Sitagliptin and the Risk for Hypoglycaemia in Type 2 Diabetes Patients

• Sponsor: Profil Institut für Stoffwechselforschung GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03359590
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 20
• Location: 1
• Arms: 2
• Actual Duration (Months): 15.9
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Sitagliptin, through its effects on sensitizing alpha-cell sensitivity to glucose, can initiate counter-regulatory glucagon responses at higher glycemic thresholds, thus reducing the number of clinically apparent hypoglycemic episodes, and/or ameliorating the severity of hypoglycemic episodes in the case that they should occur. The endpoints have defined such that consequences of this hypothesis can be measured.

Condition or Disease	Intervention/Treatment	Phase
Pharmacological Action	Drug: Sitagliptin 100 mg; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This is a postmarketing phase 2 trial. The trial is designed as single centre, randomised, double blind, two-way treatment, placebo controlled crossover trial in subjects with type 2 diabetes mellitus treated to fasting plasma glucose targets with insulin glargine and metformin.This is a postmarketing phase 2 trial. The trial is designed as single centre, randomised, double blind, two-way treatment, placebo controlled crossover trial in subjects with type 2 diabetes mellitus treated to fasting plasma glucose targets with insulin glargine and metformin.
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: This is a double-blind randomised trial. Except for the unblinded persons involved in the preparation of the IMP (these persons are not involved in any other trial activities), everyone involved in the trial will be blinded until completion of the trial and the final data review.
• Primary Purpose: Treatment
• Official Title: DPP-4 Inhibition With Sitagliptin and the Risk for Hypoglycaemia in the Fasting State in Subjects With Type 2 Diabetes Treated to Fasting Plasma Glucose Targets With Insulin Glargine and Metformin
• Actual Study Start Date: Mar 21, 2018
• Actual Primary Completion Date: Jul 17, 2019
• Actual Study Completion Date: Jul 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin arm Sitagliptin 100 mg	Drug: Sitagliptin 100 mg; The treatment consists of sitagliptin tablets (100 mg/day) for up to 24 weeks.
Placebo Comparator: Placebo arm Placebo comparator	Drug: Placebo; The treatment consists of placebo tablets for up to 24 weeks.

Outcome Measures

Primary Outcome Measures

1. The Frequency of Hypoglycaemic Episodes With Sitagliptin vs Placebo Treatment. [during the two in-house periods (54 hs each) after treatment with sitagliptin or placebo for up to 24 weeks]

   The purpose of the trial was to test the influence of DPP-4 inhibition on the risk to develop hypoglycaemia. Chemical hypoglycaemic episodes (characterised by a plasma glucose nadir ≤70 mg/dL) occurring during the in-house periods of the subjects were compared.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subject with diabetes mellitus type 2.

• Age between 18 and 64 years, both inclusive.

• HbA1c <= 8.5%.

• Stable treatment with insulin glargine (any dose) and metformin (>= 1500 mg/day or at highest tolerated dose) for at least 3 months prior to inclusion into the trial with or without additional oral glucose-lowering agents (except thiazolidinediones).

• Considered generally healthy (apart from diabetes mellitus type 2 and associated conditions such as hypertension, hyperlipidaemia and hyperuricaemia) upon completion of medical history, physical examination, vital signs, ECG and analysis of laboratory safety variables, as judged by the Investigator.

Exclusion Criteria:

• Known or suspected hypersensitivity to sitagliptin or related products.

• More than one episode of severe hypoglycaemia with seizure, coma or requiring medical assistance of another person during the past 6 months or hypoglycaemic unawareness as judged by the Investigator.

• Current or previous treatment (less than 3 months prior to screening) with insulin products other than insulin glargine and/or with Glucagon-like peptide (GLP) 1 receptor agonists and/or with thiazolidinediones.

• Unwillingness to wash-off any oral glucose-lowering agents other than metformin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Profil Institut für Stoffwechselforschung GmbH	Neuss		Germany

Sponsors and Collaborators

• Profil Institut für Stoffwechselforschung GmbH
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Christoph Kapitza, MD, Profil GmbH

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 22, 2018

More Information

Publications

None provided.

• Responsible Party: Profil Institut für Stoffwechselforschung GmbH
• ClinicalTrials.gov Identifier: NCT03359590
• Other Study ID Numbers: DPP4-Hypo
• First Posted: Dec 2, 2017
• Last Update Posted: Feb 21, 2021
• Last Verified: Feb 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hypoglycemia; Sitagliptin Phosphate

Study Results

Participant Flow

Recruitment Details	Subjects were recruited by use of the site specific database
Pre-assignment Detail	All subjects underwent outpatient insulin titration during each treatment period. The aim was to find the insulin dose that, under these conditions, stabilised individual fasting plasma glucose for at least one week

Arm/Group Title	Sequence 1	Sequence 2
Arm/Group Description	First intervention: treatment with sitagliptin tablets (100 mg/day) for up to 24 weeks. Washout 4 weeks Second intervention: treatment with placebo tablets for up to 24 weeks.	First intervention: treatment with placebo tablets for up to 24 weeks. Washout 4 weeks Second intervention: treatment with sitagliptin tablets (100 mg/day) for up to 24 weeks.
Period Title: First Intervention
STARTED	10	10
Exposed	9	10
Discontinued	1	2
COMPLETED	9	8
NOT COMPLETED	1	2
Period Title: First Intervention
STARTED	9	8
Exposed	9	8
Discontinued	0	0
COMPLETED	9	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Drug: Sitagliptin or placebo The treatment consists of sitagliptin 100 mg/day or placebo for up to 24 weeks.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	5 25%
Male	15 75%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Germany	20 100%
Body mass index (BMI, kg/m2) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.19 (4.139)
Waist circumference (cm) (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	105.9 (9.02)
Height (cm) (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	178.1 (9.20)
Weight (kg) (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	92.32 (13.79)
HbA1c (%) (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	7.35 (0.661)

Outcome Measures

1. Primary Outcome

Title	The Frequency of Hypoglycaemic Episodes With Sitagliptin vs Placebo Treatment.
Description	The purpose of the trial was to test the influence of DPP-4 inhibition on the risk to develop hypoglycaemia. Chemical hypoglycaemic episodes (characterised by a plasma glucose nadir ≤70 mg/dL) occurring during the in-house periods of the subjects were compared.
Time Frame	during the two in-house periods (54 hs each) after treatment with sitagliptin or placebo for up to 24 weeks

Outcome Measure Data

Analysis Population Description

The per protocol analysis set comprised all subjects completing the trial.

Arm/Group Title	Sitagliptin Arm	Placebo Arm
Arm/Group Description	Drug: Sitagliptin The treatment consists of sitagliptin 100 mg/day up to a maximum of 24 weeks.	Drug: Placebo The treatment consists of placebo up to a maximum of 24 weeks.
Measure Participants	17	18
Mean (Standard Deviation) [Hypoglycaemic episodes]	5.35 (4.137)	5.72 (3.045)

Adverse Events

Time Frame	For each participant from baseline to end of trial, with a range from 7-53 weeks per participant, on average 11 weeks
Adverse Event Reporting Description	In this report, only treatment-emergent adverse events (TEAEs) are reported, occurring after randomisation. No AEs were reported for the washout period.
Arm/Group Title	Sitagliptin Arm		Placebo Arm
Arm/Group Description	Drug: Sitagliptin The treatment consists of sitagliptin 100 mg/day up to a maximum of 24 weeks.		Drug: Placebo The treatment consists of placebo up to a maximum of 24 weeks.
All Cause Mortality
	Sitagliptin Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/19 (0%)
Serious Adverse Events
	Sitagliptin Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		1/19 (5.3%)
Cardiac disorders
Coronary heart diesease	0/17 (0%)	0	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Sitagliptin Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/17 (70.6%)		11/19 (57.9%)
Cardiac disorders
Cardiovascular disorder	0/17 (0%)	0	1/19 (5.3%)	1
Coronary artery disease	0/17 (0%)	0	1/19 (5.3%)	1
Tachyarrhythmia	1/17 (5.9%)	1	0/19 (0%)	0
Ventricular extrasystoles	0/17 (0%)	0	1/19 (5.3%)	1
Ear and labyrinth disorders
Ear discomfort	0/17 (0%)	0	1/19 (5.3%)	1
Gastrointestinal disorders
Diarrhoea	1/17 (5.9%)	1	4/19 (21.1%)	4
Nausea	3/17 (17.6%)	3	1/19 (5.3%)	1
Vomiting	2/17 (11.8%)	3	2/19 (10.5%)	2
Injury, poisoning and procedural complications
Arthropod bite	2/17 (11.8%)	2	1/19 (5.3%)	1
Decapitation	0/17 (0%)	0	1/19 (5.3%)	1
Infusion site thrombosis	1/17 (5.9%)	1	0/19 (0%)	0
Traumatic amputation	1/17 (5.9%)	1	0/19 (0%)	0
Investigations
Electrocardiogram ST segment depression	0/17 (0%)	0	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/17 (5.9%)	1	2/19 (10.5%)	2
Back pain	0/17 (0%)	0	1/19 (5.3%)	1
Fibromyalgia	0/17 (0%)	0	1/19 (5.3%)	1
Intervertebral disc displacement	0/17 (0%)	0	1/19 (5.3%)	1
Muscle contractions involuntary	1/17 (5.9%)	1	0/19 (0%)	0
Nervous system disorders
Allodynia	1/17 (5.9%)	1	0/19 (0%)	0
Dizziness	1/17 (5.9%)	1	1/19 (5.3%)	4
Headache	6/17 (35.3%)	6	3/19 (15.8%)	3
Psychiatric disorders
Sleep disorder	0/17 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/17 (0%)	0	1/19 (5.3%)	1
Nasopharyngitis	1/17 (5.9%)	1	1/19 (5.3%)	1
Rhinitis	0/17 (0%)	0	1/19 (5.3%)	1
Vascular disorders
Orthostatic intolerance	1/17 (5.9%)	1	0/19 (0%)	0
Syncope	0/17 (0%)	0	1/19 (5.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.