A study to Evaluate the Safety, the Tolerability, the Pharmacokinetics and the Activity of HM15136 administered in pediatric Patients with Congenital Hyperinsulinism (CHI)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hanmi Pharm. Co. Ltd.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

23 Sep 2022 → ongoing

Decision date (initial)

2024-07-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Hanmi Pharm. Co., Ltd.

External identifiers

EU CT number

2024-515290-98-00

EudraCT number

2021-000508-39

ClinicalTrials.gov

NCT04732416

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Therapy, Efficacy, Safety, Pharmacokinetic, Pharmacodynamic

Primary Objectives:
• to evaluate the safety and tolerability profile of HM15136
• to evaluate the PK profile of HM15136

Secondary objectives 2

1. To evaluate the reduction of weekly level 1 or level 2 hypoglycemia (glucose < 70 mg/dL [<3.9 mmol/L]) events by HM15136 (selfmonitored blood glucose [SMBG])
2. Objective (44-week Optional Extension Treatment Period): To evaluate the long-term safety and tolerability profile of HM15136

Conditions and MedDRA coding

Congenital Hyperinsulinism (CHI)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-003170-PIP01-21

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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
2. 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
3. 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
4. HbA1c <7%
5. 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.
6. 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
7. 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 23

1. With type 1 / type 2 diabetes mellitus
2. 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
3. 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)
4. 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.
5. Unable to tolerate adhesive tape or has any unresolved adverse skin reaction in area of CGMS sensor placement
6. 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)
7. Consumption of alcohol in subj. <18 to 21 y. and heavy drinking in older adults
8. 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
9. History of any major surgery within 6 M prior to sc (except for pancreatectomy)
10. History of any serious adverse reaction or hypersensitivity to study drug components
11. Anemia findings of hemoglobin <10 g/dL in clinical laboratory results at sc
12. 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).
13. History of any clinically significant hepatic findings including gallstones (including incidental finding by ultrasonography or other imaging modalities)
14. Hypertension or hypotension not on stable dose of supportive medication for at least 3 M prior to Scr
15. 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
16. History of any active infection, other than mild viral illness within 30D prior to dosing as judged by investigator
17. History of/ positive test for hepatitis B surface antigen, hepatitis C virus antibody, or HIV type 1 or type 2 antibody at sc
18. Any anticipated procedures (eg surgery) that might interfere with compliance or completion of trial
19. 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
20. Pregnant female subjects based on sc and baseline pregnancy tests
21. 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.
22. 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
23. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 14

1. Safety and tolerability endpoints: 1. Incidence of adverse event (AE), treatment-emergent AE (TEAE), and serious AE (SAE) for the following: ° level of severity ° related to/not related to study drug ° leading to discontinuation of study drug ° AE of special interest ° death
2. 2. Incidence of clinical laboratory abnormalities
3. 3. Immunogenicity
4. 4. Incidence and severity of clinical findings on physical examination
5. 5. Change from baseline in vital signs (blood pressure, heart rate, respiratory rate, and body temperature)
6. 6. Change from baseline in 12-lead ECG parameters; the primary ECG endpoint will be QT interval corrected for heart rate using Fridericia's formula (QTcF)
7. Pharmacokinetic endpoints: 1. Maximum concentration (Cmax)
8. 2. Time to reach Cmax (tmax)
9. 3. Trough serum concentration (Ctrough)
10. 4. Area under the concentration-time curve (AUC), eg, AUC from time 0 to time t (AUC0-t) at steady state during the period of injection
11. 5. Terminal elimination rate constant (kel)
12. 6. Terminal half-life (t1/2)
13. 7. Apparent clearance at steady state (CLss/F)
14. 8. Apparent volume of distribution at steady state during the terminal phase (Vss/F)

Secondary endpoints 8

1. Change from baseline in average weekly number and rate of level 1 or level 2 hypoglycemia events at Week 8 (Day 50 to Day 56) by the 7-point SMBG ° level 1 or level 2 hypoglycemia event: glucose <70 mg/dL (<3.9 mmol/L)
2. Change from baseline in weekly rate of level 1 or level 2 hypoglycemia events in Diary ° level 1 or level 2 hypoglycemia event: glucose <70 mg/dL (<3.9 mmol/L) 44-week Optional Extension Treatment Period
3. Incidence of AE, TEAE, and SAE for the following: ° level of severity ° related to/not related to study drug ° leading to discontinuation of study drug ° AESIs ° death
4. Incidence of clinical laboratory abnormalities
5. Immunogenicity
6. Incidence and severity of clinical findings on physical examination
7. Change from baseline in vital signs (BP, HR, respiratory rate, and body temperature)
8. Change from baseline in 12-lead ECG parameters; the primary ECG endpoint will be QTcF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hanmi Pharm. Co. Ltd.

Sponsor organisation

Hanmi Pharm. Co. Ltd.

Address

14 Wiryeseongdae-Ro

City

Songpa

Postcode

05545

Country

Korea, Republic of

Scientific contact point

Organisation

Hanmi Pharm. Co. Ltd.

Contact name

JinHee Byeon

Public contact point

Organisation

Hanmi Pharm. Co. Ltd.

Contact name

JinHee Byeon

Third parties 4

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications