Evaluation of Safety, Tolerability, Pharmacokinetics, and Activity of Efpegerglucagon in Pediatric Patients with Congenital Hyperinsulinism
- Trial ID
- 2024-515290-98-00
- Protocol
- HM-GCG-201
- Sponsor
- Hanmi Pharm. Co. Ltd.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** profile of HM15136, as well as its **pharmacokinetic (PK) profile** in subjects aged 2 years and older with **Congenital Hyperinsulinism (CHI)**. Assessing the safety and tolerability is crucial to ensure that the treatment does not pose undue risks to patients, while understanding the PK profile helps in determining the drug's absorption, distribution, metabolism, and excretion, which are essential for optimizing dosing regimens.
Secondary objectives include:
- Evaluating the reduction of weekly level 1 or level 2 **hypoglycemia** (glucose < 70 mg/dL [<3.9 mmol/L]) events by HM15136, as measured by self-monitored blood glucose (SMBG). This is important for understanding the efficacy of the treatment in managing hypoglycemic episodes, which are a significant concern in CHI.
- Assessing the long-term safety and tolerability profile of HM15136 during a 44-week optional extension treatment period. This objective aims to provide insights into the prolonged use of the treatment and its implications for patient health over an extended period.
Participants
The clinical trial involves a total of **12 participants** diagnosed with **Congenital Hyperinsulinism (CHI)**, a condition characterized by persistent hypoglycemia. The study population includes both male and female subjects, with an age range of 2 to 12 years. Participants were selected based on their experience of at least three level 1 or level 2 hypoglycemia events per week, despite current standard of care treatment. The trial includes individuals on stable therapy with medications such as diazoxide or somatostatin analogs, and those who may require nutritional supplementation. Participants must have an HbA1c level of less than 7% and adhere to specific contraceptive measures if of childbearing potential. The trial population is considered vulnerable, given the inclusion of children, and informed consent is required from parents or guardians. The study aims to evaluate the safety, tolerability, and pharmacokinetic profile of HM15136 in this specific patient group.
Plans and Procedures
The clinical trial is designed as a **Phase II**, open-label, proof-of-concept study to evaluate the safety, tolerability, pharmacokinetics, and activity of HM15136 in pediatric patients with **Congenital Hyperinsulinism (CHI)**. The trial will involve multiple ascending doses of the investigational product, administered as a **solution for injection in pre-filled syringes** via subcutaneous use. The study will span a total duration of 8 weeks, with an optional extension treatment period for eligible participants. The trial will include a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as persistent hypoglycemia and stable therapy with standard of care medications. Participants will then undergo regular follow-up visits to monitor safety and pharmacokinetic parameters, with the primary endpoints focusing on the incidence of adverse events, clinical laboratory abnormalities, and changes in vital signs and ECG parameters. The end-of-study visit will conclude the core treatment period, evaluating the overall safety and efficacy outcomes. Participants are expected to be involved for the entire 8-week period, with the possibility of early termination if they experience clinically significant adverse events or fail to comply with study protocols. The study aims to provide valuable insights into the treatment of CHI, with the potential for an extended treatment period for those who demonstrate a favorable safety profile during the initial phase. The trial is not classified as low intervention and is conducted under the sponsorship of Hanmi Pharm Co. Ltd., with the investigational product being an orphan drug designated for this rare condition. Participants must adhere to contraceptive measures throughout the study and until 60 days after the final dose, ensuring the safety and integrity of the trial outcomes.
Treatment
The clinical trial involves the administration of **efpegerglucagon**, an investigational medicinal product developed by Hanmi Pharm Co. Ltd. The pharmaceutical form of this experimental medication is a **solution for injection in a pre-filled syringe**. The active substance, efpegerglucagon, is of protein origin and is classified as "Protein - Other." The medication is administered via the **subcutaneous route**. The dosing regimen is specified in milligrams per kilogram (mg/kg), although the exact dosage and frequency are not detailed in the provided data. The maximum treatment period for this study is 52 weeks. The investigational product is designated as an orphan drug under the designation number EU/3/18/2022.
In this study, no specific non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is on evaluating the safety, tolerability, pharmacokinetics, and activity of HM15136 in subjects aged 2 years and older with **congenital hyperinsulinism**. Participant compliance with the dosing schedule will be monitored throughout the study duration to ensure adherence to the protocol. The trial is designed as a Phase 2, multiple ascending dose, open-label, proof-of-concept study, aiming to gather comprehensive data on the investigational product's effects and safety profile.
Efficacy
Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints focus on safety and pharmacokinetic parameters. Safety and tolerability will be evaluated by monitoring the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs), including their severity, relation to the study drug, and any that lead to discontinuation. Additionally, clinical laboratory abnormalities, immunogenicity, and changes in vital signs and 12-lead ECG parameters, specifically the QT interval corrected for heart rate using Fridericia's formula (QTcF), will be assessed.
Pharmacokinetic endpoints include measurements such as maximum concentration (Cmax), time to reach Cmax (tmax), trough serum concentration (Ctrough), area under the concentration-time curve (AUC), terminal elimination rate constant (kel), terminal half-life (t1/2), apparent clearance at steady state (CLss/F), and apparent volume of distribution at steady state during the terminal phase (Vss/F).
Secondary endpoints will assess changes from baseline in the average weekly number and rate of level 1 or level 2 **hypoglycemia** events at Week 8, as well as during the optional 44-week extension period. These events are defined by glucose levels below 70 mg/dL (3.9 mmol/L). The incidence of AEs, TEAEs, and SAEs, along with clinical laboratory abnormalities, immunogenicity, and changes in vital signs and ECG parameters, will also be monitored as part of the secondary efficacy assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male and female subjects with CHI and persistent hypoglycemia defined as experiencing ≥3 level 1 or level 2 hypoglycemia events per week (blood glucose <70 mg/dL [<3.9 mmol/L]) despite current SoC treatment according to the investigator's evaluation or documentation
- Stable therapy with SoC medications or documented to be nonresponsive to SoC medications with or without nutritional supplementation (nutritional supplementation includes enteral feeding such as gastric carbohydrates [administered orally, via nasogastric tube, or gastrostomy]) as described below: a) Subjects aged ≥12 years on stable therapy with diazoxide or somatostatin analog (ie, octreotide and lanreotide) for at least 3 months prior to screening Note: Subjects treated with octreotide infusion could be included after review by the investigator and medical monitor. b) Children aged 2 to 11 years on stable therapy with diazoxide or octreotide for at least 1 month prior to screening; if on lanreotide, stability should be for at least 3 months prior to screening c) Subjects receiving other medications such as sirolimus or nifedipine could be included after review by the investigator and medical monitor
- Subjects on long-acting somatostatin analog may be enrolled in the study if they have been on stable monthly (every 4 weeks) injections for at least 3 months before screening. Subjects would be required to synchronize their monthly somatostatin analog injection with the first and fifth injection of HM15136 (first dosing date = long-acting somatostatin injection date). Note: Lanreotide users not on every 4 weeks dosing regimen could be enrolled after discussion with the investigator and medical monitor
- HbA1c <7%
- Female subjects of childbearing potential must be nonpregnant and nonlactating. All females (regardless of age) of childbearing potential must have a negative urine/serum pregnancy test and must use highly effective methods of contraception throughout the duration of the study and until 60 days after final dose of HM15136 administration. Male subjects must agree to use condoms as a contraceptive measure throughout the duration of the study and until 60 days after final dose of HM15136 administration.
- Following receipt of oral and written information about the trial, the subject (children) (depending on local Institutional Review Board/Independent Ethics Committee requirements, or local regulatory requirements) must provide an assent and one or both parents (a) or guardians of the subject must provide signed informed consent before any trial-related activity is carried out. Adult subjects must provide signed informed consent. Adult subjects unable to provide informed consent and who require his/her legally authorized representative to provide informed consent will not be enrolled in the study. (a) If required by local regulations, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child one parent has legal responsibility for the care and custody of the child
- Criteria for Optional Extension Treatment Period: If the subject has not experienced any clinically significant AEs in the opinion of the investigator and sponsor during the 8-week core treatment period, the subject will be given an opportunity to participate in the optional extension treatment period.
Exclusion Criteria
- With type 1 / type 2 diabetes mellitus
- Other reasons for hypoglycemia, including but not limited to druginduced hyperinsulinemic hypoglycemia, exogenous insulin-induced hypoglycemia, insulinoma, insulin resistance syndrome, nonislet cells tumor hypoglycemia, postgastric bypass, postfundoplication for gastroesophageal reflux, or dumping syndrome with postprandial hypoglycemia, or hypoglycemia due to other endocrine or inherited metabolic diseases
- Treatment of CHI with continuous intravenous glucose or glucagon infusion (requiring hospitalization of >1 W) within 1 M prior to screening (sc) (subj. treated with a transient intravenous glucose or glucagon infusion could be included after review by investigator & medical monitor)
- History of or current active disease of any clinically-significant surgical, medical, or psychiatric condition that, in judgment of investigator, might interfere with absorption, distribution/ metabolism of study drug, interpretation of study assessments/ pose an additional safety risk in administering study drug to subj.
- Unable to tolerate adhesive tape or has any unresolved adverse skin reaction in area of CGMS sensor placement
- With current use of any drugs known to interfere with study drug, glucose metabolism/ study procedures (eg, use of systemic glucocorticoids [exclude. topical, intra-articular or ophthalmic application, nasal spray, or inhaled forms] for >10 consecutive days within 3 M prior to Sc / insulin)
- Consumption of alcohol in subj. <18 to 21 y. and heavy drinking in older adults
- Has participated in an interventional clinical trial (investigational or marketed product) within1 M of Sc or 5 half-lives of drug under investigation (whichever comes first)/ plans to participate in another interventional CT
- History of any major surgery within 6 M prior to sc (except for pancreatectomy)
- History of any serious adverse reaction or hypersensitivity to study drug components
- Anemia findings of hemoglobin <10 g/dL in clinical laboratory results at sc
- Abnormal clinical laboratory results at sc: a) History of renal disease/ abnormal kidney function tests at sc: estimated glomerular filtration rate <60 mL/min/1.73m2 as estimated using pediatric formula (Schwartz formula) for subj. <18 y. and chronic kidney disease epidemiology collaboration formula for subj. ≥18 y. b) Clinically significant thyroid function abnormality in opinion of investigator. If sc thyroid stimulating hormone is >1.5 x ULN or <0.4 mIU/L, reflex laboratory testing for T3 and free T4 will be performed c) Clinically significant abnormal hepatic function tests suggestive of hepatic impairment: alanine aminotransferase and/or aspartate aminotransferase >3 x ULN or total bilirubin >1.5 x ULN (unless due to Gilbert's syndrome, total bilirubin >3.0 x ULN and direct bilirubin >1.5 x ULN).
- History of any clinically significant hepatic findings including gallstones (including incidental finding by ultrasonography or other imaging modalities)
- Hypertension or hypotension not on stable dose of supportive medication for at least 3 M prior to Scr
- Any clinically significant abnormality at sc identified on ECG that in opinion of investigator would affect subject's ability to participate in trial or cardiac arrhythmia requiring medical or surgical treatment within 6 M prior to sc
- History of any active infection, other than mild viral illness within 30D prior to dosing as judged by investigator
- History of/ positive test for hepatitis B surface antigen, hepatitis C virus antibody, or HIV type 1 or type 2 antibody at sc
- Any anticipated procedures (eg surgery) that might interfere with compliance or completion of trial
- Presence of clinically significant physical examination, ECG, or clinical laboratory finding at sc that in opinion of investigator, may interfere with any aspect of study conduct / interpretation of results
- Pregnant female subjects based on sc and baseline pregnancy tests
- With history of major depression, anxiety, or other psychiatric disorders (within last 6 M), requiring active and ongoing medication regimen adjustments including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, antipsychotics, or lithium.
- Baseline period exclusion criteria include following: - Use of glucagon within 24 hours before 1st HM15136 administration - Significant changes to CHI medications during sc - Less than 3 hypoglycemia events/ W before baseline period
- Criteria for Optional Extension Treatment Period: if subject experiences clinically significant AEs with HM15136 treatment where the risks outweigh expected benefits or has other new complications that in the opinion of the investigator and/or sponsor would preclude continued participation, not be allowed to participate in optional extension treatment period.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 30 Dec 2021 | 4 |