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Trial registered on ANZCTR

Registration number

ACTRN12617000349347

Ethics application status

Approved

Date submitted

15/02/2017

Date registered

7/03/2017

Date last updated

10/03/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

The Impact of Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy on Gastric Emptying, Gut Hormone and Glycaemic Responses to a Meal in Type 2 Diabetes Mellitus

Scientific title

The Impact of Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy on Gastric Emptying, Gut Hormone and Glycaemic Responses to a Meal in Type 2 Diabetes Mellitus

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1187-3213

Trial acronym

PERT

Linked study record

Health condition

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

Pancreatic exocrine insufficiency in type two diabetes

The presence of postprandial hypotension in type two diabetes

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Metabolic and Endocrine

Other endocrine disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a double-blind randomised-placebo controlled cross-over study evaluating the effect of pancreatic enzyme replacement therapy (PERT) on postprandial glycaemia, gastric emptying and incretin response in subjects with type 2 diabetes with evidence of exocrine pancreatic insufficiency on faecal elastase testing. We will evaluate the effects of PERT versus placebo on postprandial glycaemia, gastric emptying and incretin responses following a high fat/high carbohydrate meal. The presence and potential reversibility of postprandial hypotension will also be evaluated.

After providing written and informed consent, each participant will be provided with a lasagne dinner the night prior to attending the trial. After the lasagne dinner, participants will undergo an overnight fast and then arrive at the Nuclear Medicine Department at the Royal Adelaide Hospital in the morning (0800) on two separate occasions. Participants will be given a high fat/high carbohydrate mashed potato meal (60g fat, 60g carbohydrate - 50% energy from fat and 50% energy from carbohydrate) to be eaten over 10 minutes (t = -10 to 0 minutes), labelled with 20 MBq 99mTc calcium phytate and C13 octanoic acid. Participants will be asked to withhold their usual morning antihypertensive medication until after the 4 hour-study. Participants will eat the meal while seated in an upright position. The management of the participant’s usual management for type 2 diabetes will be supervised by an endocrinologist (Dr Liza Phillips) who will determine requirement for any changes to usual treatment (e.g. possible dose modification of insulin). At the same time as the meal they will take two capsules of pancrelipase (total 50, 000 U) or matching placebo. Venous blood samples will be sampled at t = -15, 0, 15, 30, 60, 90, 120, 180, 240 minutes for blood glucose and plasma insulin, C-peptide, glucagon, GIP and GLP-1 concentrations. Gastric emptying will be measured using scintigraphy; images will be acquired using the gamma camera for 240 minutes (60-second frames for the first 60 minutes and 3-minute frames thereafter). Breath tests will also be collected as a contingency measure as access to Nuclear Medicine facilities may be interrupted for a substantial period during the nRAH and Medical School Building moves that will occur during 2017. The breath tests will be collected but only analysed if scintigraphy proves unfeasible for the whole cohort. We do not plan to use the gastric emptying data derived from scintigraphy and breath tests interchangeably. Appetite will be evaluated using a standardised visual analogue (VAS) scale 15 minutely for the first 2 hours and 30 minutely thereafter. Other questionnaires to be completed at each visit include the Diabetes Bowel Symptom Questionnaire (15, 16) which has been modified to include some specific questions pertaining to steatorrhea and the Bristol Stool chart. These questionnaires are designed to evaluate bowel symptoms in diabetes and capture symptoms relating specifically to pancreatic exocrine insufficiency. Blood pressure will be taken prior to ingestion of the test meal and then 3 minutely thereafter with an automated BP cuff (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA). Standardised tests of cardiovascular autonomic function will be undertaken on the first study visit in the fasted state. There will be a minimum ‘washout’ period of 72 hours.

Dose Administered: Two Pancrelipase capsules 25, 000 Units (total 50, 000 units),
Duration of Dose: Single dose - on two separate study days
Mode of Administration: Oral capsule

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

This is a cross-over trial - each subject will take both placebo and active treatment in a randomised order.

Control group

Placebo

Outcomes

Primary outcome [1]

Difference in postprandial hyperglycaemia as evaluated by incremental area under the glucose curve (iAUC) following pancrelipase versus placebo. Blood serum samples will obtained at specified time points during the study to assess postprandial hyperglycaemia. Samples will be obtained at t = -15, 0, 15, 30, 60, 90, 120, 180, 240 minutes for blood glucose and plasma insulin, C-peptide, glucagon, GIP and GLP-1 concentrations.

Timepoint [1]

The incremental area under the curve will be calculated from data obtained during the entire gastric emptying study i.e. 4 hours/240 min. Samples will be obtained at t = -15, 0, 15, 30, 60, 90, 120, 180, 240 minutes pre- and post-capsule ingestion

Secondary outcome [1]

Difference in gastric emptying (T50) as assessed by scintigraphic imaging.
Gastric emptying (T50) is the time at which 50% of meal has emptied.

Timepoint [1]

Gastric emptying will be measured using scintigraphy; images will be acquired using the gamma camera for 240 minutes post-meal (60-second frames for the first 60 minutes and 3-minute frames thereafter).

Secondary outcome [2]

Difference in gastric emptying (T100) as assessed by scintigraphic imaging.
Gastric emptying (T100) is the amount of gastric emptying at 100 min.

Timepoint [2]

Secondary outcome [3]

Difference in incretin hormone levels (glucagon like peptide-1 and gastric inhibitory polypeptide) via serum assays.

Timepoint [3]

Venous blood samples will be sampled at t = -15, 0, 15, 30, 60, 90, 120, 180, 240 minutes for blood glucose and plasma insulin, C-peptide, glucagon, GIP and GLP-1 concentrations.

Secondary outcome [4]

Difference in postprandial blood pressure response following pancreatic exocrine replacement therapy will be assessed via use of an automated blood pressure cuff (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA).

Timepoint [4]

Blood pressure readings will be obtained digitally every three minutes, beginning fifteen minutes pre-meal ingestion and will continue every 3 minutes from t = -15 to t = 240.

Eligibility

Key inclusion criteria

1.Males or females aged 40-80 years
2. Type 2 diabetes mellitus
3. HbA1c >7%
4. Stool sample demonstrating faecal elastase-1 concentration of 100 micro g/g

Minimum age

40 Years

Maximum age

80 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Evidence of renal or hepatic disease, known pancreatic disease, previous pancreatic surgery, gastric surgery, or known gastroparesis. Renal disease: creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation. Participants will be excluded if creatinine clearance is estimated at < 30 mL/min. Hepatic disease: participants will be excluded if there is documented cirrhosis or transaminases or alkaline phosphatase elevated more than 2 times the upper limit of normal. Cardiovascular disease: admission to hospital with heart failure, myocardial infarction or stroke within previous 6 months or uncontrolled hypertension (BP > 170/110 mmHg).
2. Use of drugs potentially affecting gastrointestinal motility (opiates, anticholinergics, levodopa, clonidine, nitrates, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, erythromycin, pyridostigmine, laxatives or olanzapine)
3. Use of GLP-1 agonist e.g. exenatide for the control of diabetes
4. Uncontrolled hypertension (blood pressure > 170/110 mmHg)
5. Participation in any research studies involving exposure to ionising radiation within the previous 12 months
6. Intake of > 20g alcohol on a daily basis, or cigarette smoking
7. Volunteers who have donated blood in the preceding 3 months or who are iron deficient (ferritin < 30 micro g/L)
8. Pregnancy or breastfeeding
9. Vegetarians and those with a philosophical or religious objection to beef, chicken or pork.

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)

Sealed opaque envelopes will be used to conceal the allocation.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Patients will undergo simple randomisation to either the intervention group or control group with a 1:1 allocation by a computerised random number generator.

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

Crossover

Other design features

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

We will need to complete studies in 16 patients to provide 90% power to detect a 30% reduction in incremental area under the blood glucose curve at a=0.05; we will recruit 18 subjects to allow for dropouts. Data will be evaluated by analysis of covariance, adjusted for baseline values.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

31/03/2017

Actual

Date of last participant enrolment

Anticipated

1/06/2018

Actual

Date of last data collection

Anticipated

8/06/2018

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Diabetes Australia

Address [1]

PO Box 3156
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

The University of Adelaide

Address

The University of Adelaide
SA 5005
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

None

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Adelaide Hospital Research Ethics Committee EC00192

Ethics committee address [1]

Level 6 Eleanor Harrald Building
Discipline of Medicine, The University of Adelaide
Royal Adelaide Hospital
Frome Road
Adelaide SA 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/09/2016

Approval date [1]

09/01/2017

Ethics approval number [1]

PERT Trial HREC/16/RAH/451 R20161104

Summary

Brief summary

Control of low blood sugar following a meal is a priority in many patients with T2DM, particularly in those with better overall glycaemic control (HbA1c <~7.5%). The rate of gastric emptying is a pivotal determinant of postprandial glycaemia in type 2 diabetes. Gut peptides released in response to meals; glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), modulate postprandial glycaemia through their insulinotropic effects; GLP-1 also inhibits glucagon release and slows gastric emptying. The suggestion of abnormalities of the exocrine pancreas in patients with diabetes was reported over half a century ago. The pathophysiology of pancreatic exocrine insufficiency (PEI) in patients with type 1 and type 2 diabetes remains unclear, however possible mechanisms include exocrine dysfunction due to diabetic neuropathy or vasculopathy, a shared common pathway of damage to both islets and exocrine glands and a loss of the direct trophic effects of insulin. This 'pancreatogenic' form of diabets mellitus classified as type 3c, can result from a variety of conditions involving the exocrine pancreas, e.g. chronic pancreatitis, fibrocalculous pancreatopathy or haemochromatosis. Traditionally, type 3c diabetes has been thought to comprise of only ~1-2% of all cases of diabetes, but it has been suggested that more careful evaluation of cases yields a proportion of 8% or more. The presence of PEI in patients with diabetes is important, because it potentially impacts on glycaemic control, as well as nutritional status, bone homeostasis and gastrointestinal symptoms. In particular, ingested fats must be digested in the small intestine in order to stimulate GLP-1 and GIP secretion and induce feedback mechanisms that slow gastric emptying; as discussed, the rate of the latter is a major determinant of the postprandial blood glucose excursion. Our group showed in patients with cystic fibrosis who had documented PEI, that a high fat/carbohydrate meal emptied abnormally rapidly from the stomach, associated with deficient incretin hormone secretion and marked postprandial glycaemia. PERT addition slowed gastric emptying, augmented GLP-1 and GIP secretion, and substantially lowered the blood glucose excursion. Few studies have evaluated the role of PERT in diabetes and there have been conflicting results. Of note, there is limited information on postprandial hyperglycaemia and in those patients with T2DM. We therefore propose to study patients with a diagnosis of T2DM, who have evidence of PEI on a faecal elastase assay. We will evaluate the effects of PERT versus placebo on postprandial glycaemia, gastric emptying and incretin responses following a high fat/high carbohydrate meal.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Liza Phillips

Address

Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000

Country

Australia

Phone

+61 407764422

Fax

[email protected]

Contact person for public queries

Name

Liza Phillips

Address

Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000

Country

Australia

Phone

+ 61 407764422

Fax

[email protected]

Contact person for scientific queries

Name

Liza Phillips

Address

Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000

Country

Australia

Phone

+ 61 407764422

Fax

[email protected]

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Embase	The prevalence and impact of low faecal elastase-1 in community-based patients with type 2 diabetes.	2019	https://dx.doi.org/10.1016/j.diabres.2019.107822

N.B. These documents automatically identified may not have been verified by the study sponsor.

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