A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Efficacy and Safety Study of RZ358 in Patients with Congenital Hyperinsulinism

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rezolute Inc.

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

30 Jan 2024 → ongoing

Decision date (initial)

2024-01-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Rezolute, Inc

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic

To assess the glycemic efficacy of RZ358 by hypoglycemia events on point of care self-monitored blood glucose over 24 weeks of treatment

Secondary objectives 4

1. To assess the glycemic efficacy of RZ358 by hypoglycemia time on continuous glucose monitoring over 24 weeks of treatment
2. To evaluate the safety and tolerability of RZ358
3. To assess the effect of RZ358 on additional measures of hypoglycemia by self-monitored blood glucose and continuous glucose monitoring
4. To evaluate the repeat-dose PK profile of RZ358

Conditions and MedDRA coding

Hypoglycemia associated with congenital hyperinsulinism

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

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

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Provide written informed consent and, as applicable, assent, before any study specific procedures are performed.
2. At screening, aged ≥3 months (corrected for gestational age for children under 9 months) and ≤45 years.
3. An established clinical diagnosis of congenital HI, with or without identification of a known monogenic variant by genetic testing.
4. 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.
5. 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.
6. 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.
7. 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.)
8. 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.)
9. 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 17

1. 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.
2. 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.
3. 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).
4. A known clinical diagnosis of diabetes or pre-diabetes, or a history of insulin dependency within 3 months of screening.
5. Average daily percent time with hyperglycemia ≥250 mg/dL (≥13.9 mmol/L) ≥5% of the monitored screening CGM time.
6. 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.
7. History of seropositivity (indicative of infection) for human immunodeficiency virus antibody, hepatitis B, or hepatitis C antibody (excluding immunization patterns).
8. Known allergy or sensitivity to RZ358 or any component of the drug.
9. 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.
10. 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.
11. 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.
12. 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.
13. Male participants who are planning a pregnancy with a female partner during study or within 3 months after last administration of study drug.
14. Use of mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus) within 2 weeks prior to screening and during the study.
15. Initiation, reduction, or discontinuation of medications used for the chronic management of hypoglycemia (e.g., diazoxide, SSAs, continuous glucagon) within 2 weeks of screening.
16. 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.
17. Initiation or discontinuation of enteral (tube) feeding treatments or nutritional supplementation within 2 weeks of screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in average weekly incidence of hypoglycemia events (<70 mg/dL or <3.9 mmol/L) by SMBG after 24 weeks.

Secondary endpoints 5

1. Change in average daily percent time in hypoglycemia (<70 mg/dL or <3.9 mmol/L) by CGM after 24 weeks.
2. Safety and tolerability of RZ358 based on assessments of AEs, SAEs, clinical laboratory measurements, ECG, vital signs, physical examination, immunogenicity assessments, hepatic ultrasound, and 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.)
3. a. -Change in average weekly incidence of potentially serious hypoglycemia events by SMBG -Change in average daily percent time with potentially serious hypoglycemia by CGM -Change in average 8-hour overnight percent time with hypoglycemia by CGM
4. b. -Change in average daily duration (min) with hypoglycemia by CGM -Proportion of participants achieving <4% average daily time in hypoglycemia by CGM -Proportion of participants experiencing no potentially serious hypoglycemia events by SMBG
5. The repeat-dose PK profile of RZ358 assessed by popPK modeling, which will be used to estimate PK parameters by dose and age category.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rezolute Inc.

Sponsor organisation

Rezolute Inc.

Address

201 Redwood Shores Parkway Suite 315

City

Redwood City

Postcode

94065-6141

Country

United States

Scientific contact point

Organisation

Rezolute Inc.

Contact name

Katja Schuster

Public contact point

Organisation

Rezolute Inc.

Contact name

Clinical Trials Info

Third parties 15

Locations

6 EU/EEA countries · 9 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 148 files

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

Application history

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