Treatment of Post-bariatric Hypoglycaemia (SHERRY)

Ready-to-use Dasiglucagon for the Treatment of Postprandial Hypoglycaemia in Roux-en-Y Gastric Bypass Operated Patients

This is an investigator-initiated, proof-of-concept, randomised, double-blind, placebo-controlled, single-centre phase II study aiming to evaluate the efficacy, safety and tolerability of self-administered subcutaneous 120 µg dasiglucagon with an investigational trial device (i.e. a multi-dose reusable pen) for the treatment of postprandial hypoglycaemia after Roux-en-Y gastric bypass (RYGB) surgery. The study is divided into an in-patient and out-patient part.

The primary aim of the study is to compare the effects of self-administered 120 µg dasiglucagon versus placebo on continuous glucose monitoring (CGM)-assessed time spent in hypoglycaemia in RYGB-operated individuals in an out-patient setting.

Study Overview

• Status: Active, not recruiting
• Conditions: Hyperinsulinemic Hypoglycemia; Postprandial Hypoglycemia
• Intervention / Treatment: Drug: Dasiglucagon; Device: HyoPen; Drug: Placebo

Detailed Description

Study design:

Before inclusion in the study, the participants will complete a screening visit and a blinded 14-day continuous glucose monitoring (CGM) run-in period to ascertain a regular occurrence of postprandial hypoglycaemia (IG <3.9 mmol/l, ≥3 times/week). After enrolment in the study, the participants will wear a CGM for the entirety of the study period (apart from the four weeks before the follow-up visit). Prior to the first mixed meal test (MMT) during the in-patient part, the subjects will be randomised into one of four double-blinded treatment sequences consisting of an in-patient part (two MMTs) follow by a nine weeks out-patient part (two times four weeks per out-patient part with an interposed washout period of one week) and ended with a follow-up visit four weeks after out-patient part completion.

During the in-patient part, the participants will undergo two separate MMTs, with a minimum of 7 days in-between, accompanied by one of the following double-blind, randomised, placebo-controlled crossover interventions:

1. Subcutaneous placebo self-administration
2. Subcutaneous 120 µg dasiglucagon self-administration

The out-patient part is divided into two double-blinded, randomised, placebo-controlled crossover out-patient parts with of the following interventions:

1. Subcutaneous placebo self-administration
2. Subcutaneous 120 µg dasiglucagon self-administration

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Center for Clinical Metabolic Research, Herlev-Gentofte Hospital

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:

• Documented postprandial hypoglycaemia (IG <3.9 mmol/l, ≥3 times/week) assessed by 14-days of blinded CGM recording
• Haemoglobin levels for women >7.3 mmol/l and for men >8.3 mmol/l
• Ferritin >10 μg/l
• Cobalamin >150 pmol/l
• Fasting plasma glucose concentration within the range of 4.0-6.0 mmol/l
• Normal electrocardiogram (ECG)
• Negative urine human chorionic gonadotropin (hCG) (for fertile women)

Exclusion Criteria:

• Treatment with medication(s) affecting insulin secretion, glucose metabolism or any antidiabetic drugs
• Treatment with antipsychotics
• Current participation in another clinical trial with administration of investigational drug
• Previous exposure to dasiglucagon (also known as ZP4207) within the last 30 days prior screening
• History of liver disease that is expected to interfere with the anti-hypoglycaemic action of glucagon (e.g. liver failure or cirrhosis)
• Pregnancy
• Breastfeeding
• Major surgery within 30 days before screening
• Alcohol abuse (per investigator assessment)
• Any factors that, in the opinion of the site principal investigator or clinical protocol chair, would interfere with the safe completion of the study, including medical conditions that may require hospitalization during the trial
• History of pheochromocytoma or insulinoma
• History of hypersensitivity or allergic reaction to dasiglucagon or any of the excipients
• Known or suspected allergies to glucagon or related products

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 120 µg dasiglucagon; Subcutaneous 120 µg dasiglucagon self-administration	Drug: Dasiglucagon; Abdominal s.c. self-administration 120 µg of dasiglucagon when blood glucose levels are below 3.9 mmol/L or interstitial glucose levels below 3.5 mmol/L. The frequency of the intervention is approximately once a day.; Other Names: ZP4207; Device: HyoPen; multi-dose reusable pen injector; Other Names: Zealand Pen
Placebo Comparator: Placebo; Subcutaneous placebo self-administration	Device: HyoPen; multi-dose reusable pen injector; Other Names: Zealand Pen; Drug: Placebo; Abdominal s.c. self-administration with placebo when blood glucose levels are below 3.9 mmol/L or interstitial glucose levels below 3.5 mmol/L. The frequency of the intervention is approximately once a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time spent in hypoglycaemia (IG < 3.9 mmol)	The primary endpoint is the percentage of time in hypoglycaemia (IG <3.9 mmol/l) assessed by CGM during the out-patient part.	During the four weeks of placebo and dasiglucagon treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time (percent or minutes) spent in serious hypoglycaemia (IG <3.0 mmol/l)		During the four weeks of placebo and dasiglucagon treatment.
Frequency of hypoglycaemic events (IG <3.9 mmol/l and <3.0 mmol/l, respectively)		During the four weeks of placebo and dasiglucagon treatment.
Glycaemic time in range defined as: 1) hypoglycaemia (<3.9 mmol/l), 2) normoglycaemia (3.9-10.0 mmol/l), and 3) hyperglycaemia (>10.0 mmol/l)		During the four weeks of placebo and dasiglucagon treatment.
Frequency of hyperglycaemic events (IG >7.8 mmol/l and >10.0 mmol/l, respectively)		During the four weeks of placebo and dasiglucagon treatment.
Glycaemic variability assessed as coefficient of variance (CV)		During the four weeks of placebo and dasiglucagon treatment.
Glycaemic variability assessed as standard deviation (SD)		During the four weeks of placebo and dasiglucagon treatment.
Recovery of BG 15 minutes after trial drug administration (as measured by finger prick (BG >3.9 mmol/l))		During the four weeks of placebo and dasiglucagon treatment.
Change in QoL as assessed by the World Health Organization's quality of life assessment (WHOQOL-BREF)	likert scale, zero (very poor) to five (very good)	During the four weeks of placebo and dasiglucagon treatment.
Change in hypoglycaemic symptoms will be evaluated by Edinburgh Hypoglycaemia Symptom Scale (EHSS)	likert scale, zero (not a all) to seven (a lot)	During the four weeks of placebo and dasiglucagon treatment.
Change in fear of hypoglycaemia as assessed by Hypoglycaemia Fear Scale (HFS-II)	likert scale, zero (never) to four (always)	During the four weeks of placebo and dasiglucagon treatment.
Change in administration frequency (as measured by percentage)		During the four weeks of placebo and dasiglucagon treatment.
Nadir plasma glucose as assessed both as 1) absolute lowest value, and 2) a mean of three consecutive glucose measurements during the 240-minute MMT	Nadir plasma glucose after the postprandial peak during the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Recovery of BG 15 minutes after administration (as measured by finger prick (BG >3.9 mmol/l))	After the postprandial peak during the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Time spent in level 1 and level 2 hypoglycaemia (<3.9 and <3.0 mmol/l, respectively) from study drug administration until 240 minutes	After the postprandial peak during the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Glycaemic rescue intervention due to critically low plasma glucose concentration (<1.8 mmol/l)	During the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Time spent in hyperglycaemia (>7.8 mmol/l) from study drug administration until 240 minutes	During the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Peak plasma glucose concentration after study drug administration	During the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Counter-regulatory hormonal response	Measured as area under the curve (AUC) and / or incremental (iAUC) as appropriate, peak values and values at nadir plasma glucose concentration during the MMT in the in-patient part. glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP)	Two hundred forty minutes of mixed meal test
Changes in blood pressure	During the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Changes in heart rate	During the MMT in the in-patient part	Two hundred forty minutes of mixed meal test
Frequency and severity of adverse events (AE)s and serious adverse events (SAE)s from signed consent form to end of study (visit 4 / follow-up visit)	Safety endpoint	Through study completion which is an average of 16 weeks
Frequency and severity of adverse events (AE)s and serious adverse events (SAE)s during the in-patient part MMTs	Safety endpoint	During the in-patient part (MMTs) 0-240 minutes / Two hundred forty minutes of mixed meal test
Percentage (%) of participants with treatment-induced or treatment-boosted anti-dasiglucagon antibodies who did not have anti-dasiglucagon antibodies at baseline	Safety endpoint	Through study completion which is an average of 16 weeks
Device failures/ malfunctions occurring during the trial.	Device endpoint	Through study completion which is an average of 16 weeks

Collaborators and Investigators

• Sponsor: Filip Krag Knop
• Collaborators: Zealand Pharma
• Investigators: Principal Investigator: Filip K Knop, MD, PhD, Center for Clinical Metabolic Research at Gentofte Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2021
• Primary Completion (Actual): May 15, 2022
• Study Completion (Anticipated): December 15, 2022

Study Registration Dates

• First Submitted: March 26, 2021
• First Submitted That Met QC Criteria: April 6, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): November 2, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Infant, Newborn, Diseases; Hyperinsulinism; Pancreatic Diseases; Hypoglycemia; Congenital Hyperinsulinism; Nesidioblastosis
• Other Study ID Numbers: CKN-DASI120-RYGB; 2020-005241-16 (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
• product manufactured in and exported from the U.S.: No