethics approval [1] 313680 0
23/03/2023
Approval date [1] 313680 0
26/04/2023
Ethics approval number [1] 313680 0
2023 EXP 15600

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128986 0
Prof Rozanne Kruger
Address 128986 0
School of Sport, Exercise and Nutrition, College of Health, Massey University. Sir Neil Waters Extension Building, Massey University, East Precinct, Albany Expressway, SH17, Albany, Auckland, New Zealand, 0632
Country 128986 0
New Zealand
Phone 128986 0
+61756780155
Fax 128986 0
Email 128986 0
[email protected]
Contact person for public queries
Name 128987 0
Andrew Xia
Address 128987 0
Nutrition Services, Level 8, Support Building, Auckland City Hospital, 2 Park road, Grafton, Auckland, 1023
Country 128987 0
New Zealand
Phone 128987 0
+64 21887730
Fax 128987 0
Email 128987 0
[email protected]
Contact person for scientific queries
Name 128988 0
Rozanne Kruger
Address 128988 0
School of Sport, Exercise and Nutrition, College of Health, Massey University. Sir Neil Waters Extension Building, Massey University, East Precinct, Albany Expressway, SH17, Albany, Auckland, New Zealand, 0632
Country 128988 0
New Zealand
Phone 128988 0
+61756780155
Fax 128988 0
Email 128988 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data and tissue in this study includes but is not limited to:
- Tissue samples and requisition forms.
- Case Report Forms.
- Safety and screening results entered into the analysis data set.
- Communications from the site to New Zealand and overseas laboratories.
- Data generated by the New Zealand and overseas laboratories.

De-identified tissue and data will carry the participant’s unique study code. The Investigator will retain a log linking participant code with identifiers. This log will not be made available to the New Zealand and overseas laboratories.
All data and/or tissue sent to the New Zealand and overseas laboratories will be de-identified. All data generated by these parties will be in de-identified form. No attempt will be made to re-identify participants.
When will data be available (start and end dates)?
Immediately following publication, no end date determined.
Available to whom?
Due to the small sample size and costly research, it is important that the study data can be combined with other studies for a larger pool size. Collaborators are not yet identified, however, this possibility is explained in additional participant information sheet and consent is gained for future use. Only researchers who provide a methodologically sound proposal at the discretion of Primary Sponsor can access the data.
Available for what types of analyses?
Collaborators are not yet identified, neither is the types of analysis. However, this possibility is explained in additional participant information sheet and consent is gained for future use.
This will be only to achieve the aims in the approved proposal and for IPD meta-analyses.
How or where can data be obtained?
Access subject to approvals by Principal Investigator - [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



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