Efficacy and Safety Evaluation of Anti-(Insulin Receptor) Human Monoclonal Antibody RZ358 in Congenital Hyperinsulinism-Associated Hypoglycemia
- Trial ID
- 2023-503240-13-00
- Protocol
- RZ358-301
- Sponsor
- Rezolute Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to assess the **glycemic efficacy** of RZ358 in patients with **congenital hyperinsulinism**. This will be evaluated by monitoring hypoglycemia events using point-of-care self-monitored blood glucose over a 24-week treatment period. The clinical relevance of this objective lies in its potential to provide a therapeutic option for managing hypoglycemia in patients with congenital hyperinsulinism, a condition characterized by excessive insulin production leading to dangerously low blood sugar levels.
Secondary objectives include:
- Assessing the glycemic efficacy of RZ358 by measuring hypoglycemia time using continuous glucose monitoring over 24 weeks of treatment.
- Evaluating the safety and tolerability of RZ358.
- Assessing the effect of RZ358 on additional measures of hypoglycemia through self-monitored blood glucose and continuous glucose monitoring.
- Evaluating the repeat-dose pharmacokinetic (PK) profile of RZ358.
Participants
The clinical trial involves a total of **52 participants** diagnosed with **hypoglycemia associated with congenital hyperinsulinism**. The study population includes both male and female subjects, ranging in age from 3 months to 45 years, with the age for infants corrected for gestational age if under 9 months. Participants were selected based on their failure to achieve adequate glycemic control with standard medical therapies and experiencing frequent hypoglycemia events. The trial includes individuals who have provided informed consent and, where applicable, assent. Participants are required to have a hepatic ultrasound without clinically significant findings. Female participants of childbearing potential must have a negative pregnancy test and agree to use highly effective contraceptive measures during the study and for a specified period afterward. Similarly, sexually active male participants must agree to use contraceptive measures and refrain from donating sperm during the study and for a specified period afterward. The trial population includes a vulnerable population, indicating special considerations in the study design to ensure participant safety and ethical conduct.
Plans and Procedures
The clinical trial is a **Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study** designed to evaluate the efficacy and safety of RZ358 in patients with **congenital hyperinsulinism**. The primary objective is to assess the glycemic efficacy of RZ358 by monitoring hypoglycemia events over a 24-week treatment period. The trial is expected to conclude by April 30, 2026, with recruitment starting on October 7, 2023. Participants will be randomly assigned to receive either the active treatment, RZ358, or a placebo, both administered as a **solution for infusion** via intravenous infusion.
The study involves several key visits, beginning with a screening visit to confirm eligibility based on criteria such as age, clinical diagnosis, and previous treatment history. Participants must be aged between 3 months and 45 years and have a documented failure to achieve adequate glycemic control with standard medical therapies. The screening process includes a hepatic ultrasound and, for females of childbearing potential, a pregnancy test. Following the screening, eligible participants will undergo regular follow-up visits to monitor safety and efficacy outcomes, including assessments of adverse events, laboratory measurements, and vital signs. The primary endpoint is the change in the average weekly incidence of hypoglycemia events after 24 weeks, with secondary endpoints including changes in daily percent time in hypoglycemia and safety assessments.
The expected duration of participant involvement is approximately 36 weeks, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The study is designed to ensure the safety and well-being of participants while providing valuable data on the potential benefits of RZ358 for managing hypoglycemia associated with congenital hyperinsulinism.
Treatment
The clinical trial involves the administration of **RZ358**, an experimental medication formulated as a **solution for infusion**. The active substance in RZ358 is an **anti-(insulin receptor) human monoclonal antibody**, classified as a biological product. The medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 1.4 mg/kg, with a total maximum dose of 10 mg/kg over a treatment period of up to 36 weeks. The trial aims to evaluate the efficacy and safety of RZ358 in patients with congenital hyperinsulinism, focusing on glycemic control by monitoring hypoglycemia events.
In addition to the experimental treatment, a placebo is utilized in the study. The placebo is a sterile solution for parenteral administration, provided in an ISO 2R, type I clear glass vial with a fluoropolymer-faced, grey chlorobutyl rubber stopper, and an aluminum seal with a plastic flip-off cap. The buffered vehicle of the placebo contains 10mM L-histidine, 10mM L-methionine, 270mM sorbitol, and 0.01% polysorbate 20, with a pH of 5.8. The placebo serves as a comparator to assess the efficacy of RZ358 in a double-blind, randomized, parallel-arm study design.
Efficacy
The efficacy of RZ358 in patients with **Congenital Hyperinsulinism** will be assessed through a Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study. The primary endpoint for evaluating efficacy is the change in the average weekly incidence of hypoglycemia events, defined as blood glucose levels below 70 mg/dL (3.9 mmol/L), measured by self-monitored blood glucose (SMBG) after 24 weeks of treatment. Secondary endpoints include the change in average daily percent time in hypoglycemia, also measured by continuous glucose monitoring (CGM) after 24 weeks, and the safety and tolerability of RZ358, which will be assessed through adverse events (AEs), serious adverse events (SAEs), clinical laboratory measurements, electrocardiograms (ECG), vital signs, physical examinations, immunogenicity assessments, hepatic ultrasound, and the incidence of hyperglycemia events by SMBG at thresholds of >250 mg/dL and >300 mg/dL (13.9 mmol/L and 16.7 mmol/L, respectively).
Additional secondary endpoints include changes in the average weekly incidence of potentially serious hypoglycemia events by SMBG, changes in the average daily percent time with potentially serious hypoglycemia by CGM, and changes in the average 8-hour overnight percent time with hypoglycemia by CGM. The study will also evaluate the change in average daily duration of hypoglycemia by CGM, the proportion of participants achieving less than 4% average daily time in hypoglycemia by CGM, and the proportion of participants experiencing no potentially serious hypoglycemia events by SMBG. The repeat-dose pharmacokinetic (PK) profile of RZ358 will be assessed using population PK modeling to estimate PK parameters by dose and age category. Efficacy assessments will be conducted over a 24-week treatment period, with data collection and analysis scheduled at specified intervals to ensure comprehensive evaluation of the treatment's impact on hypoglycemia management in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provide written informed consent and, as applicable, assent, before any study specific procedures are performed.
- At screening, aged ≥3 months (corrected for gestational age for children under 9 months) and ≤45 years.
- An established clinical diagnosis of congenital HI, with or without identification of a known monogenic variant by genetic testing.
- Participant has failed to achieve adequate glycemic control with appropriate and reasonable trials of locally accepted and available SOC medical therapies (e.g., diazoxide and SSAs) per the judgment of the investigator.
- Experiencing ≥3 hypoglycemia events (<70 mg/dL [<3.9 mmol/L]) per week by screening SMBG and/or according to the investigator’s evaluation, AND Average daily percent time with hypoglycemia (<70 mg/dL [<3.9 mmol/L]) of ≥8% of the monitored screening CGM time.
- Hepatic ultrasound at screening without clinically significant findings, including clinically significant gallstones as judged by the investigator (e.g., large size, obstructive, or biliary colic), or evidence of peliosis hepatitis.
- For female participants of childbearing potential*, a negative serum or urine pregnancy test within 7 days before dosing. • *Females of childbearing potential are defined as fertile following menarche and until becoming postmenopausal or permanently sterile (Postmenopausal is defined as absence of vaginal bleeding or spotting for at least 1 year. Permanently sterile is defined as having had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.)
- For female participants of childbearing potential, a willingness to use highly effective** contraceptive measures adequate to prevent a new pregnancy for the duration of the study, AND/including for at least 3 months after receiving the last dose of study drug. For women with reproductive potential who use a hormonal method of contraception, concurrent use of a second (barrier) method is recommended. • **Highly effective methods of birth control are defined as those that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (e.g., implants, injectables, oral contraceptives, some intrauterine devices, bilateral tubal occlusion, true sexual abstinence in line with the preferred and usual lifestyle of the participant, or vasectomized partner.)
- For sexually active males, a willingness to use contraceptive measures, e.g., a condom, for the duration of the study, AND/including for at least 3 months after receiving the last dose of study drug. In addition, males must agree not to donate sperm over the same study period.
Exclusion Criteria
- Participants meeting any of the following criteria will be excluded from the study: 1. Any out-of-range laboratory value at screening that is assessed as clinically significant by the investigator, other than glucose, or otherwise is not stable and documented as part of the participant’s known medical history.
- Alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TB), alkaline phosphatase (ALP), and gamma glutamyl transferase (GGT) ≥1.5 × the upper limit of normal (ULN) for the age-specific reference range, regardless of assessed significance.
- Body mass index (BMI) ≥35 kg/m2 for participants aged 18 years and above, or BMI ≥99% (percentile) per Centers for Disease Control and Prevention growth charts for participants >12 and <18 years of age (no BMI exclusion for participants ≤12 years of age).
- A known clinical diagnosis of diabetes or pre-diabetes, or a history of insulin dependency within 3 months of screening.
- Average daily percent time with hyperglycemia ≥250 mg/dL (≥13.9 mmol/L) ≥5% of the monitored screening CGM time.
- History of malignancy within 3 years before screening, other than carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell carcinoma of the skin.
- History of seropositivity (indicative of infection) for human immunodeficiency virus antibody, hepatitis B, or hepatitis C antibody (excluding immunization patterns).
- Known allergy or sensitivity to RZ358 or any component of the drug.
- Any organ condition, concomitant disease (e.g., psychiatric illness, severe alcoholism, or drug abuse, cardiac, hepatic, or kidney disease), or other abnormality that itself, or the treatment of which, could interfere with the conduct of the study (e.g., may affect absorption, distribution, metabolism, or elimination of the study drug) or that, in the opinion of the investigator and/or Sponsor’s medical monitor would pose an unacceptable risk to the participant in the study.
- Major surgery, not including gastrostomy or other enteral catheter insertions, central or peripheral catheter insertion, or similar procedures, within 3 months before screening or anticipated during the study period.
- Treatment with an investigational drug or device within 30 days or 5 half lives of the investigational drug of screening, whichever is longer. Participation in registries and purely diagnostic studies is allowed.
- Female participants who are pregnant, planning to become pregnant during the study or within 3 months after last administration of study drug, have recently delivered (within 3 months before screening), or are breastfeeding.
- Male participants who are planning a pregnancy with a female partner during study or within 3 months after last administration of study drug.
- Use of mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus) within 2 weeks prior to screening and during the study.
- Initiation, reduction, or discontinuation of medications used for the chronic management of hypoglycemia (e.g., diazoxide, SSAs, continuous glucagon) within 2 weeks of screening.
- Initiation of long-acting SSAs within 3 months of screening or receipt of the most recent dose of a long-acting SSAs (e.g., octreotide long-acting release [LAR], lanreotide) ≤10 days prior to the beginning of screening glycemic evaluation with SMBG and CGM.
- Initiation or discontinuation of enteral (tube) feeding treatments or nutritional supplementation within 2 weeks of screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 07 Oct 2023 | 2 |
 Denmark | Not Recruiting | 07 Oct 2023 | 4 |
 France | Not Recruiting | 07 Oct 2023 | 8 |
 Germany | Not Recruiting | 07 Oct 2023 | 6 |
 Greece | Not Recruiting | 07 Oct 2023 | 8 |
 Spain | Not Recruiting | 07 Oct 2023 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RZ358 placebo is a sterile solution for parenteral administration with a minimum extractable volume of 1.0 mL in an ISO 2R, type I clear glass vial with a fluoropolymer-faced, grey chlorobutyl rubber stopper, and an aluminum seal with plastic flip-off cap. The buffered vehicle nominal composition is as follows: 10mM L-histidine, 10mM L- methionine, 270mM sorbitol, 0.01% polysorbate 20, pH 5.8. | Placebo | N/A | — | — | — | N/A |