Blood Glucose Response After Oral Intake of Lactulose in Mildly Constipated Patients With Diabetes Mellitus Type 2

Blood Glucose Response After Oral Intake of Lactulose (Laevolac®) in Mildly Constipated Patients With Diabetes Mellitus Type 2

The objective of the study is to investigate whether lactulose, given orally as powder or liquid, increases blood glucose levels in patients with diabetes mellitus type 2. The dose of lactulose given in the study is normally used for treatment of constipation.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Lactulose crystals 20 g; Drug: Lactulose crystals 30 g; Drug: Lactulose liquid 20 g; Drug: Lactulose liquid 30 g; Drug: Glucose; Drug: Still water

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, A-8036
    • Clinical Research Center (CRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with non-insulin requiring diabetes mellitus type 2 treated with diet and oral antidiabetics and/or Glucagon-like Peptide 1 receptor agonists
2. Age: 18-75 years
3. Female and male
4. Caucasian
5. HbA1c ≤ 7.5 %
6. Stable treatment, i.e. no change in diabetes mellitus related medication within the last 3 months

7. Mild functional constipation according to modified Rome IV criteria fulfilled for the last 3 months with symptom onset at least 6 months before study start defined as:

   • approx. 3-5 bowel movements per week,
   • of which 1-2 usually cause discomfort e.g., straining, lumpy or hard stools, sensation of incomplete evacuation or anorectal obstructions/blockage
8. Availability and presence in the trial unit for approx. 4 hours/ week for 4 weeks
9. Women of childbearing potential must be using a medically approved method of contraception OR women must be postmenopausal for at least 12 months prior to study entry
10. Signed informed consent form

Exclusion Criteria:

1. Fasting blood glucose <4.4 mmol/L (<80 mg/dL) or >10 mmol/L (>180 mg/dL) (capillary)
2. BMI <18.5 kg/m² or ≥35 kg/m²
3. Change in body weight ≥10 % within the last 3 months
4. Smoker
5. Major medical or surgical event requiring hospitalization within the last 3 months
6. Acute gastrointestinal diseases including diarrhea and/or vomiting within the last 2 weeks
7. Presence of disease or intake of drug(s) / supplements other than antidiabetic treatment influencing digestion and absorption of carbohydrates or bowel habits (intake of laxatives in general allowed with exception see next criterion) (dietary / supplementary fibres allowed if stable dose since 1 month before study start)
8. Not willing to abstain from laxatives 2 days before the visits 1-4 and up to 24h after visits 1-4

9. Use of following medication/ supplementation within the last 4 weeks and during the study:

   • Intake of medications other than antidiabetic treatment known to affect glucose tolerance e.g., steroids, protease inhibitors or antipsychotics;
   • Intake of prebiotics or probiotics
   • Chronic intake of substances affecting blood coagulation (e.g. acetylic acid (100 mg as standard prophylactic treatment allowed when dose is stable 1 month prior to screening), anticoagulants, diuretics, thiazides (diuretics and thiazides allowed e.g. for hypertension treatment when dose is stable 1 month prior to screening)), which in the investigator's opinion would impact patient safety
10. Severe liver, renal or cardiac disease
11. Hereditary problems of galactose or fructose intolerance, lactase deficiency or glucose-galactose malabsorption
12. Suspicion of alcohol abuse (defined as an average daily intake of more than one litre of beer per day or equivalent amount of alcohol in other beverages) or drug abuse
13. Known or suspected allergy to the investigational drug(s) or other components of the study drug(s)
14. Acute inflammatory bowel disease (ulcerative colitis, Crohn's disease), gastrointestinal obstruction or subocclusive syndrome, perforations or risk of perforation in gastrointestinal tract, abdominal pain of undetermined cause
15. Known history of human immunodeficiency virus (HIV), hepatitis B and/or C
16. Pregnancy, lactation
17. Clinically relevant findings as established by medical history, physical examination, clinical laboratory and/or vital signs
18. Participation in another interventional study with an investigational drug or an investigational medical device within 30 days prior to start of study or during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Laevolac crystals 20 g; Lactulose crystals, oral intake, 20 g single dose	Drug: Lactulose crystals 20 g; White or almost white crystalline powder. The product will be provided in sachets to be dissolved in 250 mL water.; Other Names: Laevolac crystals 20 g
Experimental: Laevolac crystals 30 g; Lactulose crystals, oral intake, 30 g single dose	Drug: Lactulose crystals 30 g; White or almost white crystalline powder. The products will be provided in sachets to be dissolved in 250 mL water.; Other Names: Laevolac crystals 30 g
Experimental: Laevolac liquid 20 g; Lactulose liquid, oral intake, 20 g single dose	Drug: Lactulose liquid 20 g; Clear, viscous liquid, colourless or pale brownish-yellow liquid syrup (solution). The products will be provided in sachets to be dissolved in 250 mL water.; Other Names: Laevolac liquid 20 g
Experimental: Laevolac liquid 30 g; Lactulose liquid, oral intake, 30 g single dose	Drug: Lactulose liquid 30 g; Clear, viscous liquid, colourless or pale brownish-yellow liquid syrup (solution). The products will be provided in sachets to be dissolved in 250 mL water.; Other Names: Laevolac liquid 30 g
Active Comparator: Glucose 30 g; Glucose Monohydrate, oral intake, 33 g single dose	Drug: Glucose; White crystalline powder. To standardise for 30 g glucose, 33 g glucose monohydrate will be used. The products will be provided in sachets to be dissolved in 250 mL water.; Other Names: Glucose Monohydrate
Placebo Comparator: Water; Still water, oral intake, 250 mL single dose	Drug: Still water; 250 mL still water will be used. Water from the same source will be also used to dissolve investigational and control products; Other Names: Water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Capillary blood glucose levels as baseline corrected AUC: AUCbaseline_c (0-180 minutes) [Baseline corrected area under curve from 0 to 180 minutes for blood glucose concentration (= Area under curve from 0 to 180 minutes minus baseline*180 minutes)]	0 - 180 minutes, during 4 study visits

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum blood glucose concentration (Cmax)	0 - 180 minutes, during 4 study visits
Maximum increase of blood glucose concentration (Max_increase)	0 - 180 minutes, during 4 study visits
Relative maximum increase of blood glucose concentration (Max_increase_rel)	0 - 180 minutes, during 4 study visits
Time to reach maximum blood glucose concentration (Tmax)	0 - 180 minutes, during 4 study visits
Total area under curve from 0 to 180 minutes for blood glucose concentration (AUC(0-180 minutes))	0 - 180 minutes, during 4 study visits
Incremental area under curve from 0 to 180 minutes for blood glucose concentration, i.e., above baseline levels for blood glucose concentration after oral intake of Laevolac crystals/liquid or control products (iAUC(0-180min))	0 - 180 minutes, during 4 study visits

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs)	Adverse Events will be documented from start of fasting on the day before Screening until the day after the last study Intervention. This is up to 64 days, depending on the day of Screening (21 to 3 days before the first study Intervention) and on the duration of wash out phases between interventions.	up to 64 days
Gastrointestinal tolerability: global scaled evaluation	Gastrointestinal tolerability will be assessed by the patients by means of a global scaled evaluation with "Very good", "Good", "Moderate", or "Poor".	180 minutes and 24 hours post-dose
Gastrointestinal tolerability: diarrhoea, distension, rumbling, nausea, vomiting, burping, regurgitation/heartburn, flatulence, abdominal discomfort, abdominal pain	The single gastrointestinal symptoms will be assessed by the patients using a 4-point Likert scale: "No symptoms or discomfort", "Mild symptoms or discomfort", "Moderate symptoms of discomfort", or "Severe symptoms of discomfort".	180 minutes and 24 hours post-dose
Blood glucose concentration at 240 minutes - only when blood glucose is >10 mmol/L (>180 mg/dL) at 180 minutes		240 minutes post-dose

Collaborators and Investigators

• Sponsor: Fresenius Kabi
• Investigators: Principal Investigator: Thomas Pieber, Prof. MD, Head and Chair of Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University, Graz, Austria

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2018
• Primary Completion (Actual): March 5, 2019
• Study Completion (Actual): March 8, 2019

Study Registration Dates

• First Submitted: August 23, 2018
• First Submitted That Met QC Criteria: September 10, 2018
• First Posted (Actual): September 12, 2018

Study Record Updates

• Last Update Posted (Actual): April 12, 2019
• Last Update Submitted That Met QC Criteria: April 11, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Constipation; Diabetes Mellitus, Type 2; Blood glucose; Oral intake; Lactulose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Sympathomimetics; Adrenergic Uptake Inhibitors; Lactulose; Methamphetamine
• Other Study ID Numbers: Lact-004-CP4; 2018-002359-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No