Clinical trial NCT04836273: Treatment of Post-bariatric Hypoglycaemia
Official title: Ready-to-use Dasiglucagon for the Treatment of Postprandial Hypoglycaemia in Roux-en-Y Gastric Bypass Operated Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperinsulinemic Hypoglycemia
Postprandial Hypoglycemia
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
Collaborators: name: Zealand Pharma
First posted: 2021-04-08
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 4 weeks x 4 weeks with an interposed washout period of 1 week
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Time spent in hypoglycaemia (IG < 3.9 mmol)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
Secondary outcomes:
measure: Time (percent or minutes) spent in serious hypoglycaemia (IG <3.0 mmol/l)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Frequency of hypoglycaemic events (IG <3.9 mmol/l and <3.0 mmol/l, respectively)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: 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)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Frequency of hyperglycaemic events (IG >7.8 mmol/l and >10.0 mmol/l, respectively)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Glycaemic variability assessed as coefficient of variance (CV)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Glycaemic variability assessed as standard deviation (SD)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Recovery of BG 15 minutes after trial drug administration (as measured by finger prick (BG >3.9 mmol/l))
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Change in QoL as assessed by the World Health Organization's quality of life assessment (WHOQOL-BREF)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Change in hypoglycaemic symptoms will be evaluated by Edinburgh Hypoglycaemia Symptom Scale (EHSS)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Change in fear of hypoglycaemia as assessed by Hypoglycaemia Fear Scale (HFS-II)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: Change in administration frequency (as measured by percentage)
timeFrame: During the four weeks of placebo and dasiglucagon treatment.
measure: 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
timeFrame: Two hundred forty minutes of mixed meal test
measure: Recovery of BG 15 minutes after administration (as measured by finger prick (BG >3.9 mmol/l))
timeFrame: Two hundred forty minutes of mixed meal test
measure: Time spent in level 1 and level 2 hypoglycaemia (<3.9 and <3.0 mmol/l, respectively) from study drug administration until 240 minutes
timeFrame: Two hundred forty minutes of mixed meal test
measure: Glycaemic rescue intervention due to critically low plasma glucose concentration (<1.8 mmol/l)
timeFrame: Two hundred forty minutes of mixed meal test
measure: Time spent in hyperglycaemia (>7.8 mmol/l) from study drug administration until 240 minutes
timeFrame: Two hundred forty minutes of mixed meal test
measure: Peak plasma glucose concentration after study drug administration
timeFrame: Two hundred forty minutes of mixed meal test
measure: Counter-regulatory hormonal response
timeFrame: Two hundred forty minutes of mixed meal test
measure: Changes in blood pressure
timeFrame: Two hundred forty minutes of mixed meal test
measure: Changes in heart rate
timeFrame: Two hundred forty minutes of mixed meal test
measure: 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)
timeFrame: Through study completion which is an average of 16 weeks
measure: Frequency and severity of adverse events (AE)s and serious adverse events (SAE)s during the in-patient part MMTs
timeFrame: During the in-patient part (MMTs) 0-240 minutes / Two hundred forty minutes of mixed meal test
measure: Percentage (%) of participants with treatment-induced or treatment-boosted anti-dasiglucagon antibodies who did not have anti-dasiglucagon antibodies at baseline
timeFrame: Through study completion which is an average of 16 weeks
measure: Device failures/ malfunctions occurring during the trial.
timeFrame: Through study completion which is an average of 16 weeks
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Center for Clinical Metabolic Research, Herlev-Gentofte Hospital
Study officials:
affiliation: Center for Clinical Metabolic Research at Gentofte Hospital
name: Filip K Knop, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: