E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypoglycemia associated with congenital hyperinsulinism |
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E.1.1.1 | Medical condition in easily understood language |
Low blood glucose levels associated with abnormally high level of insulin due to a specific birth defect |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077227 |
E.1.2 | Term | Hyperinsulinemic hypoglycemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020644 |
E.1.2 | Term | Hyperinsulinism NOS |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061211 |
E.1.2 | Term | Hyperinsulinism |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022484 |
E.1.2 | Term | Insulin hypoglycaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objectives of this study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and glycemic efficacy of multiple ascending doses of RZ358 over 8 weeks in patients with hyperinsulinemic hypoglycemia due to congenital hyperinsulinism (CHI). |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provide written informed consent and, as applicable, assent, before any study specific procedures are performed 2. At Screening, aged ≥2 years and ≤45 years 3. An established clinical diagnosis, with or without a genetic diagnosis, of congenital hyperinsulinism 4. Patient is currently receiving SOC medications (i.e corticosteroids, diazoxide, lanreotide, sirolimus, and octreotide) and/or nutritional supplementation for CHI, with at least 2 months of stable treatment; OR is not on treatment, at the time of Screening. 5. Glucose values <70 mg/dL (3.9 mmol/L) for ≥4% of the overall monitored CGM time with at least 3 severe hypoglycemia events by CGM threshold of <50mg/dL (2.8mmol/L) during the last 7 days of a 10-day Screening CGM evaluation period; A discrete severe hypoglycemia event by CGM is defined by having at least 3 consecutive (15 monitored minutes) hypoglycemia readings <70 mg/dL (3.9 mmol/L) with at least one of those readings <50 mg/dL (2.8 mmol/L) and with at least 60 monitored minutes of glucose values ≥ 70 mg/dL (3.9 mmol/L) in between events. AND Experiencing ≥ 3 hypoglycemia events (<70 mg/dL) per week by SMBG and/or according to the Investigator’s evaluation. 6. Hepatic ultrasound at Screening without clinically significant findings, including clinically significant gallstones as judged by the Investigator (e.g. large size, obstructive, biliary colic, or LFT abnormalities exceeding protocol thresholds) or evidence of peliosis hepatitis 7. For female patients 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. Note: 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 patients of childbearing potential, a willingness to use highly effective* contraceptive measures adequate to prevent a new pregnancy for the duration of the study, including for at least 105 days 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 [ie, less than 1% per year] when used consistently and correctly [eg, implants, injectables, oral contraceptives, some intrauterine devices, bilateral tubal occlusion, true sexual abstinence in line with the preferred and usual lifestyle of the patient, or vasectomized partner.]) 9. For sexually active males, a willingness to use contraceptive measures, e.g. a condom, for the duration of the study, including for at least 105 days after receiving the last dose of study drug. In addition, males must agree not to donate sperm over the same study period. |
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E.4 | Principal exclusion criteria |
1. Any out-of-range laboratory value at Screening that has not been reviewed, approved, and documented as not clinically significant by the Investigator, with the exception of liver function tests for total bilirubin, ALT, AST, and ALP, which must be within 1.5X the upper limit of normal (ULN) for the reference range 2. Body mass index ≥ 35 kg/m2 for patients aged 18 years and above, or BMI ≥99% (percentile) per CDC growth charts for patients >12 and < 18 years of age. 3. 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 4. History of seropositivity for HIV antibody, hepatitis B, or hepatitis C antibody 5. Major general surgery within 3 months before Screening or anticipated during the study period 6. Use of systemic corticosteroids within 30 days before Screening 7. Known allergy or sensitivity to RZ358 or any component of the study drug 8. Treatment with an investigational drug or device within 30 days or 5 half-lives of the investigational drug before Day 1 of Week 1, whichever is longer. Participation in registries and purely diagnostic studies is allowed. 9. Female patients who are pregnant, planning to become pregnant during the course of the study, have recently delivered (within 3 months before Screening), or are breastfeeding 10. Male patients who are planning a pregnancy with a female partner during the course of the study or within 105 days after administration of study drug 11. Any organ condition, concomitant disease (eg, 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 (eg, 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 patient in the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Glycemic efficacy of RZ358 as evaluated by the average daily percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by continuous glucose monitoring (CGM); • Repeat-dose safety and tolerability of RZ358 • Repeat-dose pharmacokinetics of RZ358.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Measured at various timepoints (see schedule of events) |
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E.5.2 | Secondary end point(s) |
• Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose (SMBG) • Average daily duration and percent time with hypoglycemia at thresholds of: < 70 mg/dL (3.9 mmol/L) < 60 mg/dL (3.3 mmol/L) < 50 mg/dL (2.8 mmol/L) by continuous glucose monitoring (CGM)
• Average daily hypoglycemia incidence (event rate) at each of the specified glucose thresholds by CGM; • Average 8h overnight percent time in glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by CGM; • Occurrence of hypoglycemia during a 12h fasting challenge
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measured at various timepoints (see schedule of events) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Georgia |
Israel |
Russian Federation |
Serbia |
Turkey |
United States |
Bulgaria |
Denmark |
Germany |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |