Closed-loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL)

Closed-loop Insulin Delivery in Pregnant Women With Type 1 Diabetes: a Randomized Controlled Trial: the CRISTAL Study

Multi-centric open-label randomized controlled trial (RCT) with 11 Belgian centers and one Dutch center in pregnant women with type 1 diabetes to assess safety, efficacy, feasibility and cost-effectiveness of 780 MiniMed Medtronic hybrid closed-loop insulin system (intervention group) compared to standard of care therapy (control group).

Study Overview

• Status: Completed
• Conditions: Type1 Diabetes
• Intervention / Treatment: Device: 780G; Device: standard of care

Detailed Description

Women will be recruited with a singleton pregnancy up to 12 weeks gestation. Participants will be randomized 1/1 to 780 pump or standard of care (continue with current treatment of insulin pump without closed-loop or multiple daily insulin injections). Participants will be stratified according to study center, baseline Hba1c, and method of insulin delivery (pump or injections). Participants will be followed-up till delivery. To account for differences in the type of continuous glucose monitoring (CGM) used between the intervention group and the control group, the same CGM system as in the 780 insulin pump group (Guardian™ Sensor 3 and once available the Guardian 4 sensor) will be used in a blinded manner in the control group to collect CGM data during at least four different time points in pregnancy: at 14-17 weeks, 20-23 weeks, 26-29 weeks and 33-36 weeks.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, 2820
    • Imelda Bonheiden
  • Brugge, Belgium, 8000
    • AZ St Jan Brugge
  • Brussel, Belgium, 1090
    • UZ Brussel
  • Brussels, Belgium
    • UCLouvain
  • Gent, Belgium, 9000
    • UZ Gent
  • Kortrijk, Belgium, 8510
    • AZ Groeninge Kortrijk
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Roeselare, Belgium, 8800
    • AZ Roeselare
  • Sint-Niklaas, Belgium, 9100
    • AZ Nikolaas
  • Turnhout, Belgium
    • Az Turnhout
  • Oost-Vlaanderen
    • Aalst, Oost-Vlaanderen, Belgium, 9300
      • OLV Aalst-Asse
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women with type 1 diabetes (T1DM), diagnosed with T1DM at least 1 year before pregnancy
• Age 18-45 years
• A singleton pregnancy confirmed by b-HCG in blood and/or ultrasound-confirmed gestational age up to 11 weeks and 6 days.
• Treated with intensive insulin treatment (either MDI or insulin pump). A closed-loop system can only be used in manual mode.
• Have a booking HbA1c (measurement taken at the first antenatal clinic visit after confirmed pregnancy) level ≤10%.
• Participants need to speak and understand Flemish, French or English and have e-mail access.

Exclusion Criteria:

• The use of a closed-loop insulin delivery system in auto mode.
• A twin (multiple) pregnancy
• A physical or psychological disease likely to interfere with the conduct of the study (based on the evaluation by the treating physician)
• Medications known to interfere with glucose metabolism
• An insulin dose of ≥1.5 units/kg
• Known allergy to adhesives due to infusion set and/or CGM

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 780G closed-loop; 780 closed-loop insulin delivery system	Device: 780G; 780G closed-loop insulin delivery system (Medtronic)
Active Comparator: standard of care; standard of care treatment (continue with current treatment of insulin pump without closed-loop or multiple daily insulin injections).	Device: standard of care; continue with standard of care treatment (pump without closed-loop or MDI)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time in range	time between 63-140mg/dl (pregnancy glycemic target range)	from 14 weeks to 36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time in range during the night	time in range (63-140mg/dl) from midnight till 6am	from 14 weeks to 36 weeks
time below low day and night	time <63mg/dl day and night	from 14 weeks to 36 weeks
overnight time low	time <63mg/dl from midnight till 6am	from 14 weeks to 36 weeks
time in range during the day	time in range (63-140mg/dl) during the day	from 14 weeks to 36 weeks
time in range early pregnancy	time in range (63-140mg/dl) 9-12 weeks	from 9 weeks to 12 weeks
time in range during each trimester	time in range (63-140mg/dl) during each trimester	from 9 weeks to 36 weeks
HbA1c during each trimester	HbA1c (% and mmol/mol) during each trimester	from 9 weeks to 36 weeks
mean glucose	mean glucose based on CGM	from 14 weeks to 36 weeks
time above target (140mg/dl)	time >140mg/dl	from 14 weeks to 36 weeks
time above target (180mg/dl)	time >180mg/dl	from 14 weeks to 36 weeks
time below target (50mg/dl)	time <50mg/dl	from 14 weeks to 36 weeks
time below target (54mg/dl)	time <54mg/dl	from 14 weeks to 36 weeks
duration of hypoglycemia	low blood glucose index	from 14 weeks to 36 weeks
time in nonpregnant target range	time 70-180mg/dl	from 14 weeks to 36 weeks
CGM compliance	% of time use of CGM	from 14 weeks to 36 weeks
insulin dose	total insulin dose	from 14 weeks to 36 weeks
glycemic variability	standard deviation glucose values based on CGM	from 14 weeks to 36 weeks
variation glucose values	coefficient of variation based on CGM	from 14 weeks to 36 weeks
nocturnal hypoglycemia	glucose <50mg/dl from 23-07hour	from 9 weeks to 36 weeks
severe hypoglycemia	hypoglycemia requiring third-part assistance	from 9 weeks to 36 weeks
rate of diabetic keto-acidosis	metabolic keto-acidosis with decreased ph and/or decreased bicarbonate in blood	from 9 weeks to 36 weeks
gestational duration	duration of pregnancy (weeks)	delivery
duration hospitalization delivery	length of hospital stay (days)	delivery
type of labor	spontaneous, induced or cesarean section before labor	delivery
type of delivery	vaginal, forceps or vacuum, cesarean section during labor or planned cesarean section	delivery
rate of preterm delivery	delivery <37 weeks	delivery
rate of preeclampsia	onset of new hypertension and proteinuria and/or end-organ dysfunction after 20 weeks of gestation	from 20 weeks to delivery
rate of eclampsia	generalized convulsions and/or coma	from 20 weeks to delivery
rate of HELLP syndrome	hemolysis, elevated liver enzymes and a low platelet count	from 20 weeks to delivery
rate of fetal malformation	congenital malformation	up to 24 weeks
rate of miscarriage	fetal loss <20 weeks gestations	<20 weeks
rate of termination of pregnancy	induced abortion	up to 24 weeks
rate of stillbirth	mors in utero >20 weeks	>20 weeks
rate of neonatal death	death <1 months after delivery	1 month after delivery
sex of infant	boy or girl	delivery
birth weight	birth weight (Kg and g)	delivery
rate of shoulder dystocia	one or both of a baby's shoulders get stuck inside the mother's pelvis during labor.	delivery
rate of birth trauma	fracture, damage to nerves...	delivery
rate of respiratory distress	respiratory failure or distress	delivery
rate of hyperbilirubinaemia	hyperbilirubinaemia with need of treatment with phototherapy	delivery
rate of SGA infant (small for gestational age)	gestational age adjusted birth weight <10th percentile according to the standardized Flemish birth charts adjusted for parity and sex	delivery
number with very large gestational age infants	gestational age adjusted birth weight >97th percentile according to the standardized Flemish birth charts adjusted for parity and sex	delivery
cord blood ph	cord blood gas ph	delivery
rate of neonatal hypoglycemia	neonatal hypoglycemia requiring intravenous dextrose	up to 5 days after delivery
rate of NICU admission	Neonatal intensive care unit (NICU) admission defined as requiring a duration of at least 24 h	up to 30 days after delivery
duration NICU admission	duration of NICU admission (days or weeks)	up to 30 days after delivery
rate of fetal hyperinsulinemia	cord blood c-peptide	delivery
skinfolds newborn	sum of skinfolds (triceps, scapula and flank)	up to 3 days after delivery
MAGE (mean amplitude of glycemic excursions)	mean amplitude of glucose variations based on CGM	from 14 weeks to 36 weeks
rate of gestational hypertension	blood pressure of 140/90 mmHg or higher starting after 20 weeks of gestation	from 20 weeks to delivery
rate of worsening of chronic hypertension	blood pressure of 140/90 mmHg or higher start is present before 20 weeks of gestation	from 9 weeks to delivery
rate of IUGR (intra-uterine growth restriction)	intra-uterine growth restriction	from 20 weeks to delivery
rate of macrosomia	birth weight >4 Kg	delivery
rate with high birth weight	birth weight >4.5 Kg	delivery
rate of LGA infant (large for gestational age)	gestational age adjusted birth weight >90th percentile according to the standardized Flemish birth charts adjusted for parity and sex	delivery
neonatal fat mass	fat mass calculated by the formula of Catalano et al.	up to 3 days after delivery
number with composite neonatal outcome	pregnancy loss (miscarriage, still birth or neonatal death), LGA (large for gestational age), respiratory distress syndrome, birth trauma, shoulder dystocia, neonatal hypoglycemia and NICU admission	delivery

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: University Hospital, Ghent; Universitair Ziekenhuis Brussel; University Hospital, Antwerp; Imelda Hospital, Bonheiden; AZ Sint-Jan AV; AZ Delta; Onze Lieve Vrouw Hospital; General Hospital Groeninge; AZ Nikolaas; AZ Turnhout; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Amsterdam UMC
• Investigators: Principal Investigator: Katrien Benhalima, MD PhD, UZ Leuven

Publications and helpful links

General Publications

• Beunen K, Van Wilder N, Ballaux D, Vanhaverbeke G, Taes Y, Aers XP, Nobels F, Marlier J, Lee D, Cuypers J, Preumont V, Siegelaar SE, Painter RC, Laenen A, Gillard P, Mathieu C, Benhalima K. Closed-loop insulin delivery in pregnant women with type 1 diabetes (CRISTAL): a multicentre randomized controlled trial - study protocol. BMC Pregnancy Childbirth. 2023 Mar 16;23(1):180. doi: 10.1186/s12884-023-05481-0.
• Benhalima K, Beunen K, Van Wilder N, Ballaux D, Vanhaverbeke G, Taes Y, Aers XP, Nobels F, Marlier J, Lee D, Cuypers J, Preumont V, Siegelaar SE, Painter RC, Laenen A, Gillard P, Mathieu C. Comparing advanced hybrid closed loop therapy and standard insulin therapy in pregnant women with type 1 diabetes (CRISTAL): a parallel-group, open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2024 Jun;12(6):390-403. doi: 10.1016/S2213-8587(24)00089-5. Epub 2024 Apr 30.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2021
• Primary Completion (Actual): April 30, 2023
• Study Completion (Actual): May 10, 2023

Study Registration Dates

• First Submitted: August 12, 2020
• First Submitted That Met QC Criteria: August 19, 2020
• First Posted (Actual): August 20, 2020

Study Record Updates

• Last Update Posted (Estimated): December 10, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: closed-loop insulin delivery
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: S64308

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No