Clinical trial NCT02862730: Four Way Crossover Closed Loop With Exercise Detection
Official title: A Randomized, Four-way, Cross-over Outpatient Study to Assess the Efficacy of a Dual-hormone Versus Insulin Alone Closed-loop System With Exercise Detection vs a Predictive Low Glucose Suspend System vs Current Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 1 Diabetes
Keywords: diabetes
closed-loop
dual hormone
exercise
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
First posted: 2016-08-11
Enrollment: 25
Sex: ALL
Minimum age (years): 21
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Closed-loop systems are an emerging technology that automate hormone delivery. They are quickly paving the way to revolutionize the treatment of type 1 diabetes. Several categories have emerged: dual-hormone (insulin and glucagon) closed-loop systems and closed-loop systems with insulin only, one variety of which is the low glucose suspend safety feature now available from Medtronic (MiniMed 530G with Enlite). The study described within this protocol is designed to test the efficacy of a new closed-loop algorithm for managing blood glucose in people with type 1 diabetes before and after exercise. The new algorithm will have 3 modes: a single hormone insulin only mode, a dual-hormone insulin and glucagon mode and an insulin only mode with predictive low glucose suspend, all with an exercise detection algorithm. The purpose of this study is to determine whether a dual hormone AP with an exercise detection algorithm outperforms both single hormone AP and a low glucose suspend algorithm and sensor augmented pump therapy using the subject's own insulin pump.

Detailed description: Subjects will undergo four approximately 84 hour studies. The first day of each study will be an approximately 12 hour inpatient visit to include activities of daily living and an exercise period with 2 days spent as an outpatient. The subject will come back to the research center on the fourth day to complete another approximately 12 hour inpatient visit to include activities of daily living and an exercise period followed by removal of all devices. In randomized order, subjects will have glucose controlled using the following systems: 1) dual-hormone closed-loop system, 2) insulin only closed-loop system, 3) predictive low glucose suspend system and 4) sensor augmented pump therapy with subject using their own insulin and insulin pump. Both of the closed-loop system algorithms have an exercise detection algorithm that uses inputs from a heart rate monitor and accelerometer, the Zephyrlife BioPatch. After exercise detection, insulin is turned off for the first 30 minutes, the total insulin infusion rate is adjusted by an exercise multiplier, and for the dual-hormone system, the target glucose for glucagon is increased along with the maximum dose of glucagon allowed. The predictive low glucose suspend system will utilize the patient's optimized basal rates, correction factor, and carb ratio. The patient will bolus for meals and hyperglycemia as usual under PLGS, but will have the additional safety net of the pump suspending insulin when it predicts a hypoglycemic event. The Dexcom CGM system and the Tandem t:slim pumps will be used for all three intervention visits.

Subjects will arrive at the CTRC at 7am at the start of intervention visits. Subjects will eat breakfast, lunch and dinner in the research center. Subjects will eat breakfast at 8:30am. After breakfast, subjects will complete activities of daily living (sitting on a chair, lying on a bed, washing dishes, sweeping the floor, etc.). Subjects will eat lunch at 12pm. Subjects will exercise for 45 minutes on a treadmill around 2pm. Subjects will eat dinner at 6pm and be discharged. The subject will then go home for Day 2 and Day 3 and return on Day 4 to complete another 12 hour inpatient visit with the schedule of activities identical to Day 1.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of type 1 diabetes mellitus for at least 1 year.
* Physically willing and able to perform 45 min of exercise (as determined by the investigator after reviewing the subjects activity level)
* Current use of an insulin pump.
* Lives with another person age 18 or older who will be present while subject exercises at home and that can attend the training on using the system with the subject.
* Lives within 20 miles of OHSU.
* A1C\<10%
* Willingness to follow all study procedures, including attending all clinic visits.
* Willingness to sign informed consent and HIPAA documents.

Exclusion Criteria:

* Female of childbearing potential who is pregnant or intending to become pregnant or breast-feeding, or is not using adequate contraceptive methods. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence.
* Any cardiovascular disease, defined as a clinically significant EKG abnormality at the time of screening or any history of: stroke, heart failure, myocardial infarction, angina pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd or 3rd degree heart block or any non-physiological arrhythmia judged by the investigator to be exclusionary.
* Renal insufficiency (GFR \< 60 ml/min, using the MDRD equation as report by the OHSU laboratory).
* Liver failure, cirrhosis, or any other liver disease that compromises liver function as determined by the investigator.
* Hematocrit of less than or equal to 34%.
* Hypertensive subjects with systolic blood pressure \>= 160 mmHg or diastolic blood pressure \>= 100 mmHg despite treatment or who have treatment-refractory hypertension (e.g. requiring four or more medications).
* History of severe hypoglycemia during the past 12 months prior to screening visit or hypoglycemia unawareness as judged by the investigator. Subjects will complete a hypoglycemia awareness questionnaire. Subjects will be excluded for four or more R responses.
* Adrenal insufficiency.
* Any active infection.
* Known or suspected abuse of alcohol, narcotics, or illicit drugs.
* Seizure disorder.
* Active foot ulceration.
* Severe peripheral arterial disease characterized by ischemic rest pain or severe claudication.
* Major surgical operation within 30 days prior to screening.
* Use of an investigational drug within 30 days prior to screening.
* Chronic usage of any immunosuppressive medication (such as cyclosporine, azathioprine, sirolimus, or tacrolimus).
* Bleeding disorder, treatment with warfarin, or platelet count below 50,000.
* Allergy to aspart insulin.
* Allergy to glucagon.
* Insulin resistance requiring more than 200 units per day.
* Need for uninterrupted treatment of acetaminophen.
* Current administration of oral or parenteral corticosteroids.
* Any life threatening disease, including malignant neoplasms and medical history of malignant neoplasms within the past 5 years prior to screening (except basal and squamous cell skin cancer).
* Beta blockers or non-dihydropyridine calcium channel blockers.
* Current use of any medication intended to lower glucose other than insulin (ex. use of liraglutide).
* Diagnosis of pheochromocytoma, insulinoma, or glucagonoma, personal or family history of multiple endocrine neoplasia (MEN) 2A, MEN 2B, neurofibromatosis or von Hippel-Lindau disease.
* History of severe hypersensitivity to milk protein.
* Current use of any medication with strong anticholinergic properties, such as antihistamines, sleep aids, and antidiarrheal medications.
* Current use of indomethacin.
* Conditions that may result in low levels of releasable glucose in the liver and an inadequate reversal of hypoglycemia by glucagon such as prolonged fasting, starvation or chronic hypoglycemia as determined by the investigator.
* A positive response to any of the questions from the Physical Activity Readiness Questionnaire.
* Any chest discomfort with physical activity, including pain or pressure, or other types of discomfort.
* Any clinically significant disease or disorder which in the opinion of the Investigator may jeopardize the subject's safety or compliance with the protocol.

Primary outcomes:
measure: Percent of Time With Sensed Glucose < 3.9 mmol/L
timeFrame: entire 84 hour study
measure: Percent of Time With Sensed Glucose < 3.9 mmol/L
timeFrame: From 14:00-18:00 for each 12 hour inpatient visit
measure: Percent of Time With Sensed Glucose Between 3.9-10 mmol/L
timeFrame: entire 84 hour study
measure: Percent of Time With Sensed Glucose Between 3.9-10 mmol/L
timeFrame: From 14:00-18:00 for each 12 hour inpatient visit
Secondary outcomes:
measure: Mean Sensed Glucose
timeFrame: entire 84 hour study
measure: Number of Carbohydrate Treatments
timeFrame: entire 84 hour study
measure: Percent of Time With Sensed Glucose < 3.0 mmol/L
timeFrame: entire 84 hour study
measure: Percent of Time With Sensed Glucose > 10 mmol/L
timeFrame: entire 84 hour study
measure: Number of Events With Capillary Blood Glucose < 3.9 mmol/L
timeFrame: entire 84 hour study
measure: Number of Events With Capillary Blood Glucose < 3.0 mmol/L
timeFrame: entire 84 hour study
measure: Mean Amount of Insulin Delivered
timeFrame: 24 hours
measure: Mean Amount of Glucagon Delivered
timeFrame: 24 hours
Other outcomes:
Locations:
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
Study officials:
affiliation: Oregon Health and Science University
name: Jessica Castle, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Castle JR, El Youssef J, Wilson LM, Reddy R, Resalat N, Branigan D, Ramsey K, Leitschuh J, Rajhbeharrysingh U, Senf B, Sugerman SM, Gabo V, Jacobs PG. Randomized Outpatient Trial of Single- and Dual-Hormone Closed-Loop Systems That Adapt to Exercise Using Wearable Sensors. Diabetes Care. 2018 Jul;41(7):1471-1477. doi: 10.2337/dc18-0228. Epub 2018 May 11.