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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] 290102 0
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 300194 0
The presence of postprandial hypotension in type two diabetes 301733 0
Condition category
Condition code
Metabolic and Endocrine 300077 300077 0 0
Diabetes
Metabolic and Endocrine 300078 300078 0 0
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] 295848 0
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] 299556 0
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] 299556 0
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] 327497 0
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] 327497 0
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] 327498 0
Difference in gastric emptying (T100) as assessed by scintigraphic imaging.
Gastric emptying (T100) is the amount of gastric emptying at 100 min.
Timepoint [2] 327498 0
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 [3] 328792 0
Difference in incretin hormone levels (glucagon like peptide-1 and gastric inhibitory polypeptide) via serum assays.
Timepoint [3] 328792 0
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] 328865 0
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] 328865 0
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?
No
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
18
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 6621 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 14242 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 294473 0
Charities/Societies/Foundations
Name [1] 294473 0
Diabetes Australia
Country [1] 294473 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
The University of Adelaide
SA 5005
Australia
Country
Australia
Secondary sponsor category [1] 293403 0
None
Name [1] 293403 0
None
Address [1] 293403 0
None
Country [1] 293403 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295911 0
Royal Adelaide Hospital Research Ethics Committee EC00192
Ethics committee address [1] 295911 0
Level 6 Eleanor Harrald Building
Discipline of Medicine, The University of Adelaide
Royal Adelaide Hospital
Frome Road
Adelaide SA 5000
Ethics committee country [1] 295911 0
Australia
Date submitted for ethics approval [1] 295911 0
30/09/2016
Approval date [1] 295911 0
09/01/2017
Ethics approval number [1] 295911 0
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 68862 0
Dr Liza Phillips
Address 68862 0
Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000
Country 68862 0
Australia
Phone 68862 0
+61 407764422
Fax 68862 0
Email 68862 0
[email protected]
Contact person for public queries
Name 68863 0
Liza Phillips
Address 68863 0
Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000
Country 68863 0
Australia
Phone 68863 0
+ 61 407764422
Fax 68863 0
Email 68863 0
[email protected]
Contact person for scientific queries
Name 68864 0
Liza Phillips
Address 68864 0
Discipline of Medicine, The University of Adelaide
Level 6, Eleanor Harrald Building, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000
Country 68864 0
Australia
Phone 68864 0
+ 61 407764422
Fax 68864 0
Email 68864 0
[email protected]

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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
SourceTitleYear of PublicationDOI
EmbaseThe prevalence and impact of low faecal elastase-1 in community-based patients with type 2 diabetes.2019https://dx.doi.org/10.1016/j.diabres.2019.107822
N.B. These documents automatically identified may not have been verified by the study sponsor.