Clinical trial NCT04538989
Conditions: Congenital Hyperinsulinism
Keywords: Hypoglycemia Congenital Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases Pancreatic Diseases Digestive System Diseases Hyperinsulinism
Sponsor: Rezolute
Start date: 2020-02-24; Completion date: 2022-08-19
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The objective of this trial is to evaluate the safety, tolerability and glucose-raising effects of RZ358 in patients with Congenital Hyperinsulinism (HI).

Detailed description:
There is a significant unmet medical need to develop new therapies aimed at preventing chronic recurrent hypoglycemia in congenital HI, the most common cause of persistent hypoglycemia in children. RZ358 is a human mAb that allosterically attenuates excessive insulin action on target cells. Therefore, RZ358 is ideally suited as a potential therapy for hyperinsulinism, and it is being developed to treat the hypoglycemia associated with diseases such as congenital HI. This is a Phase 2, multicenter, open label clinical study designed to assess the safety and efficacy of four progressively higher doses of RZ358 in separate groups of patients with hyperinsulinemic hypoglycemia due to Congenital HI, not adequately controlled with or without current standard of care. A screening period of up to 5 weeks will evaluate eligibility. Once enrolled, RZ358 will be administered bi-weekly over 8 weeks, and then patients will complete a post-treatment follow-up period of 13 weeks.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: RZ358 Sequential Group Cohort 1 intervention 2: RZ358 Sequential Group Cohort 2 intervention 3: RZ358 Sequential Group Cohort 3 intervention 4: RZ358 Sequential Group Cohort 4
Intervention descriptions: intervention 1: IV infusion for 8 weeks (3 mg/kg bi-weekly for 8 weeks) intervention 2: IV infusion for 8 weeks (6 mg/kg bi-weekly for 8 weeks) intervention 3: IV infusion for 8 weeks (9 mg/kg bi-weekly for 8 weeks) intervention 4: IV infusion for 8 weeks (bi-weekly fixed dose-titration from 3 to 9 mg/kg for the first 4 weeks, followed by a fixed 9 mg/kg dose amount thereafter for the remaining 4 weeks)

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
Page 1 of 79 
Final v. 5.0, (US) 15 March 2021 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
An Open-Label Multiple-Dose Study of 
RZ358 in Patients with Congenital 
Hyperinsulinism 
Study Number: 
RZ358-606-US 
Investigational Product: 
RZ358 
Indication: 
Congenital Hyperinsulinism 
Phase of Development: 
2 
Study Sponsor: 
Rezolute, Inc. 
201 Redwood Shores Parkway 
Suite #315 
Redwood City 
CA 94065, USA 
IND Number: 
119319 
EudraCT Number: 
2016-004186-83 
Protocol Version and Date: 
Amendment 5.0 (US), 15 March 2021 
Amendment 4.0 (US), 26 May 2020 
Amendment 3.0, 12 August 2019    
Amendment 2.0: 10 May 2017             
Amendment 1.0: 15 December 2016          
Original Protocol: 01 November 
2016 
 
 
 
 
 
 
 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki, and with other applicable regulatory 
requirements. 
This document contains confidential information of Rezolute, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


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National Coordinating Investigator /Principal Investigator Agreement 
I, ____________________________________________, (NCI/PI’s name) have read 
this protocol and agree it contains all necessary details for carrying out this trial. I will 
conduct the trial as outlined herein and will complete it within the time designated. 
 
 
The information contained in this protocol is provided to me in confidence, for review 
only by myself, the ethics committee authorized to review and approve the trial at this 
trial site, and designated trial staff participating in this clinical trial.  
 
I agree to the conditions set out in this protocol and will not implement changes to or 
deviate from the protocol. I fully accept that any change requires prior approval by the 
Sponsor and prior review and approval of the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) except where necessary to eliminate an immediate hazard 
to patients, in which case I will notify the Sponsor and the IRB/IEC immediately. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this trial. I will discuss this material with 
them to ensure they are fully informed regarding the IMP and the conduct of the trial. 
 
I will use only the informed consent form approved by the Sponsor or its representative 
and will fulfill all responsibilities for submitting pertinent information to the IRB/IEC 
responsible for this trial. I will not begin to conduct the study until I am advised in 
writing of the IRB/IEC’s approval. 
 
I agree to carry out all terms of this protocol in accordance with the ICH GCP (Good 
Clinical Practice) Guidelines, the Declaration of Helsinki and local regulations. I will 
ensure that the Investigational Medicinal Product is used only as described in the 
protocol or any subsequent amendment. 
 
I understand that the information/technology contained in this protocol is proprietary 
and may not be disclosed to any other party, in any form, without prior authorization 
from the trial sponsor except to the extent necessary to obtain informed consent from 
potential trial patients.  
 
_________________________________________  
__________________ 
Investigator’s Signature 
 
 
 
 
Date 
 
________________________________________ 
Clinical Trial Site Name 


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PROTOCOL SYNOPSIS 
Title: 
An Open-Label Multiple-Dose Study of RZ358 in Patients with 
Congenital Hyperinsulinism 
Study Number: 
RZ358-606-US 
Development Phase: 
Phase 2 
Sponsor: 
Rezolute, Inc. 
 IND # / EudraCT # 
119319 / 2016-004186-83 
Objectives and 
Endpoints  
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). 
The primary endpoints in this study are as follows: 
• 
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. 
 
The secondary endpoints of this study are as follows: 
• 
Average weekly incidence of hypoglycemia (< 70 mg/dL) by 
self-monitored blood glucose (SMBG) 
• 
Average daily duration (min) and percent time with 
hypoglycemia at thresholds of <70, <60, and <50 mg/dL 
(3.9, 3.3, and 2.8 mmol/L, respectively) 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.  
Additional exploratory endpoints of this study are as follows: 
• 
Average 8h overnight duration (min) and percent time with 
hypoglycemia at thresholds of <70, <60, and <50 mg/dL 
(3.9, 3.3, and 2.8 mmol/L, respectively) by CGM; 
• 
Average 8h overnight hypoglycemia incidence (event rate) 
for each of the specified glucose thresholds by CGM; 
• 
Average daily and 8h overnight area over and under the 
glucose curve (AUC, AOC) to each of the above glucose 
thresholds by CGM; 
• 
Average glucose level between midnight and 8:00 AM (or 
nearest pre-breakfast time point) by CGM; 
• 
Average weekly hypoglycemia incidence (event rate) at each 
of the specified glucose thresholds by SMBG 
• 
Intravenous (IV) or enteral nutritional (glucose/dextrose) 
supplementation; 
• 
Use of standard of care (SOC) or rescue medications for 
hypoglycemia (dextrose or other); 
• 
Incidence of fasting blood glucose values >200, >250, and 
>300 mg/dL (>11.1, >13.9, and >16.6 mmol/L, respectively);  


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• 
PD biomarkers of RZ358 activity including fasting glucose, 
insulin, C-peptide, glucagon, free fatty acids (FFAs), and 
ketones (beta-hydroxybutarate).    
Study Design and 
Description: 
This is a Phase 2, multi-center, open-label, multiple ascending dose study 
to evaluate the safety, tolerability, PK, PD, and glycemic efficacy of 
RZ358 in patients with hypoglycemia due to CHI. The study will consist 
of up to 4 dose cohorts, which are to be enrolled independently and 
conducted sequentially, comprised of 6-8 patients per cohort. Eligible 
patients will be successively enrolled into the cohort that is open for 
enrollment at that time, at the lowest dosing cohort that is yet to be filled. 
A randomization checklist will be provided, requiring Medical Monitor 
approval prior to patient placement within a cohort.  
Following informed consent, patients will complete a Screening Period to 
determine eligibility. After the preliminary screening assessment, patients 
who are otherwise eligible will undergo scheduled self-monitoring of 
blood glucose (SMBG) by point of care (POC) glucometer as well as 
have a CGM sensor placed for completion of a 10-day outpatient CGM 
evaluation, to assess glycemic eligibility and establish a baseline. 
 
 
 
 
 
To 
meet glycemic qualification criteria, patients must have 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 <50 
mg/dL (2.8 mmol/L)  during the last 7 days of a10-day CGM evaluation 
period AND be experiencing ≥ 3 hypoglycemia events (<70 mg/dL) per 
week by SMBG and/or according to the Investigator’s evaluation. A 
 
 
 
 
 
 
 
 
 
 
During the Screening Period and throughout the study, patients will be 
requested to follow their usual diet (including enteral feeding, as 
applicable) and activity level, as evaluated and instructed by qualified 
study personnel. 
At the conclusion of the CGM and glycemic evaluation, final eligibility 
will be determined, and eligible patients will check in to the inpatient 
facility on Day -1, to begin the Treatment Period. On Day -1, patients 
will be required to start a 12h baseline fasting challenge evaluation, 
which will conclude prior to Day 1 dosing. Re-screening may be 
permitted under certain extenuating circumstances (e.g. laboratory outlier 
suggesting result artifact, insufficient duration of CGM collection), only 
with pre-approval by the Sponsor. 
Beginning at Day 1 of the Treatment Period, patients will receive study 
drug via IV infusion every two weeks over an 8 week total Treatment 
Period. 
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In Cohorts 1, 2, and 3 the dose amount will be fixed during the entire 8-
week Treatment Period, while in Cohort 4 there will be a scheduled bi-
weekly dose-titration for the first 4 weeks, followed by a fixed dose 
amount thereafter for the remaining 4 weeks. The Sponsor may decide 
to add a cohort to repeat a dose level or to study an additional dose 
level, but the dose level for any cohort will not exceed the planned dose 
level for that cohort, as specified in this protocol.  
 
Table 1   Study Design/Cohort Dosing Regimens 
 
Dosing (mg/kg) 
Cohort 
Wk  
1 
Wk  
3 
Wk  
5 
Wk  
7 
1 
3 
3 
3 
3 
2 
6 
6 
6 
6 
3 
9 
9 
9 
9 
4 
3 
6 
9 
9 
 
Day 1 will mark the beginning of the Treatment Period at Week 1, and 
“Day 1” relative to the nominal dose will also denote the beginning of 
each subsequent dosing week. At subsequent visits during the Treatment 
Period, patients must check in to the inpatient facility the day prior to 
each dose at each dosing visit (Day -1). On Day 1 of each dosing week, 
PD blood samples will be collected before breakfast for glucose, insulin, 
C-peptide, glucagon, FFAs, and ketones (beta-hydroxybutarate), and 
again at 1-hour post-dosing. Patients will remain under inpatient 
observation for at least 48h following dosing on Week 1 and for 24h 
following dosing on Weeks 3, 5, and 7, for completion of PK blood 
sampling and safety assessments. 
Samples for PK are to be taken within 1 hour before and at 1 hour (±5 
min) after the start of infusion on each dosing day (Day 1), at 24h (±15 
min) post-dose on inpatient Day 2 of each dosing week (Weeks 1, 3, 5, 
and 7), at 48h (±30 min) post-dose on inpatient Day 3 (at Week 1 only), 
and at each outpatient follow-up visit (see PK Sampling Table). The PK 
sampling timepoints may be modified as the study progresses, based on 
interim PK analyses. At the discretion of the Investigator, patients may be 
asked to remain inpatient for longer than the specified times, as necessary 
for safety monitoring. 
Throughout the Treatment Period and through post-treatment follow-up 
Day 42 (cumulative study day 85), glucose levels will be assessed and 
recorded by CGM. 
 
 
Patients will undergo CGM sensor placement or replacement at the 
beginning of the Treatment Period and no less often than every 10 days 
thereafter, or otherwise as needed for replacement (see Schedule of 
Assessments ).  
Throughout the Treatment Period and through the End of Treatment Visit 
on post-treatment follow-up Day 14 (cumulative study day 57), SMBG 
by POC glucometer must be performed 
 
 
 
 
 
 
 
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At the conclusion of Week 7 dosing and discharge from the clinic, each 
patient will complete outpatient post-treatment follow-up visits at Days 
14 (End of Treatment [EOT]), 28, and 42 (each ±3 days), and a final End 
of Study (EOS) follow-up visit on Day 105 (±3 days). This is for 
purposes of evaluating extended PK and safety over a period of 5 half-
lives of the study drug. Blood glucose will continue to be monitored by 
CGM through post-treatment follow-up Day 42 and by POC SMBG  
 through the post-treatment follow-up visit on Day 
14 (EOT). 
 
Thereafter, during the remainder of the Follow-up Period, 
CGM and scheduled POC glucometer SMBG will be stopped but blood 
glucose monitoring by POC glucometer may be performed at the 
discretion of the patient and/or Investigator. 
In addition to ensuring an acceptable safety multiple and proven safe 
dose for the initial cohort, advancement to subsequent cohorts will be 
dependent on acceptable interim safety, PK, and pharmacology reviews 
from ongoing and completed cohorts. The cohorts will be enrolled 
independently and conducted sequentially. Advancement to subsequent 
cohorts will not occur until at least 4 patients from the prior cohort have 
each received at least 4 weeks of study drug (2 bi-weekly doses), without 
safety concerns. A Dose Escalation Review Committee (see Section 10.6) 
will assess all available and relevant interim data from each cohort to 
determine the appropriateness of dose escalation to a new cohort (see 
Section 5.1.2).  
 
Study Population: 
Male and female patients aged ≥12 years and ≤45 years with clinically 
diagnosed CHI 
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Inclusion Criteria: 
Patients may be included in the study if ALL of the following criteria are 
met: 
1. Provide written informed consent and, as applicable, assent, 
before any study-specific procedures are performed. 
2. At Screening, aged ≥12 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 (e.g., diazoxide, 
lanreotide, sirolimus, pasireotide, or 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 <50 mg/dL (2.8 mmol/L) during the last 7 
days of  a 10-day Screening CGM evaluation period.  
 
 
 
 
 
 
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 or 
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. (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 (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 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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Exclusion Criteria: 
Patients will be excluded from the study if ANY of the following criteria 
are met: 
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, alanine transaminase (ALT), aspartate 
transaminase (AST), and alkaline phosphatase (ALP), which 
must be within 1.5X the upper limit of normal (ULN) for the 
reference range. 
2. Body mass index (BMI) ≥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 
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 (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 patient in the study. 
Number of Patients: 
Approximately 24 and up to 32 patients are planned to be enrolled into 
this study. Each of the (up to) 4 cohorts will comprise of ~6-8 patients per 
cohort. Patients who discontinue the study before the Week 5 treatment 
and evaluation period may be replaced at the discretion of the Sponsor, if 
discontinuation was not due to a dose-limiting toxicity (DLT). 
 
Countries/Number of 
Sites: 
This study will be conducted at approximately 15 investigative sites in 
approximately 10 countries. 
 
Investigational 
Product: 
RZ358 (a fully humanized monoclonal antibody [mAb] of IgG sub-type). 
There will be no placebo or active control in this study. 
Further details regarding study drug storage, preparation, and 
administration are provided in the Pharmacy Study Manual.   
 


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Duration of 
Participation: 
The anticipated study duration for each patient is approximately 26 
weeks. This includes a Screening Period of up to 5 weeks, a Treatment 
Period of approximately 8 weeks through the post-treatment Day 14 End 
of Treatment visit, and an additional 13-week Follow-up Period 
thereafter. At the discretion of the Sponsor and Investigator, patients 
perceived to benefit from RZ358 on the present trial may be eligible for 
continued treatment with RZ358 under an expanded access/extension 
program, which is intended to be available once RZ358 enters Phase 3 
development, as applicable and appropriate., 
Criteria for 
Evaluation: 
− 
Efficacy 
assessments 
− 
PK Assessments 
− 
PD assessments 
− 
Safety 
Assessments: 
Efficacy evaluation: 
The glycemic efficacy of RZ358 will be assessed by CGM, SMBG by 
POC glucometer, a modified 12h fasting challenge, serial fasting blood 
glucose, and the impact on background use of SOC treatment, at each of 
the specified evaluation timepoints and at end of treatment compared to 
baseline.  Criteria for evaluation will include: 
• 
CGM: Average daily (primary efficacy endpoint) and 8h 
overnight percent time in glucose target range of 70-180 mg/dL 
(3.9-10 mmol/L) ; 
• 
CGM: Average daily and 8h overnight duration (min) and 
percent time with hypoglycemia at thresholds of <70, <60, and 
<50 mg/dL (<3.9, <3.3, and <2.8 mmol/L, respectively) by 
CGM; 
• 
CGM: Average daily and 8h overnight hypoglycemia incidence 
(event rate) at each of the specified glucose thresholds; 
• 
CGM: Average daily and 8h overnight area over and under the 
glucose curve (AOC, AUC) for each of the specified glucose 
thresholds; 
• 
CGM: Average glucose level between midnight and 08:00 (or 
nearest pre-breakfast timepoint); 
• 
POC glucometer SMBG: Average weekly hypoglycemia 
incidence (event rate) at each of the specified glucose 
thresholds; 
• 
Occurrence of hypoglycemia during a 12h fasting challenge, by 
the following parameters; 
o 
Time to termination of fast; 
o 
Glucose nadir during fast; 
o 
Percentage of patients able to complete a fast; 
o 
Ketone levels at the conclusion of fast. 
• 
IV or enteral nutrition (glucose/dextrose) supplementation; 
• 
Patient incidence and rate of SOC or rescue medication use for 
hypoglycemia (dextrose or other). 
 
PK evaluation: 
Concentrations of RZ358 will be obtained throughout the treatment 
period and through post-treatment follow-up Day 105 after the final dose 
of study drug.  
The single and repeat-dose PK of RZ358 will be assessed by population 
PK modeling which will be used to estimate parameters including, but 
not limited to: 
• 
AUCss: steady state area under the concentration-time curve; 
• 
Cmaxss: steady state maximum concentration; 
• 
Cavgss: steady state average concentration; 
• 
t1/2: effective half-life; 
• 
CL: total drug clearance; 


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• 
V: volume of distribution of the central compartment. 
PD evaluation: 
The PD of RZ358 compared to baseline will be assessed by: 
• 
Fasting levels of glucose, insulin, c-peptide, glucagon, FFAs, 
and ketones (beta-hydroxybutarate) at each of the specified 
collection timepoints; 
• 
Incidence of fasting blood glucose values >200, >250, and >300 
mg/dL (>11.1, >13.9, and >16.6 mmol/L, respectively) at each 
of the specified collection timepoints. 
Safety evaluation: 
Safety assessments will adhere to all recommendations outlined in the 
International Conference on Harmonization (ICH) Guidelines for Good 
Clinical Practice (GCP) and the protection of human safety, and will 
include: 
• 
Incidence, severity, and relationship of adverse events (AEs) and 
serious adverse events (SAEs), and AEs leading to study drug 
discontinuation; 
• 
Actual values and changes from baseline, and incidence of 
clinically significant changes in clinical laboratory, 12-lead 
electrocardiogram (ECG), and vital sign assessments; 
• 
Physical examination findings, including infusion site reactions 
and tolerability.  
• 
The occurrence of anti-drug antibodies (ADAs) to RZ358. 
Statistical Methods: 
General Statistical Considerations: 
The sample size for this study was selected without statistical 
considerations. It has been determined adequate to meet the study 
objectives. Patients who withdraw from the study may be replaced on a 
case-by-case basis after discussion and agreement with the Sponsor’s 
Medical Monitor. 
Detailed methodology for analyses and summary of the data will be 
documented in a Statistical Analysis Plan (SAP), which will supersede 
the protocol, where applicable (see Section 7). However, any major 
modification of the outcome measures and/or its analysis will also be 
reflected in a protocol amendment.  
Continuous variables will be summarized by using the following 
descriptive statistics: mean, standard deviation (SD), number of 
observations, median, minimum, and maximum. The frequency and 
percent of observed levels will be reported for categorical measures.  
In general, all data will be listed, sorted by patient and dose cohort and, 
when appropriate, by study day and study timepoint. 
Analytical Methods: 
The populations used for this analysis will be further defined in the 
SAP. 
Safety Analysis: The interpretation of the safety and tolerability of 
RZ358 will be made based on the assessment of safety parameters 
evaluated throughout the study, including AEs, vital signs, ECGs, 
physical examinations results, infusion-site observations,
 
 results, and clinical laboratory evaluations including glucose 
values. The reporting of the safety data is descriptive, and will include 
all patients who received at least one dose of RZ358. Individual patient 
listings will be reviewed, and summary results with descriptive 
statistics will be provided, where appropriate. No statistical testing will 
be performed on safety data. 
Pharmacokinetics: All patients who received RZ358 and for whom the 
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primary PK data are considered to be sufficient and interpretable will 
be included in the PK analyses. Individual and mean plasma 
concentration data will be plotted over time by dose level and day, and 
summarized descriptively at the specified timepoints. Descriptive 
statistics will be presented for PK parameters, including, but not 
necessarily limited to: Cmax, Tmax, t1/2, and AUC. The relationships 
between dose and Cmax and AUC will be analyzed for dose 
proportionality. The PK results of this study may be combined with 
those of other studies for analysis and modeling (e.g., population PK 
and PK-PD), and reported separately. 
Pharmacodynamics and Efficacy: CGM glucose data will be compiled 
and output into the specified parameters that will be listed by patient 
and summarized in aggregate. Actual data and change from baseline 
will be summarized descriptively for each continuous CGM parameter, 
as well as for POC glucometer SMBG, fasting glucose, and other 
biomarkers, at the protocol-specified timepoints and pre-specified 
evaluation periods. Incidence rates will be normalized to the daily 
(CGM) or weekly (SMBG) average. Categorical events will be 
summarized by frequency counts, as applicable. The requirement for 
rescue and the use of background SOC medication or supplemental 
nutrition will be listed by patient and summarized, where appropriate. 
Statistical comparisons may be performed as appropriate, and will be 
described in the SAP and/or clinical study report.  The primary efficacy 
and PD analysis will be conducted in the per-protocol population, 
   
 
 
 
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Table of Contents 
PROTOCOL SYNOPSIS ..................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................. 17 
1 
INTRODUCTION................................................................................... 19 
1.1 
Overview of Congenital Hyperinsulinism ........................................ 19 
1.2 
Current Treatment Options .............................................................. 19 
1.3 
Overview of RZ358 ............................................................................ 20 
1.4 
 ....................................................................... 20 
1.5 
 ............................................................................... 22 
1.6 
Rationale ............................................................................................. 24 
1.7 
Risk-Benefit Assessment .................................................................... 24 
1.7.1 
 ...................... 25 
1.7.2 
 ............................................... 25 
1.7.3 
 26 
1.7.4 
 ..................................... 26 
2 
STUDY OBJECTIVES AND ENDPOINTS ......................................... 28 
2.1 
Primary Endpoints ............................................................................. 28 
2.2 
Secondary Endpoints ......................................................................... 28 
2.3 
Additional (Exploratory) Endpoints ................................................ 28 
3 
STUDY DESIGN AND DESCRIPTION .............................................. 29 
3.1 
Overview ............................................................................................. 29 
3.2 
 ................................................................ 31 
3.3 
End of Study Definitions and Study Duration ................................. 33 
4 
SELECTION AND WITHDRAWAL OF STUDY POPULATION .. 34 
4.1 
Study Population ................................................................................ 34 
4.2 
Number of Sites Planned ................................................................... 34 
4.3 
Inclusion Criteria ............................................................................... 34 
4.4 
Exclusion Criteria .............................................................................. 35 
4.5 
Patient Withdrawal and Replacement ............................................. 36 
4.5.1 
Patient Withdrawal Criteria .................................................... 36 
4.5.2 
Patients lost to follow up......................................................... 37 
4.6 
Patient Randomization and Identification ....................................... 37 
4.7 
Withdrawal Procedures ..................................................................... 37 
4.8 
Replacement of Patients .................................................................... 38 
5 
STUDY DRUG ........................................................................................ 39 
5.1 
Dosing Regimen .................................................................................. 39 
5.1.1 
 ......................................... 39 
5.1.2 
Cohort Dose Escalation and Stopping Rules .......................... 41 
5.1.2.1 
Dose Escalation Procedures ............................................. 41 
5.1.2.2 
Cohort and Individual Patient Dose Advancement 
Criteria .............................................................................. 41 
5.1.2.3 
Additional Study Stopping Criteria ................................... 41 
5.1.2.4 
Individual Patient Dose Stopping Criteria ....................... 42 
5.2 
Study Drug Materials and Management .......................................... 42 
5.2.1 
Identity and Description .......................................................... 42 
5.2.2 
Procedure for Preparation and Administration ....................... 43 
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5.2.3 
Packaging, Labeling and Storage ............................................ 43 
5.2.4 
Drug Management .................................................................. 43 
5.2.5 
Drug Accountability................................................................ 43 
5.2.6 
Compliance ............................................................................. 43 
5.3 
Prohibited Study Medications ........................................................... 44 
5.3.1 
Rescue Therapies and Guidelines ........................................... 44 
5.3.2 
 .............................................................. 44 
5.3.3 
 ........................................................... 45 
5.3.4 
Treatment of Overdose ........................................................... 45 
5.3.5 
Treatment at the End of the Study .......................................... 45 
6 
STUDY CONDUCT AND ASSESSMENTS ........................................ 46 
6.1 
Study Schedule ................................................................................... 46 
6.1.1 
Screening................................................................................. 46 
6.1.2 
8 Week Treatment ................................................................... 46 
6.1.3 
Follow-up Period and End of Study........................................ 46 
6.1.4 
Missed Visits ........................................................................... 47 
6.1.5 
Unscheduled Visits ................................................................. 47 
6.1.6 
Early Termination Visit .......................................................... 47 
6.2 
Additional Study Procedures and Restrictions ............................... 47 
6.2.1 
Management of Background Standard of Care Therapy ........ 47 
6.2.2 
Use of Rescue Therapy ........................................................... 48 
6.3 
Study Assessments and Criteria for Evaluation .............................. 48 
6.3.1 
Assessment of Efficacy ........................................................... 48 
6.3.1.1 
CGM .................................................................................. 48 
6.3.1.2 
SMBG by POC Glucometer .............................................. 48 
6.3.1.3 
Fasting Challenge ............................................................. 49 
6.3.1.4 
Other Efficacy ................................................................... 50 
6.3.2 
Assessment of Pharmacokinetics ............................................ 50 
6.3.3 
Assessment of Pharmacodynamics ......................................... 50 
6.3.4 
Assessment of Demographics, Safety, and Other Procedures 50 
6.3.5 
Medical History ...................................................................... 51 
6.3.6 
Vital Signs (Including Height and Weight) ............................ 51 
6.3.7 
Physical Examination.............................................................. 51 
6.3.8 
Electrocardiograms ................................................................. 51 
6.3.9 
Laboratory Evaluation ............................................................ 52 
6.3.10 
 ................................................................. 53 
6.3.11 
Infusion Reactions .................................................................. 54 
6.3.11.1 
Assessment of Local Infusion Site Reactions .................... 54 
6.3.11.2 
Management Guidelines for Systemic Infusion-Related 
Reactions ........................................................................... 54 
6.3.12 
Meals ....................................................................................... 55 
6.3.13 
Patient Diary ........................................................................... 55 
6.3.14 
Adverse Events ....................................................................... 56 
6.3.14.1 
Safety definitions ............................................................... 56 
6.3.14.2 
Procedures for Collecting and Recording Adverse 
Events ................................................................................ 57 
6.3.14.3 
Overdose ........................................................................... 60 
6.3.14.4 
Pregnancy ......................................................................... 60 
6.3.15 
Procedures for Reporting Serious Adverse Events ................. 61 
7 
STATISTICAL METHODS .................................................................. 62 
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7.1 
General Considerations ..................................................................... 62 
7.2 
Disposition of Patients ........................................................................ 62 
7.3 
Protocol Deviations ............................................................................ 62 
7.4 
Analysis Populations .......................................................................... 62 
7.5 
Demographics, Baseline Characteristics and Concomitant 
Medications ......................................................................................... 62 
7.6 
Treatment Compliance ...................................................................... 62 
7.7 
Efficacy and Pharmacodynamic Analyses ....................................... 62 
7.8 
Safety Analyses ................................................................................... 63 
7.9 
Pharmacokinetic Analysis ................................................................. 64 
7.10 
Interim Analyses ................................................................................. 64 
7.11 
Determination of Sample Size ........................................................... 64 
8 
DATA MANAGEMENT ........................................................................ 65 
8.1 
Data Collection ................................................................................... 65 
8.2 
Data Correction .................................................................................. 65 
8.3 
Data Handling ..................................................................................... 65 
8.4 
Data Quality Assurance ..................................................................... 65 
8.5 
Handling of Missing, Unused, and Spurious Data .......................... 65 
9 
QUALITY CONTROL AND QUALITY ASSURANCE .................... 66 
9.1 
Study Initiation Activities .................................................................. 66 
9.2 
Training of Site Staff .......................................................................... 66 
9.3 
Documentation and Filing ................................................................. 66 
9.3.1 
CRF System ............................................................................ 66 
9.3.2 
List of Patients (patient identification log) ............................. 66 
9.3.3 
Source Data ............................................................................. 66 
9.3.4 
Protocol Deviations ................................................................. 66 
9.3.5 
Investigator Site File / Regulatory Binder .............................. 67 
9.4 
Monitoring .......................................................................................... 67 
9.5 
Audits and Inspections ....................................................................... 67 
10 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .............. 69 
10.1 
Good Clinical Practice ....................................................................... 69 
10.2 
Informed Consent ............................................................................... 69 
10.3 
Protocol Approval and Amendment ................................................. 69 
10.4 
Archiving Study Records ................................................................... 69 
10.5 
Administrative Structure ................................................................... 70 
10.6 
Dose Escalation Review Committee ................................................. 70 
10.7 
Premature Termination of the Study ............................................... 70 
10.8 
Confidentiality .................................................................................... 71 
10.9 
Liability and Insurance ...................................................................... 71 
10.10 Publication of Data and Protection of Trade Secrets ..................... 71 
11 
REFERENCE LIST ................................................................................ 72 
APPENDIX 1:   SCHEDULE OF ASSESSMENTS ........................................ 74 
APPENDIX 2: PHARMACOKINETICS SAMPLING SCHEDULE ........... 79 
 
 
 


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Tables in Text 
Table 1   Study Design/Cohort Dosing Regimens ........................................................................ 6 
Table 2:   Study Design/Cohort Dosing Regimens ..................................................................... 29 
Table 3:  Study RZ358-606 Simulated Repeat Dose Exposures ............................................... 41 
Table 4:  Laboratory Parameters ............................................................................................... 53 
Table 5:  Abnormal Findings Grading Scale ............................................................................. 54 
Table 6:  Grading Scale (Terms Not Listed in NCI-CTCAE) .................................................. 59 
Table 7:  Causal Relationship of AE to Study Drug .................................................................. 59 
 
Figures in Text 
Figure 1: 
Study Design ............................................................................................................. 31 
Figure 2: 
Study RZ358-606 Simulated Repeat Dose Concentration-Time Profile .............. 40 
 
List of Appendices 
Appendix 1: Schedule of Assessments……………………………………………….…………..74 
Appendix 2: Pharmacokinetics Sampling Schedule…………………………………….……....79 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AOC 
Area over the curve 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BG 
Blood glucose 
CEOI 
Concentration at end of infusion 
CGM 
Continuous glucose monitoring 
CHI 
Congenital hyperinsulinism 
CHMP 
Committee for Medicinal Products for Human use 
cm 
Centimeters  
CPMP 
Committee for Proprietary Medicinal Products 
dL 
Deciliter  
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
eCRF 
Case report form 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HV 
Healthy Volunteers 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization 
IGF-1R 
Insulin-like Growth Factor-1 receptor 
IgG2 
Immunoglobulin G, subclass 2 
INSR 
Insulin receptor 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-treat 
IV 
Intravenous  
Kg 
Kilograms  
KATP 
Potassium adenosine triphosphate  


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Abbreviation 
Definition 
LAR 
Long-acting release 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram  
mL 
Milliliter  
NOAEL 
No-observed adverse-effect levels 
PD 
Pharmacodynamics 
PGBH 
Post-gastric bypass hypoglycemia 
PK 
Pharmacokinetics 
POC 
Point of care 
RTSM 
Randomization and Trial Supply Management 
SAE 
SMBG 
Serious adverse event 
Self-Monitored Blood Glucose 
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
WHO 
World Health Organization 
 
 
 


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1 
INTRODUCTION 
 
1.1 
Overview of Congenital Hyperinsulinism 
Insulin, secreted by the β cells of the Islets of Langerhans in the pancreas, is the major 
hormone for lowering blood glucose levels in the fasting and postprandial states. 
Abnormal elevations in insulin secretion can lead to profound hypoglycemia with 
cerebral damage and even death. Thus, under normal conditions, the control of insulin 
secretion is highly regulated to prevent hypoglycemia. Overproduction of insulin 
results in hyperinsulinemic hypoglycemia, characteristic of diseases such as CHI and 
post-gastric bypass hypoglycemia (PGBH). 
CHI is the most common cause of recurrent hypoglycemia in neonates and infants. 
The incidence of CHI is estimated at 1 in 50,000 live births in the general population, 
but in certain populations with substantial consanguinity incidence may be as high as 
1 in 2,500 (Arnoux et al., 2011). Based on information from therapeutic area experts, 
global prevalence has been calculated to be approximately 1.87 in 10,000. 
There are now 11 identified genetic loci underlying CHI. A genetic diagnosis is 
possible for up to 55% of patients with CHI (Mohamed et al., 2012). For the majority 
of these mutations, the entire pancreas is affected, resulting in dysregulated, excess 
secretion of insulin from beta-cells throughout the pancreas (i.e. diffuse disease). 
However, in the case of paternally inherited mutations of the potassium adenosine 
triphosphate channel (KATP) channel, there may be only a focal region of abnormal 
beta-cells and the remainder of the pancreas is normal (i.e. focal disease).  The 
specific genetic mutation not only affects the pattern and timing of disease expression 
and the clinical severity, but also guides medical and surgical therapy. 
CHI, despite improved recognition and early intervention with currently available 
therapies, can result in serious neurological and developmental complications, 
including persistent feeding problems (Banerjee et al., 2016), recurrent seizures, 
learning disabilities, and focal brain lesions (Avatapalle et al., 2013; Bahi-Buisson et 
al., 2008; de las Heras et al., 2010; Gataullina et al., 2012; Mazor-Aronovitch et al., 
2007). 
1.2 
Current Treatment Options 
Despite improved recognition of CHI, there is no satisfactory treatment or cure for 
this disease. The two most commonly used long-term medications, diazoxide and 
octreotide, are not Food and Drug Administration (FDA) approved for this condition, 
and often are ineffective or have intolerable side effects.    
Diazoxide is an oral KATP channel agonist that maintains the beta-cell KATP channel in 
the open state. This prevents beta-cell depolarization and thus inhibits insulin 
secretion. Although it is the preferred and most widely used medical treatment for 
chronic hyperinsulinemic hypoglycemia, the most common form of CHI results from 
mutations in the KATP channel, and so diazoxide is ineffective in this subset of 
patients. Even in individuals where diazoxide is effective, side effects are frequent 
and include fluid retention, edema, hypertrichosis, and hirsutism resulting in abnormal 
facial features in children (Mohamed et al. 2012). Less common side effects include 
bone marrow suppression, elevation of uric acid, and importantly, pulmonary 
hypertension, for which the FDA has issued a black box warning (FDA, 2015). 
 
Octreotide or long-acting release (LAR) agents in the same class (lanreotide) are 
subcutaneous somatostatin analogs, acting to prevent calcium influx and resultant 
insulin secretion, downstream of the KATP channel. While somatostatin analogs have 


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therapeutic potential in diazoxide-unresponsive patients (Buraczewska et al., 2015; 
Guemes and Hussain, 2015), this class of medications is only modestly effective in 
some patients, and can lead to tachyphylaxis. Due to the mechanism of action, 
somatostatin analogs may suppress other hormones including thyroid stimulating 
hormone and growth hormone, and have the potential to stunt growth when 
administered to children over long periods of time. Cholestasis and necrotizing 
enterocolitis are other less common but serious side effects. 
In cases of CHI that are unresponsive to medical management with diazoxide or 
somatostatin analogs, surgical removal of a portion or the entire pancreas is required. 
In those with focal pancreatic disease, surgical removal of the specific affected area 
often results in a cure. In those with diffuse pancreatic disease, a near-total 
pancreatectomy is undertaken, but residual hypoglycemia requiring adjuvant medical 
management remains in ~50% of patients (Lord and De Leon, 2013).   
Despite improved recognition of CHI and early intervention with currently available 
therapies, persistent hypoglycemia exists and can result in serious neurological and 
developmental complications, including persistent feeding problems (Banerjee et al., 
2016), recurrent seizures, learning disabilities, and focal brain lesions (Avatapalle et 
al., 2013; Gataullina et al., 2013; de las Heras et al., 2010; Bahi-Buisson et al., 2008; 
Mazor-Aronovitch et al., 2007). Current medical therapies for conditions of 
hyperinsulinism are directed at reducing or eliminating insulin production and/or 
secretion from the beta-cell, however, they achieve sub-optimal glycemic control 
and/or have undesirable side effects. Thus, there is a significant unmet medical need 
to develop new therapies aimed at preventing chronic recurrent hypoglycemia in CHI.     
1.3 
Overview of RZ358 
Current medical therapies for conditions of hyperinsulinism are directed at reducing 
or eliminating insulin production and/or secretion from the beta-cell. These current 
medications, however, achieve sub-optimal glycemic control and/or have undesirable 
side effects.     
Diminution of insulin action at target tissues may represent a novel therapeutic 
approach for the treatment of conditions associated with hyperinsulinism. RZ358, 
previously referred to as XOMA-358 or XMetD, is a fully human immunoglobulin G, 
subclass 2 (IgG2) mAb that binds with high potency and selectivity to an allosteric 
site on the insulin receptor (INSR), acting as a negative modulator of insulin action on 
target cells by attenuating both the binding of insulin and its downstream signaling 
(Corbin et al., 2014; Issafras et al., 2014). This unique mechanism of action confers 
properties of reversibility and graded activity which are dependent on the extent of 
insulin elevation. Therefore, RZ358 is ideally suited as a potential therapy for 
hyperinsulinism, and it is being developed to treat the hypoglycemia associated with 
diseases such as CHI. 
1.4 
 
 
 
 
 
 
(b) (4)


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(b) (4)
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1.5 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
 
(b) (4)
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1.6 
Rationale 
There is a significant unmet medical need to develop new therapies aimed at 
preventing chronic recurrent hypoglycemia in CHI. Current medical therapies for 
conditions of hyperinsulinism are directed at reducing or eliminating insulin 
production and/or secretion from the beta-cell; these current medications achieve sub-
optimal glycemic control and/or have undesirable side effects (Banerjee et al., 2016; 
Avatapalle et al., 2013; Gataullina et al., 2013; de las Heras et al., 2010; Bahi-Buisson 
et al., 2008; Mazor-Aronovitch et al., 2007).     
Diminution of insulin action at target tissues may represent a novel therapeutic 
approach for the treatment of conditions associated with hyperinsulinism. RZ358, 
previously referred to as XOMA-358 or XMetD, is a fully human immunoglobulin G, 
subclass 2 (IgG2) mAb that binds with high potency and selectivity to an allosteric 
site on the insulin receptor (INSR), acting as a negative modulator of insulin action on 
target cells by attenuating both the binding of insulin and its downstream signaling 
(Corbin et al., 2014; Issafras et al., 2014). This unique mechanism of action confers 
properties of reversibility and graded activity which are dependent on the extent of 
insulin elevation. Therefore, RZ358 is ideally suited as a potential therapy for 
hyperinsulinism, and it is being developed to treat the hypoglycemia associated with 
diseases such as CHI. The combined non-clinical and clinical programs conducted to 
date support continued clinical development of RZ358 for CHI, and the present study 
represents the progression of the clinical development plan into repeat-dose studies in 
younger patients with CHI, in a cohort-based dose-escalation manner. 
1.7 
Risk-Benefit Assessment 
The available information suggests that the present study has a favorable risk-benefit 
ratio. Previous studies have shown that single-dose administration of RZ358 up to 9 
mg/kg, and repeat-dose administration of up to 3 mg/kg weekly for 4 weeks, was 
generally safe and well tolerated, with evidence of proof-of-mechanism and concept. 
No experiments have been performed to determine a specific antidote to RZ358 in the 
setting of an overdose. General supportive measures should be taken as appropriate. 
 
 
 
 
 
 
 
  
 
  
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As of yet there are no identified risks associated with the use of RZ358 in humans. A 
summary of non-specific and compound-specific potential risks, based on the 
presumptive mechanism of action and non-clinical safety data, are described 
subsequently, along with a summary of mitigation strategies that are implemented into 
clinical studies of RZ358. 
1.7.1 
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
   
 
 
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(b) (4)
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(b) (4)
(b) (4)
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•
 
 
 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this study are to evaluate the safety, tolerability, PK, PD, and 
glycemic efficacy of multiple ascending doses of RZ358 over 8 weeks in patients with 
hyperinsulinemic hypoglycemia due to CHI. 
2.1 
Primary Endpoints 
• 
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 CGM; 
• 
Repeat-dose safety and tolerability of RZ358; 
• 
Repeat-dose PK of RZ358. 
2.2 
Secondary Endpoints 
• 
Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored 
blood glucose (SMBG) 
• 
Average daily duration (min) and percent time with hypoglycemia at 
thresholds of <70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, 
respectively) by 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. 
2.3 
Additional (Exploratory) Endpoints 
• 
Average 8h overnight duration (min) and percent time with hypoglycemia 
at thresholds of <70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, 
respectively) by CGM; 
• 
Average 8h overnight hypoglycemia incidence (event rate) at each of the 
specified glucose thresholds by CGM; 
• 
Average daily and 8h overnight area over and under the glucose curve (AUC, 
AOC) for each of the specified glucose thresholds by CGM; 
• 
Average glucose level between midnight and 8:00 AM (or nearest pre-
breakfast time point) by CGM; 
• 
Average weekly hypoglycemia incidence (event rate) at each of the specified 
glucose thresholds by SMBG; 
• 
IV or enteral nutritional (glucose/dextrose) supplementation; 
• 
Use of SOC or rescue medications for hypoglycemia (dextrose or other); 
• 
Incidence of fasting blood glucose values >200, >250, and >300 mg/dL 
(>11.1, >13.9, and >16.6 mmol/L, respectively); 
• 
PD Markers of RZ358 activity including fasting levels of glucose, insulin, c-
peptide, glucagon, FFAs, and ketones (beta-hydroxybutarate). 
 


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3 
STUDY DESIGN AND DESCRIPTION 
3.1 
Overview 
This is a Phase 2, multi-center, open-label, multiple ascending dose study to evaluate 
the safety, tolerability, PK, PD, and glycemic efficacy of RZ358 in patients with 
hypoglycemia due to CHI. The study will consist of up to 4 dose cohorts, which are to 
be enrolled independently and conducted sequentially, comprised of 6-8 patients per 
cohort. Eligible patients will be successively enrolled into the cohort that is open for 
enrollment at that time, at the lowest dosing cohort that is yet to be filled.  
Advancement to subsequent cohorts will not occur until at least 4 patients from the 
prior cohort have each received at least 4 weeks of study drug (2 bi-weekly doses), 
without safety concerns. A Dose Escalation Review Committee will assess all 
available and relevant interim data from each cohort to determine the appropriateness 
of dose escalation to a new cohort (see Section 5.1.2).   
In Cohorts 1, 2, and 3 the dose amount will be fixed during the entire 8-week 
Treatment Period, while in Cohort 4 there will be a scheduled bi-weekly dose-titration 
for the first 4 weeks, followed by a fixed dose amount thereafter for the remaining 4 
weeks. The Sponsor may decide to add a cohort to repeat a dose level or to study an 
additional dose level, but the dose level for any cohort will not exceed the planned 
dose level for that cohort, as specified in this protocol. 
 
Table 2:   Study Design/Cohort Dosing Regimens 
 
 
Dosing (mg/kg) 
Cohort 
Wk 1 
Wk 3 
Wk 5 
Wk  7 
1 
3 
3 
3 
3 
2 
6 
6 
6 
6 
3 
9 
9 
9 
9 
4 
3 
6 
9 
9 
 
 
Following informed consent, patients will complete a Screening Period to determine 
eligibility. After the preliminary screening assessment, patients who are otherwise 
eligible will undergo scheduled self-monitoring of blood glucose (SMBG) by point of 
care (POC) glucometer as well as have a CGM sensor placed according to the 
instruction manual, for completion of a 10-day outpatient CGM evaluation to assess 
glycemic eligibility and establish a baseline.
 
patients will use an SMBG for their POC 
throughout the trial.  Patients taking existing and stable doses of SOC medications or 
nutritional supplementation for CHI at the time of screening should continue the same 
regimen and doses throughout this period. 
 
o meet glycemic qualification criteria, patients must have 
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 (2.8 
mmol/L) during the last 7 days of a 10-day CGM evaluation period AND be 
experiencing ≥ 3 hypoglycemia events (<70 mg/dL) per week by SMBG and/or 
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according to the Investigator’s evaluation. 
 
 
 
 
  
 
 
 
 
 
During the Screening Period and throughout the study, patients will be requested to 
follow their usual diet (including enteral feeding, as applicable) and activity level, as 
evaluated and instructed by qualified study personnel. 
At the conclusion of the CGM and glycemic eligibility evaluation, final eligibility 
will be determined, and fully eligible patients will check in to the inpatient facility on 
Day -1, to begin the Treatment Period. On Day -1, patients will begin a 12h baseline 
fasting challenge evaluation, which will conclude prior to Day 1 dosing. Re-screening 
may be permitted under certain extenuating circumstances (e.g. laboratory outlier 
suggesting result artifact, insufficient duration of CGM collection), only with pre-
approval by the Sponsor. 
Beginning at Day 1 of the Treatment Period, patients will receive study drug via IV 
infusion every 2 weeks over an 8 week total Treatment Period. Thus, patients who 
complete the entire Treatment Period will receive 4 doses of study drug over a total of 
8 weeks (Figure 1). Patients will remain under inpatient observation for at least 48h 
following dosing on Week 1 and for at least 24h following dosing on Weeks 3, 5, and 
7, for completion of PK blood sampling and safety assessments. Throughout the 
Treatment Period and through post-treatment follow-up Day 42 after the patient’s 
final dose in the study (cumulative study Day 85), glucose levels will be assessed and 
recorded by CGM.
 
 
patients will continue to use an 
SMBG as their POC throughout the trial. 
Throughout the Treatment period and through the End of Treatment visit (EOT) on 
post-treatment follow-up Day 14 (cumulative study Day 57), SMBG by POC 
glucometer must be performed at
 
 
 
 
 
 
 
 
 
 
 
 
 
(b) (4)
(b) (4)
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Otherwise, changes in the dose or regimen of background SOC therapies should not 
occur, except in the event that hypo- or hyperglycemic rescue criteria are met (see 
Section 5.3.1), or changes are deemed medically necessary by the Investigator. 
 
 
 
 
 
 
 
At the conclusion of Week 7 dosing and discharge from the clinic, each patient will 
complete outpatient follow-up visits at Days 14 (EOT), 28, and 42 (each ±3 days), 
and a final End of Study (EOS) follow-up visit on Day 105 (±3 days), for purposes of 
evaluating extended PK and safety over a period of 5 half-lives of the study drug.  
 
A detailed description of study procedures and assessments are provided in Section 6 
and are outlined in Appendix 1 (Schedule of Assessments).  
Figure 1: Study Design  
 
 
3.2 
 
 
 
 
 
   
(b) (4)
(b) (4)


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(b) (4)
(b) (4)


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3.3 
End of Study Definitions and Study Duration 
End of Treatment (EOT) is defined as the time at which a patient has received all 4 
doses of study drug over the course of the 8-week Treatment Period AND completed 
the associated key EOT assessments at Day 14 (EOT). 
A patient is considered to have completed the study if he/she has completed all phases 
of the study including the last (EOS) visit and the last scheduled procedure shown in 
the Schedule of Assessments (Appendix 1). The anticipated study duration for each 
patient is approximately 26 weeks. This includes a Screening Period of approximately 
5 weeks, a Treatment Period of approximately 8 weeks, and an additional 13-week 
Follow-up Period. 
The end of the study is defined as the date of the last scheduled procedure shown in 
the Schedule of Assessments for the last patient in the trial globally (Appendix 1). 
(b) (4)


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4 
SELECTION AND WITHDRAWAL OF STUDY POPULATION   
4.1 
Study Population 
The study population will consist of male and female patients aged ≥12 years and ≤45 
years with clinically diagnosed CHI. 
 
4.2 
Number of Sites Planned 
This study will be conducted at approximately 15 investigative sites in approximately 
10 countries. 
 
4.3 
Inclusion Criteria 
Patients who meet ALL of the following criteria are eligible to participate in the study. 
1. 
Provide written informed consent and, as applicable, assent, before any study-
specific procedures are performed. 
2. 
At Screening, aged ≥12 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 (e.g., diazoxide, lanreotide, 
sirolimus, pasireotide, or 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 
<50 mg/dL (2.8 mmol/L) during the last 7 days of a 10-day Screening CGM 
evaluation period.  
 
 
 
 
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 or peliosis hepatitis. 
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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. (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 alone or 
in combination 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 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.  
 
 
 
4.4 
Exclusion Criteria 
Patients will be excluded from the study if ANY of the following criteria are met:  
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, alanine 
transaminase (ALT), aspartate transaminase (AST), and alkaline 
phosphatase (ALP), which must be within 1.5X the upper limit of normal 
(ULN) for the reference range. 
2. 
Body mass index (BMI) ≥35 kg/m2 for patients aged 18 years and above, or 
BMI ≥99% (percentile) per CDC growth charts for patient >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 
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6. 
Use of systemic corticosteroids within 30 days before Screening. 
7. 
Known allergy or sensitivity to RZ358 or any component of the 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 (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 
patient in the study. 
  
4.5 
Patient Withdrawal and Replacement 
4.5.1 Patient Withdrawal Criteria 
An individual patient may be withdrawn from the study at any time, for any of the 
following reasons: 
• Withdrawal of written informed consent (a patient has the right to withdraw from 
the study at their own request, at any time, without giving a reason [although 
whenever possible, the reason should be obtained], and without prejudice to their 
continued care); 
• Required treatment with any concomitant medication known or suspected to 
interfere with the study drug or study evaluations or be prohibited/contraindicated. 
However, patients should not be automatically discontinued from the study if this 
occurs, unless it poses a significant risk to the patient in the opinion of the 
Investigator: otherwise, such instances should first be discussed between the 
Investigator and Sponsor Medical Monitor; 
• Adverse events, where the Investigator or Medical Monitor feels that 
discontinuation from the study is in the best interest of the patient; 
• Patient becomes pregnant or begins breast-feeding; 
• Lack of compliance with the study protocol; 
• Lost to follow-up; 
• Study termination by the Sponsor; 
• Any other condition which, in the opinion of the Investigator or Sponsor, no 
longer permits safe participation in the study. The investigator can stop a patient’s 
participation in the study at any time if continuation could lead to disadvantages 
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• The patient meets one of the pre-specified stopping criteria outlined in Section 
5.1.2.3. 
 
4.5.2 Patients lost to follow-up 
A patient will be considered lost to follow-up if he or she fails to return for their 
scheduled visits and is unable to be contacted by the site staff.  The following actions 
must be taken if this occurs: 
• The site must attempt to contact the patient and reschedule the missed visit as 
soon as possible. 
• The site will counsel the patient on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the patient wishes to and/or should 
continue in the study. 
• If multiple attempts to regain contact with the site are unsuccessful (e.g. 
multiple phone calls at different dates/times, followed-by a certified letter to 
the patient’s last known mailing address), the patient may then be considered 
to have withdrawn from the study with a primary reason of discontinuation as 
‘Lost to Follow-up’. These contact attempts should be documented in the 
patient’s study file.  
 
4.6 
Patient Randomization and Identification 
This is an open-label study, but the study will utilize a randomization and trial supply 
management (RTSM) application built within the EDC platform to unify 
randomization, trial supply and EDC. Each patient will be provided a unique 6-digit 
patient ID number. The first three digits will represent the site number and the last 
three digits will represent the patient number at the site. The patient ID number will 
remain the same for both Screening and randomization.  
 
4.7 
Withdrawal Procedures 
Once enrolled, every effort should be made by the Investigator to keep patients in the 
study for the duration, unless patient consent has been withdrawn or the Investigator 
or Sponsor deems it in the best interest of the patient to withdraw from the study. 
Interruption of the study drug does not automatically and/or immediately require 
discontinuation from the study, and remaining study procedures should be completed 
as indicated by the study protocol, until such time that the final disposition is 
determined. Once it becomes apparent that the patient will not be able to resume study 
drug in a reasonable timeframe (final disposition), then the patient should be 
withdrawn from the study, and undergo Early Termination (ET) procedures within 2 
weeks of the last dose received, as outlined in Section 6.1.6 and the Schedule of 
Assessments. After ET, patients should also complete the Follow-up Period, if 
possible. Patients who terminate the study early (at any point during the study) will 
not be considered Study Completers, even if they complete ET procedures and the 
post-ET Follow-up Period. In the event an enrolled patient is withdrawn from the 
study, the Study Monitor and Sponsor should be informed immediately. Patients 
should be treated with SOC after ET, as appropriate. In the event of a withdrawal due 
to an AE, the event will be followed until resolution, or until it is deemed stable, in 
the Investigator’s opinion, or until a determination of a cause unrelated to the study 
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The Investigator should attempt to obtain information on patients in the case of 
withdrawal or discontinuation.  Results of any evaluations and observations, together 
with a narrative describing the reason(s) for withdrawal, must be recorded in the 
source documents.  The eCRF must document the primary reason for withdrawal or 
discontinuation. 
4.8 
Replacement of Patients 
Patients who discontinue the study before the Week 5 treatment and evaluation period 
may be replaced at the discretion of the Sponsor, if the reason for discontinuation was 
not a dose-limiting toxicity (DLT). The allocation of a replacement patient will be 
managed by the Medical Monitor to help ensure that each cohort meets the thresholds 
for sample size.  
  


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5 
STUDY DRUG 
5.1 
Dosing Regimen 
Beginning at Day 1 of the Treatment Period, patients will receive study drug via IV 
infusion every two weeks over an 8 week total Treatment Period. Thus, patients who 
complete the entire Treatment Period will receive a total of 4 doses. Study drug will 
be administered as a 30-minute IV infusion in the clinic, ideally in the morning at 
approximately the same time on each dosing day, after the collection of fasting blood 
samples followed by a standardized breakfast. 
The planned RZ358 dose levels and regimen are described in Table 2. The Sponsor 
may decide to add a cohort to repeat a dose level or to study an additional dose level, 
but the dose level for any cohort will not exceed the planned dose level for that 
cohort, as specified in this protocol. Cohorts will be enrolled independently and 
conducted sequentially. Advancement to subsequent cohorts will not occur until at 
least 4 patients from the prior cohort have each received at least 4 weeks of treatment 
with 2 bi-weekly doses of study drug, without safety concerns.  
In Cohorts 1, 2, and 3 the dose amount will be fixed during the entire 8-week 
Treatment Period, while in Cohort 4 there will be a scheduled bi-weekly dose-titration 
for the first 4 weeks, followed by a fixed dose amount thereafter for the remaining 4 
weeks.  
 
5.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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(b) (4)
(b) (4)


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5.1.2 Cohort Dose Escalation and Stopping Rules 
5.1.2.1 Dose Escalation Procedures 
In addition to ensuring an acceptable safety multiple for the Cohort 1 starting dose, 
advancement to subsequent cohorts will be dependent on acceptable interim safety, 
PK, and pharmacology reviews from ongoing and completed cohorts. Advancement 
to subsequent cohorts will not occur until at least 4 patients from the prior cohort have 
each received at least 4 weeks of treatment with 2 bi-weekly doses of study drug 
without safety concerns. A Dose Escalation Review Committee will be established to 
assess all available and relevant interim data from each cohort to determine the safety 
and appropriateness of dose escalation to a new cohort. In the study, dose escalation 
will follow pre-specified criteria. If 2 or more patients within the same dosing cohort 
experience DLTs, dose escalation to the planned dose will be stopped, or an 
intermediate dose may be tested. If dose escalation is stopped due to DLTs, the 
maximum tolerated dose (MTD) will be defined by the dose in the previous cohort, 
unless an intermediate dose is subsequently tested by the same algorithm. Toxicity 
will be evaluated as described in Section 5.1.2.2. Dose escalation may also be halted 
based on a review of drug PK (e.g., if exposures do not increase between successive 
dose cohorts).  
More conservative dose escalation or evaluation of intermediate doses are permissible 
following discussions between the Sponsor and Investigator(s) if needed for patient 
safety or for a better understanding of the toxicity, exposure, or other properties of the 
study drug.   
Patients withdrawn from treatment before completing Week 5 dosing, for reasons 
other than a DLT, may be replaced within the cohort, at the discretion of the Sponsor. 
5.1.2.2 Cohort Dose Advancement Criteria 
Upon review of pooled cohort data by the Dose Escalation Review Committee, dose 
escalation to the next highest cohort may proceed upon review, confirmation, and 
documentation of acceptable interim safety, PK, and pharmacology findings from all 
available interim data.
 
 
 
 
 
 
5.1.2.3 Additional Study Stopping Criteria 
In addition to the pooled cohort criteria that prospectively define the events that will 
result in halting escalation to the next cohort, under certain additional circumstances 
(b) (4)
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further study dosing in the representative patient(s), as well as enrollment and dosing 
of new patients, will be halted until the Dose Escalation Review Committee deems it 
safe to proceed, based on a comprehensive review of all relevant case and interim 
study data. Additionally, a safety report will be submitted to the applicable Regulatory 
Agency (e.g. MHRA) for review, before study dosing may resume. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5.1.2.4 Individual Patient Dose Stopping Criteria 
• Study drug infusion/administration will be stopped for an individual patient 
if an infusion reaction is suspected, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
5.2 
Study Drug Materials and Management 
5.2.1 Identity and Description 
RZ358 is a sterile, aqueous, colorless to slightly yellow solution for infusion and will 
be provided as single use vials of 1.27 mL filled with RZ358 drug product of 80 g/L 
(80 mg/mL) in a pH 5.8 formulation buffer. There is approximately 270 ul of overfill 
in each vial, allowing for a minimum of 1.0 mL to be extracted. For details on the 
formulation composition, formulation dose strength, packaging, and container fill, 
please see the Investigator’s Brochure. 
(b) 
(4)
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5.2.2 Procedure for Preparation and Administration 
The study drug will be administered as an IV infusion over 30 minutes. Further details 
regarding the preparation and administration procedures for RZ358 will be provided 
in the study Pharmacy Manual. 
5.2.3 Packaging, Labeling and Storage 
 
 
 
 
 
Packaging and labelling of study drug will comply with Good Manufacturing Practice 
(GMP) Annex 13, Good Clinical Practice (GCP) rules, and country-specific 
regulatory requirements; this information will be available in the local language. 
5.2.4 Drug Management 
Drug management will be the responsibility of the Investigator and can be delegated 
to the pharmacist or other qualified personnel of the medical institution. The 
Investigator, the pharmacist of the medical institution, or another designated person 
must complete, in real time, all the documents concerning treatment management. 
Treatment management will be verified on a regular basis by the Study Monitor. 
The study drug can only be administered by health care professionals who are 
qualified by training and experience in the safe use and handling of investigational 
drugs. The study drug should not be used if the solution is cloudy or opaque.  
For additional information about the study drug, refer to the Investigator’s Brochure 
and Pharmacy Manual. 
5.2.5 Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability 
records throughout the study. 
The Investigator or their assigned designee is responsible for maintaining up-to-date 
inventory and accountability logs. Each dispensing of study drug will be documented 
in the medical records and/or inventory/accountability logs and reported to the 
Sponsor through the RTSM. The study site pharmacy should dispense drug kits 
sequentially, starting with the lowest kit number. 
Local destruction of all unused or partially used study drug is permissible if the study 
site has an SOP to govern this procedure. Alternatively, the Investigator is responsible 
for returning all unused or partially used study drug to the Sponsor and must verify 
that they have been returned and that no remaining supplies are in the Investigator’s 
possession. 
5.2.6 Compliance 
The administration of the study drug should be recorded in the Source Data and 
transferred to the appropriate sections of the eCRF.  
Study drug will be administered at the study site by qualified personnel under the 
supervision of the Investigator or their designee during inpatient periods. Study drug 
will only be administered to eligible patients, according to the procedures stipulated in 
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this Protocol. It is strictly prohibited to use the supplied medication for any purpose 
other than those described in this Protocol.  
 
5.3 
Prohibited Study Medications 
Restrictions on pre-study use of medications are described in the exclusion criteria 
(Section 4.4 ), and these restrictions will continue throughout the study. Initiation or 
escalation of therapies or interventions for the underlying disease under study is 
limited to circumstances meeting protocol-specified rescue criteria, 
 
 
 
 
 
5.3.1 Rescue Therapies and Guidelines 
Rescue therapy guidelines are provided to standardize the use of rescue therapy 
across the study, and to optimize the safety of study patients. Blood glucose 
monitoring will be performed throughout the duration of the study. CGM values or 
trends may be used to guide the conduct of a POC glucometer blood glucose 
measurement but should not be exclusively used to make rescue or treatment 
decisions, without confirmation from a POC glucometer measurement. 
 
5.3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
(b) (4)
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5.3.4 Treatment of Overdose 
In case of an overdose of study drug, treatment should be suspended, and the patient 
should receive appropriate medical treatment according to the clinical condition. See 
Section 6.3.15.3 for a description of the requirements for overdose reporting.  
5.3.5 Treatment at the End of the Study 
After the completion of the study, the Investigator is responsible for ensuring that 
consideration has been given to the patient’s post-study care. At the conclusion of the 
study, patients should be treated with SOC, as appropriate.  
(b) (4)


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6 
STUDY CONDUCT AND ASSESSMENTS 
6.1 
Study Schedule 
A signed and dated IRB/IEC-approved informed consent must be obtained before any 
study-specific assessments are performed. Assessments that are part of routine care 
are not considered study-specific and may be used at Screening to determine 
eligibility. All patients will be screened for eligibility before enrollment. Only eligible 
patients will be enrolled into the study. The schedule of assessments to be performed 
during the study is provided in Appendix 1.    
6.1.1 Screening 
All screening procedures must be performed within 35 days of Day 1. Study 
procedures to be performed during the Screening Period can be found in the Schedule 
of Assessments (Appendix 1). Inclusion and exclusion criteria and other study 
assessments required in the screening period, including CGM, SMBG by POC 
glucometer, and Central laboratory results, will be used to determine eligibility. An 
RTSM system will be utilized for this study. All enrolled patients will be entered in 
the clinical database (EDC). 
6.1.2 8 Week Treatment 
The Treatment Period for this study is 8 weeks. Patients will receive bi-weekly dosing 
for Weeks 1, 3, 5 and 7. Therefore, patients who complete the study will receive a 
total of 4 doses of study drug (at the specified dose corresponding to the cohort to 
which the patient is assigned). Throughout the Treatment Period, safety will be 
monitored, and blood samples will be collected for the PK of RZ358. CGM, SMBG 
by POC glucometer, fasting challenges, and fasting blood samples will be performed 
to assess the PD and glycemic efficacy of the study drug. Study procedures to be 
performed during the Treatment Period can be found in the Schedule of Assessments 
(Appendix 1). 
6.1.3 Follow-up Period and End of Study 
After the patient’s last dose of study drug and post-treatment Day 14 End of 
Treatment visit, thereafter the follow-up period will be for an additional 13 weeks. 
Each patient will return for 4 outpatient post-treatment follow-up visits, scheduled at 
Days 14 (EOT), 28, 42, and Day 105 (EOS), all ±3 days. 
During this period, safety will continue to be monitored, and blood samples will 
continue to be collected for the PK of RZ358. In addition to the scheduled follow-up 
visits, patients may be asked, at the Investigator’s discretion, to undergo additional 
safety procedures, additional PK and PD sample collection, or both. Various PD 
markers, including glucose, ketones (beta-hydroxybutyrate), insulin, glucagon, FFAs, 
and c-peptide, will be assessed.  
Under extenuating circumstances, home-health follow-up visits and/or virtual care 
may be conducted in lieu of on-site follow-up visits. 
A patient is considered to have completed the study if he/she has completed all phases 
of the study including the last (EOS) visit and the last scheduled procedure shown in 
the Schedule of Assessments. 
The end of the study is defined as the date of the last scheduled procedure shown in 
the Schedule of Assessments for the last patient in the trial globally. 


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6.1.4 Missed Visits 
Study treatment may be withheld/interrupted due to safety reasons, resulting in a 
“missed” visit. Adjustments to the dosing schedule for RZ358 should be discussed 
with the study Medical Monitor. If a visit is missed and not rescheduled, it will be 
captured accordingly in the clinical database. 
6.1.5 Unscheduled Visits 
Unscheduled visits/assessments may be required at the discretion of the 
Investigator. These data will be captured accordingly in the clinical database. 
6.1.6 Early Termination Visit 
Interruption of the study drug does not automatically and/or immediately require 
discontinuation from the study, and remaining study procedures should be completed 
as indicated by the Protocol, until such time that the final disposition is determined. If 
it becomes apparent that the patient will not be able to resume study drug in a 
reasonable timeframe (final disposition), then the patient should be withdrawn from 
the study, and undergo Early Termination (ET) procedures within 2 weeks of the last 
dose received, as outlined in Appendix 1, Schedule of Assessments.  
  
6.2 
Additional Study Procedures and Restrictions 
6.2.1 Management of Background Standard of Care Therapy 
Eligibility criteria for this study permit the inclusion of patients currently receiving 
SOC medications (e.g., diazoxide, lanreotide, sirolimus, pasireotide, or octreotide) 
and/or nutritional supplementation for CHI, with at least 2 months of stable treatment, 
or are not on treatment at the time of Screening. 
Those patients taking existing and stable doses of SOC medications or nutritional 
supplementation (including enteral feeding, as applicable) for CHI at the time of 
Screening should continue the same regimen and doses during the Screening Period 
and throughout the remainder of the study until the post-treatment follow-up Day 42. 
 
 
Throughout the study, patients will also be requested to follow their usual diet 
(including enteral feeding, as applicable) and activity level, as evaluated and 
instructed by qualified study personnel. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(b) (4)
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Otherwise, changes in the dose or regimen of background SOC therapies should not 
occur, except in the event that hypo- or hyperglycemic rescue criteria are met, or 
changes are deemed medically necessary by the Investigator.
 
 
 
 
  
6.2.2 Use of Rescue Therapy 
Rescue therapy guidelines are provided to standardize the use of rescue therapy across 
the study, and to optimize the safety of study patients. A
 
 
 
6.3 
Study Assessments and Criteria for Evaluation 
The schedule of activities to be performed during the study is provided in Appendix 1. 
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.   
6.3.1 Assessment of Efficacy 
6.3.1.1 CGM 
A CGM system will be used to evaluate glycemic eligibility and efficacy endpoints 
for glycemic control. Throughout the study, the CGM device will continuously 
monitor glucose levels. 
 
 
Several parameters to measure glycemic control by CGM will be evaluated over the 
2-week End of Treatment period after the final dose, compared to baseline. Criteria 
for evaluation will include: 
• 
The average daily (primary efficacy endpoint) and 8h overnight percent time 
in glucose target range of 70-180 mg/dL (3.9-10 mmol/L); 
• The average daily and 8h overnight duration (mins) and percent time with 
hypoglycemia will be measured, using thresholds of <70, <60, and <50 mg/dL 
(<3.9, <3.3, and <2.8 mmol/L, respectively); 
• The average daily and 8h overnight hypoglycemia incidence (event rate) at 
each of the specified glucose thresholds will be recorded; 
• The average daily and 8h overnight glucose AOC and AUC at each of the 
specified glucose thresholds; 
• The average glucose level by CGM between midnight and 08:00 (or nearest 
pre-breakfast timepoint). 
6.3.1.2 SMBG by POC Glucometer 
Throughout the study glucose will be robustly monitored and evaluated via CGM and 
POC glucometer. As a supplement to CGM, self-monitoring of blood glucose by POC 
glucometer will be used as an additional tool to evaluate glycemic eligibility and 
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efficacy endpoints for glycemic control. POC glucometer readings will be collected 
 from Screening through the 
Follow-up/EOT Visit on Day 14 after the patient’s final dose in the study (cumulative 
study Day 57).
 
 
 
glucometer 
manufacturer and model should be recorded in the study records. Several parameters 
to measure glycemic control by SMBG will be evaluated over the 2-week End of 
Treatment period after the final dose, compared to baseline. Criteria for evaluation, 
during treatment will include: 
• The average weekly incidence (event rate) of hypoglycemia at the glucose 
thresholds of <70, < 60, and < 50 mg/dL (or < 3.9, < 3.3, and < 2.8 mmol/L, 
respectively) 
6.3.1.3 Fasting Challenge 
Patients will undergo a 12h fasting challenge on Day -1 both at baseline (Week 1) and 
Week 7 of treatment. 
 
 
 
 
 
 
 
 
 
 
 fast should be ended when any of the following criteria have 
been met: 
• Predetermined fasting time of 12 hours has been reached; or 
• Blood glucose is <60 mg/dL (3.3 mmol/L); or 
• Patient has symptoms consistent with hypoglycemia. 
 
 
 
Several parameters from the fasting challenge will be evaluated at Week 7 of 
Treatment, compared to baseline.  Criteria for evaluation of the 12h fasting challenge 
will include: 
• Occurrence of hypoglycemia during a 12h fasting challenge: 
o Time to termination of fast; 
o Glucose nadir during fast; 
o Percentage of patients able to complete a fast; 
o Ketone levels at the conclusion of fast. 
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6.3.1.4 Other Efficacy 
Data collected regularly from patient diaries, dietary reviews/counseling, fasting 
glucose blood draws, concomitant medications and other assessments (see Schedule 
Appendix 1) will be utilized to assess efficacy outcomes including, but not limited to: 
• 
IV or enteral nutrition (glucose/dextrose) supplementation; 
• 
Patient incidence and rate of SOC or rescue medication use for hypoglycemia 
(dextrose or other); 
6.3.2 Assessment of Pharmacokinetics 
The single and repeat dose PK of RZ358 will be assessed throughout this study. 
Blood samples will be collected for RZ358 at time points per the SOAs in Appendix 1 
and Appendix 2. For the first 48 hours after each dose, all samples should be collected 
from the contralateral arm from infusion. Allowable deviations from the nominal time 
points are described in the SOAs. In all cases, the actual time of blood collection 
should be accurately recorded. The Sponsor will supply complete written instructions 
for collection, handling, processing, storage, and shipping of samples before study 
initiation. 
The single and repeat-dose PK of RZ358 will be assessed by population PK modeling 
which will be used to estimate parameters including, but not limited to: 
• AUCss: steady state area under the concentration-time curve 
• Cmaxss: steady state maximum concentration 
• Cavgss: steady state average concentration  
• t1/2: effective half-life 
• CL: total drug clearance 
• V: volume of distribution of the central compartment 
6.3.3 Assessment of Pharmacodynamics 
Blood samples will be drawn throughout the Treatment and Follow-up Periods of the 
study to evaluate the PD effects of the study drug, as specified in Appendix 1.  
Samples should be drawn as close to the scheduled time as possible, and in all cases 
the actual time of blood collection should be accurately recorded. The PD of RZ358 
compared to baseline will be assessed by:  
• Average levels of glucose, insulin, c-peptide, glucagon, FFAs, and ketones 
(beta-hydroxybutarate), at each of the specified collection timepoints; 
• Incidence of fasting blood glucose values >200, >250, and >300 mg/dL 
(>11.1, >13.9, and >16.6 mmol/L, respectively). 
6.3.4 Assessment of Demographics, Safety, and Other Procedures 
Safety assessments will adhere to all recommendations outlined in the International 
Conference on Harmonization (ICH), GCP and the protection of human safety. The 
interpretation of the safety and tolerability of RZ358 will be made based on the 
collection and assessment of safety parameters evaluated throughout the study, 
including vital signs, ECGs, physical examinations results, local (site) and systemic 
infusion observations, 
, clinical laboratory evaluations 
including glucose values, and AEs/SAEs. 
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6.3.5 Medical History 
Medical history will be recorded at Screening and will include full CHI history, 
clinically significant diseases, surgeries, cancer history, reproductive status or 
cardiovascular events. At the time of each follow-up physical examination, an interval 
medical history should be obtained and any changes in medications and allergies 
should be recorded.  
6.3.6 Vital Signs (Including Height and Weight) 
Vital signs will be measured and recorded at the time points designated on the 
Schedule of Assessments (see Appendix 1). The following measurements must be 
performed: systolic/diastolic blood pressure, pulse, and oral temperature. Vital signs 
will be measured after the patient has been in the supine position for at least 
5 minutes. All measurements will be recorded on the vital signs eCRF. Abnormal test 
results may be repeated at the discretion of the investigator and must be reported on 
the corresponding eCRF. When vital signs, ECGs, and/or blood sample collection 
occur at the same time, vital signs should be performed before ECGs and/or blood 
sample collection. 
Vital signs may be measured at unscheduled timepoints, if deemed necessary by the 
Investigator. 
Body height will be measured in centimeters (cm) and body weight in kilograms (kg).  
6.3.7 Physical Examination 
The investigator or qualified designee will perform a complete physical examination 
(genitourinary examination not required) and targeted abbreviated physical 
examinations as specified in the SOA (see Appendix 1). All pre-dose abnormal 
findings will be reported on the medical history eCRF. Any adverse change from the 
baseline physical examination will be documented on the AE eCRF. 
A full physical examination will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
An abbreviated physical examination is inclusive of neurological, cardiac, 
gastrointestinal, and pulmonary assessments.  
6.3.8 Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points designated on 
the Schedule of Assessments. 
The patient must be in a supine position in a rested and calm state for at least 
5 minutes before the ECG is conducted. If the patient is unable to be in the supine 
position, they should be in the most recumbent position possible. All ECGs should be 
performed in a standardized method, prior to blood draws or other invasive 
procedures. Each ECG must include the following measurements: QRS, QT, 
corrected QT, RR, and PR intervals, as well as an overall interpretation.  
The Principal Investigator (PI) or designated site physician will review and sign all 
ECGs. Results must be summarized in writing and classified as normal; abnormal; 
abnormal, clinically significant; or abnormal, not clinically significant. Once signed, 
the original ECG tracing will be retained with the patient’s source documents. At the 
request of the Sponsor, a copy of the original ECG will be made available. 
Unscheduled ECGs may be performed if there is a change from baseline or as deemed 
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6.3.9 Laboratory Evaluation 
Laboratory assessments will be performed by a central laboratory (see Laboratory 
Manual). Central laboratory results should be reviewed by the Investigator as it is 
received.  Any abnormalities must be evaluated in clinical context and the Investigator 
should determine if it is clinically significant.  Patient management is dependent upon 
close review of the laboratory data. 
The tests listed in Table 4 will be conducted on samples collected and analyzed by 
standard laboratory procedures at the time points designated on the Schedule of 
Assessments. Tests that are not done must be reported as such on the eCRFs.  
 


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6.3.11 Infusion Reactions 
6.3.11.1 Assessment of Local Infusion Site Reactions 
A local infusion site reaction is any local reaction occurring at the site of injection 
following study drug administration. A local infusion site reaction, including, but not 
limited to, erythema, induration, and pain, should be reported as an AE. If needed, 
local infusion site reactions should be treated, and any treatments should be reported 
on the eCRF and will be monitored closely. Detailed information regarding local 
infusion site reactions that occur during the study will be collected regardless of 
whether the events are serious or non-serious. 
 
 
 
 
6.3.11.2 Management Guidelines for Systemic Infusion-Related Reactions 
Signs of a possible anaphylactic, anaphylactoid or hypersensitivity reaction include 
but are not limited to, the following: 
• Fever, chills, pruritus, urticaria, angioedema, and skin rash; 
• Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, or 
hypertension; 
• Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting). 
Investigators and health care professionals should be trained to recognize and manage 
the signs and symptoms of a potential anaphylactic, anaphylactoid, or hypersensitivity 
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reaction and also be trained to accurately and appropriately report these events. If a 
patient experiences a suspected mild and/or non-serious hypersensitivity reaction, the 
case should be discussed with the Medical Monitor prior to continued dosing. Patients 
who experience a moderate to severe infusion-related anaphylactic, anaphylactoid or 
hypersensitivity reaction should have their infusion stopped immediately and should 
be treated according to the SOC for management for these reactions. In the case of 
any serious or severe infusion-related reaction, the study drug should be permanently 
discontinued. In these cases, the actual time and amount of study drug should be noted 
in the source and eCRF. Detailed information regarding anaphylactic, anaphylactoid, 
or hypersensitivity reactions that occur during the study will be collected, regardless 
of whether the events are serious or non-serious. 
In the event of an infusion-related reaction, unscheduled ADA and PK serum samples 
should be collected at the following three timepoints, in addition to the pre-specified 
collection schedule: as close to investigator-determined onset of the event as feasible, 
at investigator-determined resolution of the event, and 30 days after the resolution of 
the event. 
6.3.12 Meals  
The patient will be requested to follow his/her usual standard diet. At Screening, a 
dietician or other qualified medical professional will discuss with the patient/parent 
the usual diet consumed by the patient and will record the percent fat, protein, and 
carbohydrate the patient typically consumes per day, along with the patient’s usual 
food choices and frequency and timing of the usual eating pattern.  
During the inpatient portions of the study, meals and snacks will be provided by the 
inpatient facility per the patient’s usual standard diet. 
Meals will be served at the same time of day while patients are in the inpatient 
research facility.  
An afternoon and evening snack will be served. The evening snack must be consumed 
at a time that ensures at least 8 hours of fasting can occur before the following 
morning’s breakfast (for patients for whom fasting is feasible). Additional snacks may 
be served, if needed, at the Investigator’s discretion.  
Patients will be asked to try to consume their meals in their entirety, as often as 
possible. The date and time, content, and percent of the total not consumed of each 
meal and snack will be recorded. 
For outpatient days, the patient will be requested to follow the patient’s usual standard 
diet.  
6.3.13 Patient Diary 
Patients will use an electronic device to record and capture daily glucose events, 
 
 
device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with FDA regulations for electronic 
records (21 CFR Part 11). The data will be transmitted to a centralized database 
maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web 
server. The Sponsor will have view access only. System backups for data stored by 
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the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s or designee’s standard procedures. 
6.3.14 Adverse Events 
6.3.14.1 Safety definitions 
6.3.14.1.1 Adverse Event 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical study 
patient, which is either new in onset or pre-existing but worsened in severity or 
frequency, whether or not it has a causal relationship to the study investigational 
(medicinal) products or procedures. This includes events with onset from the time of 
providing written informed consent for participation in the study until the end of study 
visit, as defined in the protocol. Therefore, an AE may or may not be temporally or 
causally associated with the use of a medicinal (investigational) product. 
 
 
 
 
 
A clinical laboratory AE is any clinically significant laboratory abnormality that 
suggests a disease and/or organ toxicity and is of a severity, which requires active 
management, (i.e., change of dose, discontinuation of study product, more frequent 
follow-up or diagnostic investigation).
 
 
A treatment-emergent AE (TEAE) is defined as any clinically significant event that is 
not present before exposure to study drug or any event already present that worsens in 
either intensity or frequency after exposure to study drug. 
6.3.14.1.2 Adverse Drug Reaction 
AEs judged by either the reporting medically qualified professional or the Sponsor as 
having a reasonable suspected causal relationship to the study medication qualify as 
adverse drug reactions. 
6.3.14.1.3 Unexpected Adverse Reaction 
An unexpected adverse event is an adverse reaction, the nature or severity of which is 
not consistent with the applicable product information (e.g. Investigator’s Brochure 
for an unauthorized investigational medicinal product or summary of product 
characteristics for an authorized product). 
6.3.14.1.4 Serious Adverse Event (SAE) or Serious Adverse Reaction 
Any untoward medical occurrence (AE) that at any dose meets any of the following 
criteria:  
1. Results in death;  
2. Is life-threatening; 
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(Note: The term “life-threatening” refers to an event in which the patient is at 
immediate risk of death at the time of the event, not an event that might have 
caused death if it was more severe.) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization;  
(Note: Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. Hospitalization for administrative, study-related, or social 
purposes, for elective treatment of a pre-existing condition that did not worsen 
from baseline, or hospitalization scheduled in advance of study participation is 
not considered to be an AE/SAE, under this criterion.) 
4. Results in persistent or significant disability/incapacity;  
(Note: The term(s) disability/incapacity means a substantial disruption of a 
person’s ability to conduct normal life functions [e.g., following the event or 
clinical investigation the patient has significant, persistent or permanent 
change, impairment, damage or disruption in his/her body function or 
structure, physical activity and/or quality of life]. This definition is not 
intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or 
accidental trauma (e.g. sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption);  
5. Is a congenital anomaly/birth defect in a neonate/infant born to a biologic 
parent exposed to study drug;  
6. Is an important medical event, based on the Investigator’s medical judgement. 
(Note: Other events that may not result in death, are not life threatening, or do 
not require hospitalization, may be considered a SAE when, based upon 
appropriate medical judgment, the event may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed 
above.  
6.3.14.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse 
reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator’s Brochure for an unapproved investigational product or 
Summary of Product Characteristics for an approved product). 
6.3.14.2 Procedures for Collecting and Recording Adverse Events 
6.3.14.2.1 General 
Collection of all AEs (serious AEs and non-serious AEs) will commence from the 
time the patient signs the informed consent to participate in the study, and continue 
through the End-of-Study follow-up visit, as specified in the study Schedule of 
Assessments (Appendix 1). The occurrence of AEs must be sought by non-directive 
questioning of the patient or the patient’s Legally Authorized Representative (LAR) at 
each visit during the study (e.g., “How are you feeling?”, “How has the patient been 
feeling?”) or may be spontaneously reported by the patient (or LAR) during or 
between visits or through physical examination findings, laboratory test findings, or 
other assessments. All identified AEs, regardless of seriousness, severity, or presumed 
relationship to study drug, must be recorded and described in the patient’s source 
records and eCRF Events that occur after the conclusion of the study should also be 
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that the event is related to study drug, and such events meeting serious criteria should 
also follow SAE reporting guidelines.  
The following attributes must be evaluated and recorded for each event, and 
guidelines for doing so are provided:  
1. Description (i.e. event term);  
2. Dates of onset and resolution, including timing of onset relative to 1st dose of 
study drug;  
3. Severity (as described in Section 6.3.15.2.2);  
4. Assessment of causality / relatedness to study drug (as described in Section 
6.3.15.2.2);  
5. Seriousness (as described in Section 6.3.15.2.2);  
6. Action taken 
 
 
 
 
 
 
7. Outcome/status of the event. (Note: All AEs and SAEs should be followed up 
until resolution or permanent outcome of the event [i.e. deemed stable], or 
until the Investigator and Sponsor conclude that further follow-up is not 
necessary. 
 
 
 
 
 
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6.3.14.2.2 Adverse Event Severity Grading 
The severity of AE will be assessed by the Investigator and graded according to the 
NCI Clinical Trial Classification for Adverse Events (CTCAE). Event terms not listed 
in the NCI-CTCAE will be evaluated using the following grading scale (see Table 6). 
Table 6:  Grading Scale (Terms Not Listed in NCI-CTCAE) 
Term 
Definition 
Grade 1, Mild 
Signs or symptoms easily tolerated and 
generally not causing interference with 
normal activities; of little concern to the 
patient and of little or no clinical 
significance; is not expected to have any 
effect on the patient’s health or well-being; 
may or may not require medical intervention 
Grade 2, Moderate 
Causes interference with some usual 
activities; experience is of some concern to 
the patient’s health or well-being; may 
require medical intervention 
Grade 3, Severe 
Causes interference with most regular 
activities; experience is of definite concern 
to the patient and/or poses substantial risk to 
the patient’s health or well-being; likely to 
require medical intervention 
Grade 4, Life-threatening 
The patient was at immediate risk of death 
from the experience, as it occurred 
Grade 5, Death 
The event resulted in death (but death is not 
an AE)  
6.3.14.2.3 Relationship of AEs 
The causal relationship of AEs to the study drug must be assessed by the Investigator, 
or by a medically qualified designee, in accordance with the following criteria 
detailed in Table 7. 
 
Table 7:  Causal Relationship of AE to Study Drug 
Term 
Definition 
Related 
There is a temporal relationship between administration of the study 
drug and the event, and: 
• 
The event is known to occur with the study drug or represents a 
known reaction to drugs in the same class, or is predicted by 
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• 
The event cannot be reasonably explained by the patient’s 
clinical state or other factors (e.g. medical history, concurrent 
medications, or concomitant medications); 
• 
The event resolves with interruption of study drug (de-
challenge) and recurs with resumption of study drug (re-
challenge), as applicable. 
Not Related 
There is not a reasonable possibility that the administration of the study 
drug caused the event, there is no reasonable temporal relationship 
between the study drug and event onset, and/or the event can be 
explained by the patient’s clinical state or other factors, i.e. an alternate 
etiology has been established (eg, disease under the study, concurrent 
diseases and concomitant medications). 
 
6.3.14.3 Overdose 
An overdose is defined as any dose administered to or taken by a study patient, either 
accidentally or intentionally, that exceeds the highest intended per dose amount or 
frequency for the assigned cohort, based on the protocol. Investigators should decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.  
Any occurrence of an overdose should be reported to the Sponsor (or designee) within 
24 hours of becoming aware, regardless of whether the event represents an AE. The 
event should also be recorded in the patient’s source file and the eCRF. Unless the 
overdose also meets AE definitions, it should not be reported as an AE.   
6.3.14.4 Pregnancy 
Pregnant patients will not be allowed to participate in this study. If a patient becomes 
pregnant while on study, the patient will be discontinued and will complete end of 
study procedures for safety. The Sponsor must be notified if any patient becomes 
pregnant either while receiving study drug or within 105 days after having received 
the last study drug dose. This includes any pregnancies in the partner of a male study 
patient, or if a patient’s sperm is used to impregnate a female during the study. The 
Investigator must inform the Sponsor as soon as possible and no later than 24 hours 
after knowing of the pregnancy, by completing the Pregnancy eCRF page. If the site 
has a temporary interruption in its internet or computer access, the back-up Pregnancy 
paper form will be completed and e-mailed to the sponsor within 24 hours of 
awareness. When the eCRF becomes available, the Pregnancy must be entered by the 
site within 24 hours. Pregnancy should not be recorded on the AE eCRF. 
Upon knowledge of a pregnancy, the pregnant female will be asked to sign a release 
of information form to allow the Investigator to collect information about the 
pregnancy, delivery, and final outcome, including health of the baby, as required for 
regulatory reporting purposes. All reported pregnancies (even if a patient withdraws 
from the study) must be followed up by the Investigator to final outcome, using the 
pregnancy and pregnancy follow-up forms. Follow-up and outcome, including any 
premature termination, must be reported to the Sponsor (or designee) in a timely 
manner. An evaluation after the birth of the child may also be conducted.  
Pregnancy itself should not be recorded as an AE, although any complications 
ensuing from a pregnancy must be recorded as AE(s). If the infant has a congenital 
anomaly/birth defect this must be reported and followed up as a SAE. 


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6.3.15 Procedures for Reporting Serious Adverse Events 
All new SAEs, regardless of causal relationship, should be reported to the Sponsor (or 
designee) in writing within 24 hours of the site’s knowledge of the event. A copy of 
the initial SAE report must be received within 1 business day. 
The SAE report should provide as much of the required information as is available at 
the time. The following minimum information is required for reporting an SAE: 
patient identification, reporting source, event term and a short description of the 
event, criterion for seriousness, and initial causality assessment. Supplemental 
information may be transmitted using a follow-up report and should not delay the 
initial report. The Sponsor (or designee) may contact the investigational site to solicit 
additional information or to follow-up on the event. The SAE Report Form should be 
completed by an Investigator following the specific completion instructions. 
If there is any doubt whether the information constitutes an SAE, the information will 
be treated as an SAE for the purposes of this protocol. 
All relevant documentation pertaining to the SAE (additional laboratory tests, 
consultation reports, discharge summaries, post-mortem reports, etc.) will be provided 
by an Investigator to the Sponsor (or designee) in a timely manner. Investigators must 
respond to any request for follow-up information (e.g., additional information, 
outcome, final evaluation, other records where needed) or to any question the Sponsor 
(or designee) may have on the AE. 
The Sponsor will be responsible for notifying the FDA of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the Sponsor’s initial receipt of the information, and no later 
than 15 days for all other suspected unexpected serious adverse reactions (SUSARs). 
The Sponsor must notify FDA and all participating Investigators in an Investigational 
New Drug Application safety report of potential serious risks, from clinical trials or 
any other source, as soon as possible, but in no case later than 15 calendar days after 
the Sponsor determines that the information qualifies for reporting. 
The Sponsor will be responsible for reporting all SUSARs and any other applicable 
SAEs to regulatory authorities, including the FDA, European Medicines Agency 
(according to Directive 2001/20/EC), and to all country Regulatory Authorities where 
the study is being conducted, according to local applicable regulations. Any SUSARs 
will be reported to the IRB/Independent Ethics Committee (IEC) per their institutional 
policy by an Investigator or Sponsor (or designee) according to country requirements. 
Investigators should keep copies of each report, documentation of IRB/IEC 
notification, and acknowledgement of receipt in the site’s study file. 


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7 
STATISTICAL METHODS 
7.1 
General Considerations 
This is a Phase 2 Proof of Concept study and is not powered for statistical 
significance. Detailed methodology for analyses and summary of the data will be 
documented in the study Statistical Analysis Plan (SAP), which will supersede the 
protocol, where applicable. However, any major modification of the outcome 
measures and/or its analysis will also be reflected in a protocol amendment. 
Continuous variables will be summarized by using the following descriptive statistics: 
mean, standard deviation (SD), coefficient of variation (CV), number of observations 
(N), median, minimum, and maximum. The frequency and percent of observed levels 
will be reported for categorical measures. In general, all data will be listed, sorted by 
patient and, when appropriate, by study day and study time point within patient. 
Confidence intervals or p-values, without correction for multiplicity, may be produced 
for hypothesis generating purposes. 
Subgroup analyses may also be performed to further explore the study data. These 
analyses may include t-tests, Wilcoxon rank-sum tests, and Pearson 
correlation/Spearman correlation for continuous measures; for categorical variables, 
chi-square and Fisher’s exact tests may also be performed, as appropriate. Populations 
used for sub-analysis will be defined in the SAP. 
7.2 
Disposition of Patients 
The disposition of patients will be described with summaries of the number of 
patients treated and discontinued from the study, including the primary reason for 
premature discontinuation by cohort. 
7.3 
Protocol Deviations 
See Section 9.3.4. 
7.4 
Analysis Populations 
For the purposes of this study, the following populations will be identified: 
Safety population: all patients enrolled in the study who receive at least one dose of 
study drug.  
Per Protocol Population: All patients who receive at least 4 weeks of study drug (2 bi-
weekly doses), with no major protocol violations. 
PK population: all patients who receive study drug and have a sufficient number and 
quality (biologically plausible) of results.  
7.5 
 Demographics, Baseline Characteristics and Concomitant Medications  
Summaries of patient disposition, demographics, and baseline characteristics will be 
provided by cohort. 
7.6 
Treatment Compliance 
Frequency and distribution of the number of received doses will be presented. 
Treatment duration for all patients will be described. 
7.7 
Efficacy and Pharmacodynamic Analyses 
The primary efficacy and PD analysis will be conducted in the per-protocol 
population, which will include all patients who received at least 4 weeks of study drug 
(2 bi-weekly doses), without significant protocol deviations. CGM data will be 
compiled and output into parameters for analysis. Actual data and change from 


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baseline will be summarized descriptively for the primary endpoint and each 
secondary or exploratory continuous CGM parameter, as well as for SMBG by POC 
glucometer, fasting glucose, and other PD markers, at the protocol-specified 
timepoints and pre-specified evaluation periods. Corresponding mean (SD) and/or 
Box-plots will be produced for CGM parameters, to illustrate the descriptive statistics, 
as appropriate. Figures and graphs will be created to display mean and individual PD 
results, as appropriate. Incidence rates will be normalized to the daily (CGM) or 
weekly (SMBG) average. Categorical events will be summarized by frequency 
counts, as applicable. The requirement for rescue medications and the use of 
background SOC medication or supplemental nutrition will be listed by patient and 
summarized, where appropriate. Statistical comparisons may be performed as 
appropriate, and will be described in the SAP and/or clinical study report.   
7.8 
Safety Analyses 
Safety analyses will involve an examination of AEs, vital signs, ECGs, physical 
examinations results, infusion-site observations, 
 and 
clinical laboratory evaluations including glucose values. Individual patient listings 
will be reviewed, and summary results with descriptive statistics will be provided, 
where appropriate. No statistical testing will be performed on safety data. 
A by-patient TEAE data listing, including verbatim term, preferred term and SOC, 
treatment, severity, and relationship to cohort, will be provided. 
The number of patients experiencing AEs and number of AEs will be summarized by 
cohort using frequency counts. 
Safety data, including laboratory evaluations and vital signs assessments, will be 
summarized by cohort and time point of collection. 
The occurrence of immunogenicity will be assessed and if confirmed, titer values will 
be reported by cohort and time point collection. No formal statistical evaluation will 
be performed. Any patient in which ADAs are detected will be followed for further 
assessment. 
Descriptive statistics (arithmetic mean, standard deviation [SD], sample size [N], 
median, minimum, and maximum) will be calculated for quantitative safety data and 
frequency counts will be compiled for classification of qualitative safety data.   
A mean change-from-baseline table will be provided for vital signs, ECGs and 
clinical laboratory results, per cohort. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results, as appropriate.  
A normal-abnormal shift table will be presented for ECGs, as appropriate. 
Changes from baseline in physical examinations and 
 will be 
described in the text of the final report. 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available to the Sponsor or designee.  
Concomitant medications will be listed by treatment and coded using the most current 
World Health Organization (WHO) drug dictionary available to the Sponsor or 
designee. 
Medical history will be listed by patient. 
Infusion site reaction will be assessed. 
No formal inferential statistics will be applied to safety assessments. 
Additional analyses will be performed as appropriate. 
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7.9 
Pharmacokinetic Analysis 
The individual and mean RZ358 serum concentrations will be summarized by 
treatment cohort and planned sample times in tables and figures. Serum 
concentrations for samples collected within 30 min after the dosing infusion will be 
reported as the observed concentration at the end of infusion (CEOI). Concentrations 
will be summarized using descriptive statistics. The study design and planned PK 
sample collection are not suitable for the calculation of PK parameters by 
noncompartmental methods. Specifically, the number of PK samples within dosing 
intervals is insufficient to support noncompartmental estimation of AUC; and due to 
the long half-life of RZ358, steady state is not expected to be achieved by the end of 
the 8-week Treatment Period. Therefore, the observed serum RZ358 concentration-
time data will be used to develop a population PK (popPK) model to describe the PK 
of RZ358 in patients with CHI. PopPK modeling will also investigate the effects of 
selected covariates on RZ358 PK such as age, body weight, gender and race, as data 
permit.  
 
The popPK model will be used to estimate PK parameters for each treatment cohort, 
including but not limited to the following: 
• AUCss: steady state area under the concentration-time curve; 
• Cmaxss: steady state maximum concentration; 
• Cavgss: steady state average concentration;  
• t1/2: effective half-life; 
• CL: total drug clearance; 
• V: volume of distribution of the central compartment. 
 
Descriptive statistics will be presented for PK parameters, including but not limited to 
Cmax, Tmax, t1/2, and AUC. The relationships between dose and Cmax and AUC will be 
analyzed for dose proportionality. The PK results of this study may be combined with 
those of other studies for analysis and modeling (e.g., population PK and PK-PD), and 
reported separately Detailed methods for the PK modeling will be provided in a 
separate PK modeling analysis plan.   
7.10 Interim Analyses 
This is an open label study. Safety, PD, and PK data will be examined on an ongoing 
basis to ensure safety of the study patients. 
7.11 Determination of Sample Size 
The sample size chosen for this study was selected without statistical considerations. 
It has been determined adequate to meet the study objectives. Patients who withdraw 
from the study may be replaced on a case-by-case basis after discussion and 
agreement with the Medical Monitor. 


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8 
DATA MANAGEMENT 
8.1 
Data Collection 
The trained investigator site staff will enter the data required by the protocol into the 
eCRFs from source documents (e.g., medical records and study-specific data capture 
tools as needed), and will upload the CGM data into a 21 CFR Part 11 Web Based 
Data Capture System. All data collection information must be traceable to these 
source documents.  
Direct recording of the data in the eCRF is not allowed for this study 
Responsible Monitor will review eCRFs entered by investigational staff for 
completeness and accuracy. Checks for data discrepancies in the eCRFs will be 
performed and the resulting queries will be notified to the investigational site. 
Designated investigator site staff are required to respond to queries and make any 
necessary changes to the data.  
A validated, electronic database will be employed from the EDC system. An audit 
trail of all changes to this database, including the date, reason for the data change and 
who made the change, will be maintained within the same database. The audit trail 
will be part of the archived data at the end of the study. 
The complete data management process (data capture, data entry, data validation, 
checks on plausibility, query handling, data editing after entry, coding, data base 
closure, etc.) will be defined in advance within a data handling plan/ data 
management plan with a description of the personnel responsible for data entry. 
8.2 
Data Correction 
Automatic and manual queries will be defined according to the data validation plan. 
These queries will be generated by the Data Management Department and sent 
through the electronic data capture (EDC) system for clarification. Corrections will be 
entered directly into the system. This procedure will be repeated until all queries are 
resolved. All query forms will be linked to the eCRF in the EDC system. 
8.3 
Data Handling 
The final data will be transferred to the SAS-system for analyses in accordance with 
the SAP. The MedDRA dictionary will be used for coding of AEs and concomitant 
diseases. Concomitant medication will be coded using the World Health Organization 
Drug Dictionary A(natomical) T(herapeutical) C(hemical) code. 
8.4 
Data Quality Assurance 
The Sponsor and/or their designee (i.e. Monitor engaged by CRO company) will 
conduct a site visit to verify the qualifications of each investigator, inspect the site 
facilities, and inform the investigator of responsibilities and the procedures for 
ensuring adequate and correct documentation. 
The investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study for 
each study participant. All information recorded on the eCRFs for this study must be 
consistent with the patient’s source documentation (i.e. medical records). 
8.5 
Handling of Missing, Unused, and Spurious Data  
All available efficacy and safety data collected for the study will be included in data 
listings and/or summary tables. The handling of missing data will be described in the 
study SAP. 


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9 
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
Study Initiation Activities 
The investigator(s) are informed about study objectives and methods, the inclusion 
and exclusion criteria, the time-schedule, and study procedures at a Pre-Study Visit by 
the Monitor (if necessary), an investigators’ meeting, and during the Site Initiation 
Visit by the Monitor. 
9.2 
Training of Site Staff 
The PI will ensure that everyone assisting with the clinical study is adequately 
informed about the protocol, the investigational product(s), and their study-related 
duties and functions. Furthermore, the investigator will maintain a list of qualified 
persons to whom the investigator has delegated study-related duties. 
9.3 
Documentation and Filing 
9.3.1 CRF System 
The Investigator and persons authorized by the Investigator will be instructed about 
how to complete the eCRF. Entries in the eCRF must only be made by the 
Investigator or persons authorized by the Investigator. A list of all persons who are 
allowed to make entries in the eCRF must be available in each study site. 
The investigator must ensure that all data entries in the eCRF are complete, accurate, 
legible and reported in a timely manner. Data reported on the eCRF should be 
consistent with the source documents or the discrepancies should be explained. 
Entries will be checked against appropriate source documentation by the Monitor. 
9.3.2 List of Patients (patient identification log) 
The Investigator will keep a confidential list of names of all patients participating in 
the study, so that the patients’ records can be identified if necessary.  
In addition, the Investigator will keep a list of all patients screened on a screening log 
to document identification of patients who were consented and entered study 
screening. If someone is not eligible to participate in the study, a reason should be 
provided. 
9.3.3 Source Data 
Per ICH, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. Source 
data are contained in source documents which comprise clinical documentation, data, 
and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, patients’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study).  
9.3.4  Protocol Deviations 
The Investigator should document and explain any protocol deviations.  The 
Investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and IRB/EC in accordance with 
established IRB/EC policy and procedures. 


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The Sponsor will review all protocol deviations and assess whether any represent a 
serious breach in GCP guidelines and require reporting to health authorities.  As per 
the Sponsor’s or authorized designee’s standard operating procedures, prospective 
requests to deviate from the protocol, including request to waive protocol eligibility 
criteria are not allowed. 
Deviations from the protocol will be judged during the study and/or when an 
individual patient’s eCRF is completed (monitored) and will be recorded as either 
major or minor.  
Before analyzing the data, a data review meeting (DRM) will take place where 
protocol deviations will be classified (major/minor protocol deviations) for statistical 
analysis 
9.3.5 Investigator Site File / Regulatory Binder 
Before site initiation, the CRO will provide an Investigator Site File (ISF) to each site. 
The ISF will include essential documents as defined by the ICH GCP guideline and 
applicable local requirements that are required for study initiation at the investigational 
site. 
From that point onwards, the Investigator will be responsible for the update and 
maintenance of the ISF, which will be reviewed periodically by the Monitor(s). These 
documents will be reviewed during an audit by the Sponsor or an inspection by the 
Regulatory Authorities. 
All study-related documents are to be archived and stored according to the local 
regulatory requirements and agreement with the study Sponsor. 
Details pertaining to the retention and archiving of study documents are found in 
Section 10.4. 
9.4 
Monitoring 
The Monitor is responsible for checking the quality of data and ensuring that the 
investigative site is adhering to the study protocol. Additionally, the Monitor ensures 
that the site is following the legal and ethical requirements as stated in local laws and 
the principles of GCP. 
Following the site prequalification and/or initiation of the study site, periodic 
monitoring visits will be conducted by Sponsor or their designee. The interval between 
monitoring visits will depend on the recruitment rate and the complexity of the study. 
Source data verification is an essential part of the monitoring process and the 
investigator must grant direct access to the original patient’s source documents. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
9.5 
Audits and Inspections 
Audits will be performed according to the corresponding audit program. The 
Sponsor’s Quality Assurance Department or designee may visit the investigative site 
to audit the performance of the study, as well as all study documents. Audits may also 
be performed by contract auditors who will be instructed about the timing and extent 
of the audits. In the event of an audit at the investigational site, the Monitor will 
usually accompany the auditor(s).  
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at 
any time, even after the end of the study. The Investigator is to notify the Sponsor 
immediately of any such inspection. The Investigator and institution will permit 
study-related monitoring, audits, reviews by the IEC/IRB and/or Regulatory 


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Authorities, and will allow direct access to original source documents for monitoring, 
audits, and inspections. 


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10 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor 
and investigator abide by the principles of the GCP guidelines of the ICH, and of the 
Declaration of Helsinki. The study also will be carried out in keeping with local legal 
requirements.  
10.2 Informed Consent 
Before the first study specific screening procedure can be performed each patients 
informed consent must be obtained (or his/her legally authorized representative) 
according to the regulatory and legal requirements of the participating country 
(i.e., the Declaration of Helsinki, ICH GCP, US Code of Federal Regulations for 
Protection of Human Subjects (21 Code Federal Regulation [CFR] 50.25 [a] and [b], 
CFR 50.27, and CFR Part 56, Subpart A), and other applicable local regulations. This 
consent form must be approved by responsible IRB/IEC and must be signed and dated 
by the patient (or his/her legally authorized representative) and authorized consenter 
and retained by the investigator as part of the study records. The investigator will not 
undertake any investigation specifically required only for the clinical study until valid 
consent has been obtained. The terms of the consent and when it was obtained must 
also be documented in the patient’s medical records and eCRF. 
The explicit wish of a minor, or mentally incapacitated adult, who is capable of 
forming an opinion and assessing the study information, to refuse participation in or 
to be withdrawn from the study at any time will be considered by the investigator. 
If a protocol amendment is required, the informed consent form may need to be 
revised to reflect the changes to the protocol. If the consent form is revised, it must be 
reviewed and approved by the appropriate IEC/IRB, and signed by all patients 
subsequently enrolled in the study, and potentially those currently enrolled in the 
study if applicable. 
10.3 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will 
be approved by the IEC/IRB/Competent Authorities, in accordance with local 
regulatory requirements. The Sponsor must ensure that all ethical and regulatory 
requirements have been met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Regulatory Agency approval prior to implementation, in accordance with 
national regulations.  
All amendments will be distributed to all protocol recipients, with appropriate 
instructions. 
10.4 Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum 
of 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However, these documents should be retained for a longer 
period if required by the applicable regulatory requirements. 


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Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification 
to the Sponsor. 
10.5 Administrative Structure 
This study will be sponsored and managed by Rezolute, Inc. The Sponsor will provide 
oversight of the CRO(s) managing the following; clinical operations, data, 
programming and statistical management, medical monitoring oversight and CGM 
device procurement including CGM data uploads and reporting. CRO(s) will provide 
study, site and patient management, global regulatory support, medical and site 
monitoring pharmacovigilance activities, device services and data management which 
includes both EDC and CGM data collection.  
Randomization and drug distribution will occur through an RTSM system that is fully 
integrated into the EDC which will be used for data collection. 
CGM data collection will be done through the internet in a software-as-a-service 
model. The software will provide a system-compliant audit trail of all relevant data 
collected and uploaded from the CGM device and all changes made within the data. 
Each activated site will upload the CGM device specific software to a workstation 
computer at the site enabling the site to be able to access and upload patient as often 
as needed throughout the duration of the CGM monitoring.  
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests, biomarker and PK analyses). 
 
10.6 Dose Escalation Review Committee 
A Dose Escalation Review Committee will assess all available and relevant interim 
data from each cohort to determine the appropriateness of cohort escalation. The 
criteria for halting dose escalation are further specified in the protocol in Section 
5.1.2. 
 
10.7 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions 
or events that suggest a possible hazard to patients if the study continues, the study 
may be terminated after appropriate consultation between the relevant parties. The 
study may also be terminated early at the Sponsor’s discretion in the absence of such 
a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study; 
• Failure to enroll patients at an acceptable rate; 
• A decision on the part of the Sponsor to suspend or discontinue development of 
the drug. 
 


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10.8 Confidentiality 
Patient medical information obtained as part of this study is confidential. The use, 
transfer and disclosure of all personal information, including health related 
information, shall be in strict compliance with all applicable privacy laws. The 
anonymity of participating patients must be maintained. Patients will be identified on 
eCRFs and other documents submitted to CRO by their patient number allocated in 
the trial, not by name. Documents not to be submitted to CRO that identify the patient 
(e.g., the signed informed consent, patient identification list) must be maintained by 
the investigator as part of the ISF in a secure and confidential manner.  
10.9 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in 
accordance with all local legal requirements. The civil liability of the Investigator, the 
persons instructed by the Investigator and the hospital, practice or institute in which 
they are employed and the liability of the Sponsor with respect to financial loss due to 
personal injury and other damage that may arise as a result of the carrying out of this 
study are governed by the applicable law. 
The Sponsor will arrange for patients participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being 
tested or by medical steps taken in the course of the study.  
 
10.10 Publication of Data and Protection of Trade Secrets 
Regardless of the outcome of the trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for disclosure of study results in appropriate government registries such 
as ClinicalTrials.gov and EudraCT, as applicable. 
The Investigator must agree to submit for review and approval all manuscripts or 
abstracts/posters to the Sponsor prior to submission for publication or presentation.  
This allows the Sponsor to protect proprietary information and to provide comments 
based on information from other studies that may not be available to the Investigator. 
 
 


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11 REFERENCE LIST 
 
Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current 
trends in diagnosis and therapy. Orphanet J Rare Dis  2011;6:63. 
 
Avatapalle HB, Banerjee I, Shah S, et al. Abnormal Neurodevelopmental Outcomes 
are Common in Children with Transient Congenital Hyperinsulinism. Front 
Endocrinol (Lausanne)  2013;4:60. 
 
Bahi-Buisson N, Roze E, Dionisi C, et al. Neurological aspects of hyperinsulinism-
hyperammonaemia syndrome. Dev Med Child Neurol  2008;50(12):945-9. 
 
Banerjee I, Forsythe L, Skae M, et al. Feeding Problems Are Persistent in Children 
with Severe Congenital Hyperinsulinism. Front Endocrinol (Lausanne)  2016;7:8. 
 
Beltrand J, Caquard M, Arnoux JB, et al. Glucose metabolism in 105 children and 
adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care  
2012;35(2):198-203. 
 
Buraczewska M, Szymanska E, Brandt A, et al. Congenital hyperinsulinism in Polish 
patients—how can we optimize clinical management? Endokrynol Pol  
2015;66(4):322-8. 
 
Corbin JA, Bhaskar V, Goldfine ID, et al. Inhibition of insulin receptor function by a 
human, allosteric monoclonal antibody: a potential new approach for the treatment of 
hyperinsulinemic hypoglycemia. Mabs  2014;6(1):262-72. 
 
De las Heras J, Garin I, de Nanclares GP, et al. Familial hyperinsulinism-
hyperammonemia syndrome in a family with seizures: case report. J Pediatr 
Endocrinol Metab  2010;23(8):827-30. 
 
FDA. Drug Safety Communication. FDA warns about a serious lung condition in 
infants and newborns treated with Proglycem (diazoxide). 16 July 2015. Available at: 
https://www.fda.gov/media/93285/download  Last accessed: 22 July 2019. 
 
FDA. Guidance for Industry. Drug-induced liver injury: premarketing clinical 
evaluations. July 2009. 
 
Gataullina S, Dellatolas G, Perdry H, et al. Comorbidity and metabolic context are 
crucial factors determining neurological sequelae of hypoglycemia. Dev Med Child 
Neurol  2012;54(11):1012-7. 
 
Guemes M and Hussain K. Hyperinsulinemic Hypoglycemia. Pediatr Clin North Am  
2015;62(4):1017-36. 
 
Iannaccone R, Federle MP, Brancatelli G, et al. Peliosis hepatis: spectrum of imaging 
findings. AJR Am J Roentgenol  2006;187(1):W43-52. 
 
Issafras H, Bedinger DH, Corbin JA, et al. Selective allosteric antibodies to the 
insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. J 
Diabetes Sci Technol  2014a. 


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Lord K and De Leon DD. Monogenic hyperinsulinemic hypoglycemia: current 
insights into the pathogenesis and management. Int J Pediatr Endocrinol  
2013;2013(1):3. 
 
Lovvorn HN, 3rd, Nance ML, Ferry RJ, Jr., et al. Congenital hyperinsulinism and the 
surgeon: lessons learned over 35 years. J Pediatr Surg  1999;34(5):786-92; discussion 
792-3. 
 
Mazor-Aronovitch K, Gillis D, Lobel D, et al. Long-term neurodevelopmental 
outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol  
2007;157(4):491-7. 
 
Mohamed Z, Arya VB and Hussain K. Hyperinsulinaemic hypoglycemia: genetic 
mechanisms, diagnosis and management. J Clin Res Pediatr Endocrinol  
2012;4(4):169-81. 
 
Neylon OM, Moran MM, Pellicano A, Nightingale M and O’Connell MA. Successful 
subcutaneous glucagon use for persistent hypoglycemia in congenital 
hyperinsulinism. J Pediatr Endocrinol Metab  2013:1-5. 
 
Senniappan S, Arya VB and Hussain K. The molecular mechanisms, diagnosis and 
management of congenital hyperinsulinism. Indian J Endocrinol Metab  
2013;17(1):19-30. 


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Appendix 1 
 
 
 
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SAP_001.pdf: 
Rezolute, Inc. 
Statistical Analysis Plan  
Final Version 2.0 
                                                              Private and Confidential 
                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
 
STATISTICAL ANALYSIS PLAN 
 
TITLE PAGE 
 
 
 
An Open-Label Multiple-Dose Study of RZ358 in Patients with 
Congenital Hyperinsulinism 
 
 
 
 
 
Final Version 2.0: AUG 17, 2022 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from  
Rezolute, Inc. 
 


Rezolute, Inc. 
Statistical Analysis Plan  
Final Version 2.0 
                                                              Private and Confidential 
                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
CONFIDENTIAL  
 
 
 
 
 
 
 
 
 
 Page 2 of 63 
 
TABLE OF CONTENTS 
PAGE 
 
 
TITLE PAGE ........................................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................................... 2 
DECLARATION ..................................................................................................................... 4 
REVISION HISTORY............................................................................................................. 5 
LIST OF ABBREVIATIONS .................................................................................................. 6 
1. 
INTRODUCTION ................................................................................................... 8 
2. 
STUDY DETAILS .................................................................................................. 8 
2.1. 
Study Objectives...................................................................................................... 8 
2.2. 
Study Design ........................................................................................................... 8 
2.2.1. 
Schedule of Assessments....................................................................................... 12 
2.3. 
Determination of Sample Size ............................................................................... 19 
2.4. 
Randomization....................................................................................................... 19 
2.5. 
Blinding ................................................................................................................. 19 
3. 
DATA ANALYSIS CONSIDERATIONS ........................................................... 19 
4. 
DEFINITIONS & DERIVATIONS ...................................................................... 23 
4.1. 
ENDPOINT DERIVATIONS ............................................................................... 25 
5. PRIMARY AND SECONDARY ENDPOINTS ............................................................... 28 
5.1. 
Primary Endpoint .................................................................................................. 28 
5.2. 
Secondary Endpoints ............................................................................................. 28 
5.3. 
Additional (Exploratory) Endpoints ...................................................................... 28 
6. 
ANALYSIS POPULATION AND TREATMENT GROUPS ............................. 29 
6.1. 
Analysis Population ............................................................................................... 29 
6.2. 
Treatment Groups .................................................................................................. 29 
7. 
ANALYSIS METHODS AND REPORTING DESCRIPTION ........................... 30 


Rezolute, Inc. 
Statistical Analysis Plan  
Final Version 2.0 
                                                              Private and Confidential 
                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
CONFIDENTIAL  
 
 
 
 
 
 
 
 
 
 Page 3 of 63 
 
 
 
7.1.1. 
Subject Disposition................................................................................................ 30 
7.1.2. 
Demography and Baseline Characteristics ............................................................ 30 
7.1.3. 
Medical and Surgical History ................................................................................ 30 
7.1.4. 
Prior and Concomitant Medications ...................................................................... 31 
7.1.5. 
Protocol Deviation ................................................................................................. 31 
7.1.6. 
Study Drug Exposure and Treatment Compliance ................................................ 32 
7.1.7. 
Efficacy Analysis .................................................................................................. 33 
7.1.7.1. 
Primary Endpoint .................................................................................................. 33 
7.1.7.2. 
Secondary Endpoints ............................................................................................. 33 
7.1.7.3. 
Exploratory Endpoints ........................................................................................... 34 
7.1.7.4. 
Summary of Efficacy Endpoint Analysis Strategy................................................ 37 
7.1.8. 
Safety Analysis ...................................................................................................... 42 
7.1.9. 
PK Analysis ........................................................................................................... 49 
7.1.10. 
Pooled Analyses .................................................................................................... 50 
7.1.11. 
Subgroup Analyses ................................................................................................ 50 
7.1.12. 
Interim Analysis .................................................................................................... 51 
7.1.13. 
Changes to Analyses Specified in Protocol ........................................................... 51 
9. 
APPENDIX ........................................................................................................... 53 
9.1.1. 
AUC and AOC Derivation .................................................................................... 53 
9.1.2. 
Anticipated List of TLFs ....................................................................................... 55 

 


Rezolute, Inc.
Statistical Analysis Plan
Final Version 2.0
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                                                          Study No. RZ358-606
                                                              Date: AUG 17, 2022
CONFIDENTIAL
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DECLARATION
I, the undersigned, declare that I have prepared the statistical analysis plan along with TLF mockups
and that to the best of my knowledge this document is internally consistent with protocol and
scientifically rational.
Prepared by:
I, the undersigned declare that I have reviewed the statistical analysis plan along with TLF mockups
and that to the best of my knowledge the document is internally consistent with protocol and
scientifically rational.
Reviewed by:
AUTHORIZATION: I, the undersigned, declare that I have reviewed the statistical analysis plan along
with TLF mock-ups and that to the best of my knowledge the document accurately reflects the protocol
objectives.
Authorized by:
(b) (4)
(b) (4)
(b) (4)


Rezolute, Inc. 
Statistical Analysis Plan  
Final Version 2.0 
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                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
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REVISION HISTORY 
Version 
Date 
 
Reasons 
1.0 
APR 20, 2022 
 
1. Changes in versions, MedDRA-
25.0 and WHODD- WHODRUG 
B3 SEP2019. 
2. Anticipated list of TLFs has been 
updated. 
3. Added the two new listings for 
derived endpoint variables (CGM 
and SMBG). 
4. Updated the section “Subgroup 
Analysis (7.1.11.)” due to the 
addition of one subgroup (Patients 
ages 2-6 years old) for two 
endpoints. 
5. Updated the section “Safety Analysis 
(7.1.8.)” by adding a table of Vitals 
Abnormality.  
6. Updated the section “Analysis 
Population (6.1)” with the 
modification of Per Protocol 
Population definition. 
7. Updated the section “Efficacy 
Analysis” with addition of percent 
change summary and analysis for two 
efficacy endpoints. 
 
 
 
 
 
 
 
 
 
(b) (4)
(b) (4)


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                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
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LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AM 
Ante Meridiem 
AOC 
Area over the curve 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
CGM 
Continuous glucose monitoring 
CHI 
Congenital hyperinsulinism 
cm 
Centimeters  
CS 
Clinically significant 
CV                       
Coefficient of variation 
DERC   
Dose Escalation Review Committee 
dL 
Deciliter  
ECG 
Electrocardiogram 
eCRF 
Case report form 
FFA 
Free fatty acids 
HbA1c 
Hemoglobin A1c 
Kg 
Kilograms  


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Statistical Analysis Plan  
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Abbreviation or special term 
Explanation 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
mg 
Milligram  
mL 
Milliliter  
msec 
Millisecond 
NCS 
Not clinically significant 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
TLF 
Table, Listing and Figure 
PM 
Post Meridiem 
POC 
Point of care 
RTSM 
Randomization and Trail Supply 
Management 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard Error 
SoC 
Standard of care 
SOC 
System Organ Class 
SMBG 
Self-Monitoring of Blood Glucose 
TEAE 
Treatment emergent adverse event 


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Statistical Analysis Plan  
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                                                          Study No. RZ358-606  
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1. INTRODUCTION 
 
Insulin, secreted by the β cells of the Islets of Langerhans in the pancreas, is the major hormone for 
lowering blood glucose levels in the fasting and postprandial states. Abnormal elevations in insulin 
secretion can lead to profound hypoglycemia with cerebral damage and even death. Thus, under 
normal conditions, the control of insulin secretion is highly regulated to prevent hypoglycemia. 
Overproduction of insulin results in hyperinsulinemic hypoglycemia, characteristic of diseases such 
as CHI and post-gastric bypass hypoglycemia (PGBH). Congenital hyperinsulinism (CHI) is the most 
common cause of recurrent hypoglycemia in neonates and infants. 
 
Diminution of insulin action at target tissues may represent a novel therapeutic approach for the 
treatment of conditions associated with hyperinsulinism. RZ358, previously referred to as XOMA-
358 or XMetD, is a fully human immunoglobulin G, subclass 2 (IgG2) mAb that binds with high 
potency and selectivity to an allosteric site on the insulin receptor (INSR), acting as a negative 
modulator of insulin action on target cells by attenuating both the binding of insulin and its 
downstream signaling. 
This statistical analysis plan (SAP) describes the statistical methods and data handling procedures to 
be followed during the final reporting and analyses of data collected for the study Protocol RZ358-
606.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This 
version of the plan has been developed using the protocol: RZ358-606, version amendment 5.0, dated 
17MAR2021 and RZ358-606, version amendment 5.0 US, dated 15MAR2021 and eCRF: version 
3.40, dated 04JUN2021.  
This study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and 
glycemic efficacy of multiple ascending doses of RZ358 over 8 weeks in patients with 
hyperinsulinemic hypoglycemia due to congenital hyperinsulinism (CHI). 
2. STUDY DETAILS 
2.1. 
Study Objectives 
The objectives of this study are to evaluate the safety, tolerability, PK, PD, and glycemic efficacy of 
multiple ascending doses of RZ358 over 8 weeks in patients with hyperinsulinemic hypoglycemia due 
to CHI. 
2.2. 
Study Design 
This is a Phase 2, multi-center, open-label, multiple ascending dose study to evaluate the safety, 
tolerability, PK, PD, and glycemic efficacy of RZ358 in patients with hypoglycemia due to CHI. The 


Rezolute, Inc. 
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                                                          Study No. RZ358-606  
                                                              Date: AUG 17, 2022 
 
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study will consist of up to 4 dose cohorts, which are to be enrolled independently and conducted 
sequentially, comprised of up to 6-8 patients per cohort to ensure each cohort includes at least 3 
patients aged ≤10 years. Eligible patients will be successively enrolled into the cohort that is open for 
enrollment at that time, at the lowest dosing cohort that is yet to be filled.  
In Cohorts 1, 2, and 3 the dose amount will be fixed during the entire 8-week Treatment Period, while 
in Cohort 4 there will be a scheduled bi-weekly dose-titration for the first 4 weeks, followed by a fixed 
dose amount thereafter for the remaining 4 weeks. The Sponsor may decide to add a cohort to repeat 
a dose level or to study an additional dose level, but the dose level for any cohort will not exceed the 
planned dose level for that cohort, as specified in this protocol. 
Advancement to subsequent cohorts will not occur until at least 4 patients from the prior cohort have 
each received at least 4 weeks of study drug (2 bi-weekly doses), without safety concerns. A Dose 
Escalation Review Committee will assess all available and relevant interim data from each cohort to 
determine the appropriateness of dose escalation to a new cohort.   
 
Table 1: Study Design/Cohort Dosing Regimens 
 
Dosing (mg/kg) 
Cohort 
Wk 1 
Wk 3 
Wk 5 
Wk 7 
1 
3 
3 
3 
3 
2 
6 
6 
6 
6 
3 
9 
9 
9 
9 
4 
3 
6 
9 
9 
 
Following informed consent, patients will complete a Screening Period to determine eligibility. After 
the preliminary screening assessment, patients who are otherwise eligible will undergo scheduled self-
monitoring of blood glucose (SMBG) by point of care (POC) glucometer as well as have a CGM 
sensor placed according to the instruction manual, for completion of a minimum10-day outpatient 
CGM evaluation to assess glycemic eligibility and establish a baseline.
 
 
patients will use an SMBG for their POC throughout the trial. Patients 
taking existing and stable doses of standard of care (SoC) medications or nutritional supplementation 
for CHI at the time of screening should continue the same regimen and doses throughout this period. 
(b) (4)


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 To meet glycemic qualification criteria, patients must have 
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 <50 mg/dL (2.78 mmol/L) during the last 7 days of 
a 10-day CGM evaluation period AND be experiencing ≥ 3 hypoglycemia events (<70 mg/dL) per 
week by SMBG and/or according to the Investigator’s evaluation
 
 
 
 
 
 
 
 
During the Screening Period and throughout the study, patients will be requested to follow their usual 
diet (including enteral feeding, as applicable) and activity level, as evaluated and instructed by 
qualified study personnel. 
At the conclusion of the CGM and glycemic eligibility evaluation, final eligibility will be determined, 
and fully eligible patients will check in to the inpatient facility on Day -1, to begin the Treatment 
Period. On Day -1, patients will begin a 12h baseline fasting challenge evaluation, which will conclude 
prior to Day 1 dosing. Re-screening may be permitted under certain extenuating circumstances (e.g. 
laboratory outlier suggesting result artifact, insufficient duration of CGM collection), only with pre-
approval by the Sponsor. 
Beginning at Day 1 of the Treatment Period, patients will receive study drug via IV infusion every 2 
weeks over an 8 week total Treatment Period. Thus, patients who complete the entire Treatment Period 
will receive 4 doses of study drug over a total of 8 weeks. Patients will remain under inpatient 
observation for at least 48h following dosing on Week 1, and for at least 24h following dosing on 
Weeks 3, 5, and 7, for completion of PK blood sampling and safety assessments. Throughout the 
Treatment Period and through post-treatment follow-up Day 42 after the patient’s final dose in the 
study (cumulative study Day 85), glucose levels will be assessed and recorded by CGM.
 
 
 
All patients will continue 
to use an SMBG as their POC throughout the trial. 
Throughout the Treatment period and through the End of Treatment (EOT) visit on post-treatment 
follow-up Day 14 (cumulative study Day 57), SMBG by POC glucometer must be performed 
 
 
 In 
addition, SMBG by POC glucometer should be performed to confirm suspected hypoglycemia (by 
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)


Rezolute, Inc. 
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                                                          Study No. RZ358-606  
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CGM or symptoms) prior to implementing rescue measures. 
 
 Thereafter, during the remainder of the Follow-up period, CGM and 
scheduled SMBG by POC glucometer will be stopped, but the latter may continue to be performed 
and recorded in the diary at the discretion of the patient and/or Investigator. 
 
 
 
Otherwise, changes in the dose or regimen of background SoC therapies should not occur, except in 
the event that hypo- or hyperglycemic rescue criteria are met, or changes are deemed medically 
necessary by the Investigator. 
 
 
 
 
 
 
 
At the conclusion of Week 7 dosing and discharge from the clinic, each patient will complete 
outpatient post-treatment follow-up visits at Days 14 (EOT), 28, and 42 (each ±3 days), and a final 
End of Study (EOS) follow-up visit on Day 105 (+3 days) for purposes of evaluating extended PK and 
safety over a period of 5 half-lives of the study drug. 
Protocol versions 1.0, 2.0, and 3.0 were never implemented. Prior to implementing protocol version 
amendment 5.0, three patients in Cohort 1 were enrolled and treated under protocol version 
amendment 4.0, which differed from version 5.0 in dosing regimen (frequency) and the glucose entry 
criterion by CGM, as noted below:  
 
1. To meet glycemic qualification criteria, patients must have glucose values <70 mg/dL (3.9 
mmol/L) for ≥8% of the overall monitored time and for ≥60 min per day on at least 5 of the 10 
CGM evaluation days AND be experiencing ≥ 3 hypoglycemia events (<70 mg/dL) per week 
by SMBG and/or according to the Investigator’s evaluation. 
2. Beginning at Day 1 of the Treatment Period, patients will receive study drug via IV infusion 
weekly for the first 4 weeks (induction dosing), followed by subsequent infusions every 2 
weeks for an additional 4 weeks (maintenance dosing). Thus, patients who complete the entire 
Treatment Period will receive 6 doses of study drug over a total of 8 weeks. 
 
 
 
(b) (4)
(b) (4)
(b) (4)
(b) (4)


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Figure 1: Study Design 
 
 
 
 
 
 
 
2.2.1. Schedule of Assessments  
The schedules of study assessments and pharmacokinetics sampling schedule are presented in 
APPENDIX 1 and APPENDIX 2 of Protocol below 
 
(b) (4)


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(b) (4)


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(b) (4)


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(b) (4)


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(b) (4)


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(b) (4)


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(b) (4)


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2.3. 
Determination of Sample Size  
The sample size chosen for this study was selected without statistical considerations. It has been 
determined adequate to meet the study objectives. Patients who withdraw from the study may be 
replaced on a case-by-case basis after discussion and agreement with the Sponsor’s Medical Monitor.  
Up to approximately 24 to 32 patients are planned to be enrolled into this study if all cohorts are 
completed. Each of the (up to) 4 cohorts will comprise up to 6-8 patients to ensure there are a minimum 
of 3 patients ≤10 years of age per cohort. Patients who discontinue the study before the Week 5 
treatment and evaluation period may be replaced at the discretion of the Sponsor, if discontinuation 
was not due to a dose-limiting toxicity (DLT). 
2.4. 
Randomization 
This is an open-label study, but the study will utilize a randomization and trial supply management 
(RTSM) application built within the EDC platform to unify randomization, trial supply and EDC. Each 
patient will be provided a unique 6-digit patient ID number. The first three digits will represent the 
site number and the last three digits will represent the patient number at the site. The patient ID number 
will remain the same for both screening and randomization. In the event a cohort has not completed 
the enrollment criteria of at least 3 patients ≤10 years of age, patients >10 years of age can be stratified 
into a higher cohort as long as the dose escalation review has been completed and approved. 
2.5. 
Blinding 
This is an open-label study. Therefore, no blinding is applicable. 
3. DATA ANALYSIS CONSIDERATIONS 
The statistical analyses will be performed by Quartesian Clinical Research, using SAS Version 9.3 (or 
higher). All Tables, Listings and Figures (TLFs) will be produced in landscape format. In general, all 
data will be listed by the patient, cohort, and visit/timepoint, but not limited only to these variables. 
The number of variables presented in each listing can vary. Please refer to Mock tables, listings, and 
figures. 
Data will be summarized by cohort and by RZ358 pooled treatment. The total number of patients in 
the study group (N) under the stated population will be displayed in the cohort header of summary 
tables. 
 
Data will be summarized using descriptive statistics for continuous variables. Unless otherwise stated, 
descriptive statistics will include Number of patients (n), Mean, Standard Deviation (SD), Standard 
Error (SE), Minimum, Median, Maximum, and confidence interval (for efficacy parameters only). 
First Quartile (Q1) and Third Quartile (Q3) will also be included for duration (absolute time) 
parameters. Area over the curve (AOC) and area under the curve (AUC) of glucose will also include 
coefficient of variation (CV %), Geometric Mean, Geometric CV (%). In case of n=1, where n 


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indicates the number of evaluable patients at the particular time point, only n, mean, minimum and 
maximum will be displayed. The statistic “Missing” will also be evaluated by enumerating the number 
of missing entries/patients, if any at that visit, and presented as a summary statistic only for the 
available time points.  
 
In summary tables of categorical variables, counts and percentages will be used. The count [n] 
indicates the actual number of patients with a particular value of a variable or event, which should 
always be less than or equal to the total number of patients in the respective cohort [N].  
 
Decimal Precision Convention: The minimum and maximum statistics will be presented to the same 
number of decimal places as the raw data. The mean, median, Q1, Q3, Confidence interval (CI) for 
mean and proportion will be presented to one more decimal place than the raw data, whereas the 
standard deviation (SD), Standard Error (SE), coefficient of variation (CV %), Geometric Mean, and 
Geometric CV (%) will be presented to two more decimal places than the raw data.  
The number and percentage of patients with missing values for a variable/category/event will also be 
presented for the resulting visits/time points under the “Missing” category. Percentage will be obtained 
by: % = (n/N) *100. Unless otherwise stated, all percentages will be expressed to one decimal place. 
P-value will be presented three decimal places or P-value closer to zero will be presented as <0.001 
and p-value closer to one will be presented as >0.999. 
The following conventions will be applied to analyses/data presentation: 
 
All dates will be displayed in DDMMMYYYY format. 
 
Unscheduled data for assessments that are specific to a discrete visit (rather than continuously 
measured e.g., SMBG or CGM) will be presented in Listings but not in Tables and Figures, unless 
missing data imputation rules (windows) are met, as described below. 
 
Prior to implementing protocol version amendment 5.0, three patients in Cohort 1 were enrolled and 
treated under protocol version amendment 4.0, which differed from version 5.0 in dosing regimen 
(frequency) so, the following visit mapping will be followed for efficacy analysis, considering the 
dosing period:  
“Subjects who were enrolled in Cohort 1 under protocol version amendment 4.0, their Week 1 and 
Week 2 data are aggregated and reported under '2 Weeks' timepoint. Similarly, Week 3, Week 4 and 
Week 5 data are aggregated and reported under '4 Weeks’, their Week 6 and Week 7 are aggregated 
and reported under '6 Weeks', their Week 8 and Week 9 data are aggregated and reported under '8 
Weeks/EOT' timepoint.” 
 
 
 
 


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Handling of Missing Data 
If the Adverse Event Relationship flag is missing, the relationship for adverse event will be imputed 
and will be considered as “Related”. If the Adverse Event Severity grade is missing, the severity will 
be imputed and will be considered as “Severe”. To handle missing or partial AEs and concomitant 
medication dates, the following rules will be applied.  
 
For partial AE/CM Onset/Start Date: 
 
1. If the year is unknown, then do not impute the date but assign a missing value. 
 
Missing day and month 
 
If the year is same as the year of first day on study medication, then the day and month of the 
start date of study medication will be assigned to the missing fields. 
If the year is prior to the year of first day on study medication, then December 31 will be 
assigned to the missing fields. 
If the year is after the year of first day on study medication, then January 1 will be assigned to 
the missing fields. 
Missing month only 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only  
 
i. 
If the month and year are same as the year and month of first dose date of study medication, 
then the start date of study medication will be assigned to the missing day. 
ii. 
If either the year is before the year of the first dose date of study medication or if both years 
are the same, but the month is before the month of the first dose date of study medication, 
then the last day of the month will be assigned to the missing day. 
iii. 
If either the year is after the year of the first dose date of study medication or if both years are 
the same, but the month is after the month of the first dose date of study medication, then the 
first day of the month will be assigned to the missing day. 
 
 
 
 


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For AE Stop Date: 
 
If the stop date is complete and the imputed start date as above is after the stop date, the start date 
will be imputed by the stop date.  
If the stop date is incomplete, no imputation needed. 
For CM End Date: 
 
CM end date will not be imputed if CM ongoing is checked. 
1. If the year is unknown, then do not impute the date but assign a missing value. 
2.  If the month is unknown, then assign “December.” 
3. If the day is unknown, then assign the last day of the month. 
 
If AE onset date is non-missing and is before the first dose date then the AE is considered to be prior 
treatment. 
If AE onset date is non-missing and is occurred on the same date as the first dose with the event marked 
as start prior to first dose of study drug on the CRF then the AE is considered to be prior treatment. 
If AE onset date is missing and is marked as start prior to the first dose of study drug on the CRF then 
the AE is considered to be prior treatment. 
If CM start date is taken prior to the first dose of study drug regardless continuing to take the 
medication while on study treatment, then the CM is considered to be prior treatment. 
 
Missing data imputation for Visit-Specific Assessments (e.g., safety labs, vital signs, hepatic 
ultrasound, 12-lead ECG): 
An unscheduled assessment (full visit or partial assessment) that is discrete and associated with a 
specific visit will be imputed as the scheduled assessment for the nearest visit where the applicable 
assessment is missing. Unscheduled data collected prior to the first dose will be assigned to the nearest 
missing screening visit or assessment (instead of nearest post-treatment visit). Unscheduled data 
collected after the final dose will be assigned to the nearest missing treatment or post-treatment visit 
or assessment. When an unscheduled assessment represents a value that is repeated (to a scheduled 
value, i.e., no missing data), then these will be adjudicated by medical review prior to database lock, 
to determine the value for the scheduled summary.  If the unscheduled/repeat value affirms the 
legitimacy of the original value, the original value will be used and the unscheduled/repeat value will 
be additionally included in listings.  When the value refutes the legitimacy of the original value 


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(suggesting spurious original value), the unscheduled/repeat value will be imputed to that scheduled 
visit, and the original value will be excluded from the dataset and listings.   
 
4. DEFINITIONS & DERIVATIONS 
Baseline: Baseline is defined as the last non-missing value (or aggregate/integrated values in the case 
of CGM or SMBG) prior to the first administration of the study drug, unless otherwise stated. If the 
assessment occurs on the same day as the first study drug administration, then the time of assessment 
should be compared to the time of first dose administration. 
Change from Baseline: The change from baseline values will be calculated as post-baseline value 
minus the baseline value. 
Percent change from Baseline = 
ࡼ࢕࢙࢚ ࢈ࢇ࢙ࢋ࢒࢏࢔ࢋ ࢜ࢇ࢒࢛ࢋ – ࡮ࢇ࢙ࢋ࢒࢏࢔ࢋ ࢜ࢇ࢒࢛ࢋ
࡮ࢇ࢙ࢋ࢒࢏࢔ࢋ ࢜ࢇ࢒࢛ࢋ
× ૚૙૙      
(b) (4)


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SMBG data entered by the patient into the electronic patient diary cannot be edited retroactively by 
the patient. It is both the source data and the data record, so correction of potentially spurious values 
cannot be performed
 
 
 
 
listing of possible 
spurious values will be medically reviewed and adjudicated for exclusion from the analysis datasets 
prior to database lock. 
 
Missing data for CGM or SMBG will otherwise not be imputed since it is collected continuously or 
semi-continuously. 
  
Treatment-Emergent Adverse Event (TEAE): A TEAE is defined as any clinically significant event 
that starts or that worsens in severity (intensity or frequency) after the first dose of study drug. For 
purposes of this study, TEAEs for summary tabulation will be further defined as those events which 
occur within a period of time through the +42 days follow-up visit after the final dose of study drug.  
Adverse events with onset after ICF but before first dose of study drug or after last dose of study drug 
+42 days will be summarized and listed separately from TEAEs.  
 
(b) (4)
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4.1. 
ENDPOINT DERIVATIONS 
x Daily percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by CGM 
will be derived by, 
 
Daily percent time (%) = (Actual number of readings satisfying glucose target range of 70-180 
mg/dL (3.9-10 mmol/L) / Total number of readings obtained in 24h period from 12 AM to 12 AM) 
× 100. (Note: The day (24 hours) will be derived using date and time). 
 
x 8h overnight percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) 
by CGM will be derived by, 
 
8h overnight percent time (%) = (Actual number of readings satisfying glucose target range of 70-
180 mg/dL (3.9-10 mmol/L) / Total number of readings obtained in 8h overnight period from 12 
AM (midnight) to 8 AM) × 100.  
 
x Daily duration (min) and Daily percent time with hypoglycemia at each threshold of <70, 
<60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM will be derived by, 
 
Daily percent time (%) with hypoglycemia <70 mg/dL = (Actual number of readings satisfying 
glucose level less than 70 mg/dL (3.9 mmol/L) / Total number of readings obtained in 24h period 
from 12 AM to 12 AM) × 100. (Note: The day (24 hours) will be derived using date and time. 
Similarly, it will be derived for other glucose thresholds). 
 
Daily duration (min) with hypoglycemia <70 mg/dL: (Actual number of readings satisfying 
glucose level less than 70 mg/dL (3.9 mmol/L) in 24h period from 12 AM to 12 AM) × 5.  
(Note: The day (24 hours) will be derived using date and time. Similarly, it will be derived for other 
glucose thresholds). 
 
x 8h overnight duration (min) and 8h overnight percent time with hypoglycemia at each 
threshold of <70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM will 
be derived by, 
 
8h overnight percent time (%) with hypoglycemia <70 mg/dL = (Actual number of readings 
satisfying glucose level less than 70 mg/dL (3.9 mmol/L) / Total number of readings obtained in 8h 
overnight period from 12 AM (midnight) to 8 AM) × 100. 
(Note: similarly, it will be derived for other glucose thresholds). 
 
8h overnight duration (min) with hypoglycemia <70 mg/dL: (Actual number of readings 
satisfying glucose level is less than 70 mg/dL (3.9 mmol/L) in 8h overnight period from 12 AM 
(midnight) to 8 AM) × 5. (Note: similarly, it will be derived for other thresholds). 
 
x Daily hypoglycemia incidence (event rate) at each of the specified glucose thresholds by 


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CGM will be derived by, 
 
 
Daily hypoglycemia incidence (event rate) <70 mg/dL =
 
 
 
  
 
Daily hypoglycemia incidence (event rate) <60 mg/dL 
 
 
 
 
 
 
Daily hypoglycemia incidence (event rate) <50 mg/dL = 
 
 
 
 
 
x 8h overnight hypoglycemia incidence (event rate) at each of the specified glucose thresholds 
by CGM will be derived by, 
 
8h overnight hypoglycemia incidence (event rate) <70 mg/dL
 
 
 
 
 
 
8h overnight hypoglycemia incidence (event rate) <60 mg/dL = 
 
 
 
 
 
8h overnight hypoglycemia incidence (event rate) <50 mg/dL = 
 
 
 
 
 
x The average glucose level by CGM between midnight and 08:00 AM (or nearest pre-
breakfast timepoint) will be derived by, 
 
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)


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Average glucose level by CGM between midnight and 08:00 AM = Sum of all actual glucose 
reading values in same units / Total number of glucose readings obtained between midnight (12 AM) 
and 8 AM. 
 
x Daily glucose AOC0-24h,<70mg/dL and AUC0-24h,>70mg/dL at each of the specified glucose 
thresholds will be derived by, 
 
The daily (24h period from 12 AM to 12 AM) glucose AOC (area over the curve) less than 70 mg/dL 
(3.9 mmol/L) and AUC (area under the curve) greater than 70 mg/dL (3.9 mmol/L) will be calculated 
using Trapezoidal rule, 
 
ܣܷܥ= න݂(ݔ)݀ݔ≈(ܾ−ܽ) ∗݂(ܽ) + ݂(ܾ)
2
௕
௔
 
 
a and b are the fixed timepoints. f(a) and f(b) are the glucose concentration values of the respective 
timepoints. (Note: AOC will be calculated using the same formula. Similarly, it will be derived for 
other glucose thresholds). For detailed example, see section 9.1.1 (Appendix) 
 
 
x 8h overnight glucose AOC0-8h, <70mg/dL and AUC0-8h,>70mg/dL at each of the specified glucose 
thresholds will be derived by, 
 
The 8h overnight (12 AM midnight to 8 AM) glucose AOC (area over the curve) less than 70 mg/dL 
(3.9 mmol/L) and AUC (area under the curve) greater than 70 mg/dL (3.9 mmol/L) will be calculated 
using Trapezoidal rule, 
 
ܣܷܥ= න݂(ݔ)݀ݔ≈(ܾ−ܽ) ∗݂(ܽ) + ݂(ܾ)
2
௕
௔
 
 
a and b are the fixed timepoints. f(a) and f(b) are the glucose concentration values of the respective 
timepoints. (Note: AOC will be calculated using the same formula. Similarly, it will be derived for 
other glucose thresholds). For detailed example, see section 9.1.1 (Appendix) 
 
x Weekly incidence of hypoglycemia (event rate) at each of the specified glucose thresholds 
by SMBG will be derived by, 
 
 
Weekly incidence of hypoglycemia (event rate) <70 mg/dL = The number of unique, discrete, and 
non-continuous hypoglycemia events (<70 mg/dL threshold) per week over the evaluable period.  


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Weekly incidence of hypoglycemia (event rate) <60 mg/dL = The number of unique, discrete, and 
non-continuous moderate hypoglycemia events (<60 mg/dL threshold) per week over the evaluable 
period. 
 
Weekly incidence of hypoglycemia (event rate) <50 mg/dL = The number of unique, discrete, and 
non-continuous severe hypoglycemia events (<50 mg/dL threshold) per week over the evaluable 
period. 
 
 
 
 
 
 
 
5. PRIMARY AND SECONDARY ENDPOINTS 
5.1. 
Primary Endpoint 
x 
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 CGM 
x 
Repeat-dose safety and tolerability of RZ358  
x 
Repeat-dose pharmacokinetics of RZ358 
5.2. 
Secondary Endpoints 
x 
Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose 
(SMBG) 
x 
Average daily duration (min) and percent time with hypoglycemia at thresholds of <70, 
<60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM 
x 
Average daily hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by CGM 
x 
Average 8h overnight percent time in glucose target range of 70-180 mg/dL (3.9-10 
mmol/L) by CGM 
x 
Occurrence of hypoglycemia during a 12h fasting challenge. 
5.3. 
Additional (Exploratory) Endpoints 
x 
Average 8h overnight duration (min) and percent time with hypoglycemia at thresholds of 
<70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM 
x 
Average 8h overnight hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by CGM 
(b) (4)


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x 
Average daily and 8h overnight area over and under the glucose curve (AUC, AOC) for 
each of the specified glucose thresholds by CGM 
x 
Average glucose level between midnight and 8:00 AM (or nearest pre-breakfast time point) 
by CGM 
x 
Average weekly hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by SMBG 
x 
Intravenous or enteral nutritional (glucose/dextrose) supplementation 
x 
Use of SoC or rescue medications for hypoglycemia (dextrose or other) 
x 
Incidence of fasting blood glucose values >200, >250, and >300 mg/dL (>11.1, >13.9, and 
>16.6 mmol/L, respectively) 
x 
PD Markers of RZ358 activity including fasting levels of glucose, insulin, c-peptide, 
glucagon, FFAs, and ketones (beta-hydroxybutarate). 
6. ANALYSIS POPULATION AND TREATMENT GROUPS 
6.1. 
Analysis Population  
 ITT Population: All patients who are enrolled into the study. 
Safety Population: All patients enrolled in the study who receive at least one dose of study drug.  
 
Per protocol Population: All patients who receive at least 4 weeks of study drug (2 bi-weekly 
doses), with no major protocol violations. A patient in the Per protocol population may be excluded 
from one or more specific efficacy analyses (i.e. SMBG-related endpoints or CGM-related endpoints), 
if they have a major protocol deviation affecting only that endpoint (e.g. non-compliance with SMBG 
only, or non-compliance with CGM only). 
 
PK Population: All patients who receive study drug and have a sufficient number and quality 
(biologically plausible) of results.  
6.2. 
Treatment Groups 
The study will consist of up to 4 dose cohorts, which are to be enrolled independently and conducted 
sequentially, comprised of up to 6-8 patients per cohort to ensure each cohort includes at least 3 
patients aged ≤10 years with hypoglycemia due to CHI. 
In Cohorts 1, 2, and 3 the dose amount will be fixed during the entire 8-week Treatment Period, while 
in Cohort 4 there will be a scheduled bi-weekly dose-titration for the first 4 weeks, followed by a fixed 
dose amount thereafter for the remaining 4 weeks. (Refer section 2.2, Table 1: Study Design/Cohort 
Dosing Regimens). 
 


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The cohorts will be labelled in the TLFs as Cohort 1 (3 mg/kg), Cohort 2 (6 mg/kg), Cohort 3 (9 
mg/kg), Cohort 4 (Dose Escalation mg/kg), and RZ358 Total. 
7. ANALYSIS METHODS AND REPORTING DESCRIPTION 
7.1.1. Subject Disposition 
Subject disposition will be summarized using frequency count and percentage by cohort and RZ358 
Total, for number of subjects screened, number of subjects enrolled, number of subjects in the ITT 
population, number of subjects in the Safety populations, number of subjects in the Per protocol (PP) 
population, number of subjects in the PK population, number of subjects who completed the study 
treatment, number of subjects who completed the study, number of subjects who discontinued the 
study but completed the treatment and number of patients who discontinued from the study along with 
the reasons for discontinuation from the study.  
A listing of subject’s disposition will be presented to describe dates of completion or early withdrawal 
for each patient with the reason for early discontinuation, if applicable.  
7.1.2. Demography and Baseline Characteristics 
The demographic and baseline characteristics will include age (years), age group (2-6, 7-11, 12-17 
and ≥18 years), gender, ethnicity, race, height (cm), weight (kg), and BMI (kg/m2 ). These will be 
summarized by cohort and RZ358 Total, for the ITT Population and Per protocol (PP) Population.  
Baseline CHI characteristics will include genetic type, CHI medication history, pancreatectomy, 
exocrine pancreatic insufficiency, repeat surgeries, tube feeding catheter, and type of nutrition and 
will be summarized by cohort and RZ358 Total, for ITT Population. 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be presented for 
continuous variables. Count and percentage will be presented for each class of the categorical 
variables. 
All individual patient demographic and baseline characteristic data will be listed. 
7.1.3. Medical and Surgical History 
Medical and Surgical history will be summarized by system organ class (SOC) and preferred term 
(PT) using count and percentage by cohort and RZ358 Total, for the Safety Population. Patients will 
be counted only once at the PT, only once at the SOC, and only once at patient level for the counting 
of total number of patients with a medical history term. Counts will be presented in descending 
frequency unless otherwise specified. Medical history will be coded using MedDRA version 25.0 Mar 
2022. 


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Listing of medical and surgical history will also be presented for Safety Population.  
7.1.4. Prior and Concomitant Medications 
Any medication other than study drug, either prescription drug or over the counter (OTC) will be 
treated as concomitant medication. 
Prior Medications 
For a patient in the Safety Population, prior medications will include any medication taken within 30 
days of signing ICF but stopped prior to patient’s first dose of Study Medication. 
Concomitant Medications 
Concomitant medications are defined as prescribed medications and over the counter (OTC) 
preparations, including herbal preparations and vitamins, other than Study Medication taken within 30 
days of ICF and during the treatment and follow-up phase. 
 
Prior and concomitant medication will be categorized by preferred Term and ATC level X class per 
World Health Organization Drug Dictionary (WHODRUG; Version Global B3 SEP2019) will be 
summarized by cohort and RZ358 Total, for the Safety Population. The count and percentage of 
patients using each medication will be displayed. Patients who taken the same medication (in terms of 
PT) more than once will be counted only once for that medication. 
 All prior and concomitant medications will be presented in a listing for the Safety Population.  
7.1.5. Protocol Deviation 
Protocol deviations will be identified and classified by ICH category 1 through 5 and as minor or major 
and Important Protocol Deviations (as defined by ICH) will be summarized using count and percentage 
by cohort and RZ358 Total, for the Safety Population. A listing of patients with protocol deviations 
will be presented. 
Compliance will be check for CGM & SMBG and below definitions will be used for the same. 
 
CGM (Continuous glucose monitoring) 
Percent compliance of CGM data will be defined as >=70% data capture during the overall monitored 
time during the treatment period, including >= 70% data capture during the efficacy evaluable period 
between last dose of study drug and the Day 14 EOT/Follow-up Visit.  
ܥܩܯ ܥ݋݉݌݈݅ܽ݊ܿ݁ (%) =
୅ୡ୲୳ୟ୪ ୬୳୫ୠୣ୰ ୭୤ ହ ୫୧୬୳୲ୣୱ ୧୬୲ୣ୰୴ୟ୪ ୭୤ େୋ୑ ୰ୣୟୢ୧୬୥ୱ 
୉୶୮ୣୡ୲ୣୢ ୬୳୫ୠୣ୰ ୭୤ ହ ୫୧୬୳୲ୣୱ ୧୬୲ୣ୰୴ୟ୪ ୭୤ େୋ୑ ୰ୣୟୢ୧୬୥ୱ× 100  


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Subjects will be considered compliant if the % compliance is calculated to be >=70% by each of the 
above criteria and compliance rate will be summarized using descriptive statistics. Overall compliance 
will also be summarized using counts and percentages by categorizing it into compliant and non-
compliant.  
 
Note: Data capture is defined as available recordings in the 10-day sensor period. 
 
SMBG (Self-Monitoring of Blood Glucose) 
Percent compliance of SMBG data will be defined as >=50% data capture during the overall monitored 
time during the treatment period, including >=75% data capture during the efficacy evaluable period 
between the last dose of study drug and the Day 14 EOT/Follow-up Visit.  
 
ܵܯܤܩ ܥ݋݉݌݈݅ܽ݊ܿ݁ (%) =
୅ୡ୲୳ୟ୪ ୬୳୫ୠୣ୰ ୭୤ ୗ୑୆ୋ ୰ୣୟୢ୧୬୥ୱ  
୉୶୮ୣୡ୲ୣୢ ୬୳୫ୠୣ୰ ୭୤ ୗ୑୆ୋ ୰ୣୟୢ୧୬୥ୱ× 100  
 
Subjects will be considered compliant if the % compliance meets each of the above criteria, and 
compliance rate will be summarized using descriptive statistics. Overall compliance rate will be 
summarized using counts and percentages by categorizing it into compliant and non-compliant. 
 
 
  
 
7.1.6. Study Drug Exposure and Treatment Compliance 
Duration of study drug exposure will be summarized by cohort using descriptive statistics (n, mean, 
SD, minimum, median, and maximum) for the Safety Population. For each subject, duration of study 
drug exposure (days) will be calculated as below:   
((Date of last administration of study drug+14 Days) - Date of first administration of study drug) + 1.  
 
Compliance to the study drug will be calculated as: 
 
Treatment Compliance (%) = 
஺௖௧௨௔௟ ௡௨௠௕௘௥ ௢௙ ௗ௢௦௘௦ ௧௔௞௘௡
்௢௧௔௟ ௡௨௠௕௘௥ ௢௙ ௦௖௛௘ௗ௨௟௘ௗ ௗ௢௦௘௦× 100 
 
Subjects will be considered compliant, if the % compliance is calculated at least 75% and have at least 
completed 4 weeks of study treatment. The compliance rate will be summarized by cohort using 
descriptive statistics (n, mean, SD, minimum, median, and maximum) for the Safety Population. Also, 
(b) (4)


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overall compliance will be summarized by cohort using counts and percentages by categorizing it into 
compliant and non-compliant for the Safety Population. Separate listing will also be provided. 
 
7.1.7. Efficacy Analysis 
7.1.7.1. Primary Endpoint 
A CGM system will be used to evaluate glycemic eligibility and efficacy endpoints for glycemic 
control. Several parameters to measure glycemic control by CGM will be evaluated over the 2-week 
End of Treatment period after the final dose, compared to baseline. The efficacy analysis will be 
conducted in the Intent–to–Treat (ITT), and Per-Protocol (PP) Populations.  
 
The primary endpoint is the 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 CGM. The derivation of daily 
percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) is presented in section 
4.1. The primary endpoint of actual and change from baseline values will be summarized by visit, 
cohort and RZ358 Total using descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum, 
and 95% CI for Mean). Within cohort comparative analysis will be performed using paired t test by 
comparing each post baseline visits with baseline visit, p-value from the test will be reported and 
analysis will be performed using ITT and PP Populations. Corresponding mean (SD) plot will also be 
produced to illustrate the descriptive statistics as appropriate.  
 
7.1.7.2. Secondary Endpoints 
The secondary endpoints to measure glycemic control by CGM and SMBG will be evaluated, at each 
of the specified timepoints, compared to baseline. The analysis of CGM parameters and SMBG 
parameters will be evaluated over the 2-week End of Treatment period after the final dose, compared 
to baseline.   The secondary endpoints analysis will be conducted in the Intent–to–Treat (ITT), and PP 
Populations. The following secondary endpoints include: 
 
x 
Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose 
(SMBG) 
x 
Average daily duration (min) and percent time with hypoglycemia at thresholds of <70, 
<60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM 
x 
Average daily hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by CGM 
x 
Average 8h overnight percent time in glucose target range of 70-180 mg/dL (3.9-10 
mmol/L) by CGM 
 


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The derivations of above secondary endpoints are presented in section 4.1. The secondary endpoints 
of actual and change from baseline values will be summarized by visits, cohort and RZ358 Total using 
descriptive statistics (n, Mean, SD, SE,  Median, Minimum, Maximum and 95% CI for Mean). Along 
with these, First Quartile (Q1) and Third Quartile (Q3) will also be presented for duration (min) 
parameters. Within cohort comparative analysis will be performed using paired t test by comparing 
each post baseline visits with baseline visit, p-value from the test will be reported and analysis will be 
performed using ITT and PP Populations. Corresponding mean (SD) plots will also be produced for 
parameters to illustrate the descriptive statistics as appropriate.  
 
The secondary endpoints “Average daily Percent time with hypoglycemia at thresholds of <70, <60, 
and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM” and “Average weekly incidence of 
hypoglycemia (< 70, <60, <50 mg/dL) by self-monitored blood glucose” will also be summarized by 
the percent change from baseline by visit, cohort and RZ358 Total using descriptive statistics (n, Mean, 
SD, SE, Median, Minimum, Maximum and 95% CI for Mean). Within cohort comparative analysis 
will be performed using paired t test by comparing each post baseline visits with baseline visit, p-value 
from the test will be reported and analysis will be performed using ITT and PP Populations.  
 
 
Occurrence of hypoglycemia during a 12h fasting challenge: 
x Time to termination of fast 
x Glucose nadir during fast 
x Percentage of patients able to complete a fast 
x Ketone levels at the conclusion of fast 
 
Above mentioned parameters i.e., Time to termination of fast, Glucose nadir during fast, and Ketone 
levels at the conclusion of fast will be summarized by visit, cohort and RZ358 Total using descriptive 
statistics (n, Mean, SD, SE, Median, Minimum, Maximum and 95% CI for Mean). Within cohort 
comparative analysis will be performed using paired t test by comparing week 7 visit with baseline 
visit, p-value from the test will be reported and analysis will be performed using Intent–to–Treat 
(ITT), and PP Populations.  
 
Also, Percentage of patients able to complete a fast will be summarized using frequency count and 
percentage by visit, cohort, and RZ358 Total. Within cohort comparison of proportions will be 
performed using McNemar’s test by comparing week 7 visit with baseline visit, p-value from the 
test will be reported and analysis will be performed using Intent–to–Treat (ITT), and PP Populations. 
 
7.1.7.3. Exploratory Endpoints 
The exploratory endpoints to measure glycemic control by CGM and SMBG will be evaluated, at each 
of the specified timepoints, compared to baseline. The analysis of CGM parameters and SMBG 


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parameters will be performed over the 2-week End of Treatment period after the final dose, compared 
to baseline. The exploratory endpoints analysis will be conducted in the PP and ITT Populations.  
The following exploratory endpoints include: 
 
x 
Average 8h overnight duration (min) and percent time with hypoglycemia at thresholds of 
<70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by CGM 
x 
Average 8h overnight hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by CGM 
x 
Average daily and 8h overnight area over and under the glucose curve (AUC, AOC) for 
each of the specified glucose thresholds by CGM 
x 
Average glucose level between midnight and 8:00 AM (or nearest pre-breakfast time point) 
by CGM 
x 
Average weekly hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds of <70, <60, and <50 mg/dL (3.9, 3.3, and 2.8 mmol/L, respectively) by SMBG 
 
Additionally, Average weekly hyperglycemia incidence (event rate) at each of the specified 
glucose thresholds of >180, >250, and >300 mg/dL (10.0, 13.9 and 16.6 mmol/L, 
respectively) by SMBG 
 
The derivations of above exploratory endpoints are presented in section 4.1. The exploratory 
endpoints of actual and change from baseline values will be summarized by visit, cohort and RZ358 
Total using descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum and 95% CI for 
Mean). Along with these, First Quartile (Q1) and Third Quartile (Q3) will also be presented for 
duration (min) parameters. AOC and AUC of above glucose parameters will also be summarized by 
visit, cohort and RZ358 Total using descriptive statistics (n, Mean, SD, SE, CV (%), Geometric 
Mean, Geometric CV (%), Median, Minimum, Maximum and 95% CI for Geometric Mean). Within 
cohort comparative analysis will be performed using paired t test by comparing each post baseline 
visits with baseline visit, p-value from the test will be reported and analysis will be performed using 
ITT and PP Populations. Corresponding mean (SD) plots will also be produced for above endpoints 
to illustrate the descriptive statistics as appropriate.  
 
Comparison of glycemic efficacy of RZ358 by CGM/SMBG endpoints 
The within cohort comparison of post baseline visits to baseline visit in glycemic efficacy of CGM/ 
SMBG endpoints over the 2-week End of Treatment period after the final dose will be analyzed using 
paired t-test and p-value from the test will be reported. 
 
The null and alternative hypothesis are, 
 
ܪ଴∶ ߤௗ= 0             and                 ܪଵ∶ ߤௗ≠0 
 
 


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Where, ߤௗ is the mean difference in glycemic efficacy of CGM/SMBG parameters within cohort. 
The normality of the CGM/SMBG endpoints will be performed using Shapiro-Wilk Test. If the p-
value from the test result is normal, that is, p-value ≥ 0.05, then paired t-test will be used; otherwise, 
a non-parametric Wilcoxon Sign Rank Test will be used. 
 
Additional endpoints 
Listings will be presented for the following additional endpoints.  
x Intravenous or enteral nutritional (glucose/dextrose) supplementation 
 
x Use of SoC or rescue medications for hypoglycemia (dextrose or other) 
 
Pharmacodynamic Biomarker Analyses 
Blood samples will be collected at scheduled timepoints, throughout the treatment periods of the study 
to evaluate the PD effects of the study drug. The PD of RZ358 compared to baseline will be assessed 
by: 
x Average levels of glucose, insulin, c-peptide, glucagon, FFAs, and ketones (beta-
hydroxybutarate), at each of the specified collection timepoints. 
 
The actual and change from baseline values of the above parameters will be summarized using 
descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum and 95% CI for Mean) at each 
of the specified collection timepoints by visit, cohort and RZ358 Total for the PP population.  
 
x Incidence of safety fasting blood glucose values >200, >250, and >300 mg/dL (>11.1, >13.9, 
and >16.6 mmol/L, respectively). 
 
Incidence of safety fasting blood glucose values >200, >250, and >300 mg/dL (>11.1, >13.9, and 
>16.6 mmol/L, respectively) will be summarized using frequency count and percentage at each of the 
specified collection timepoints by visit, cohort and RZ358 Total for the PP population.  
 


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7.1.7.4. Summary of Efficacy Endpoint Analysis Strategy 
Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Primary Endpoint 
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 CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average daily 
percent time, 
cohort  
8 Weeks 
/EOT 
Secondary Endpoint 
Average weekly incidence 
of hypoglycemia (< 70 
mg/dL) by self-monitored 
blood glucose (SMBG) 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 
weekly 
incidence, 
cohort 
8 Weeks 
/EOT 


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Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Average daily duration 
(min) and percent time 
with hypoglycemia at 
thresholds of <70, <60, 
and <50 mg/dL (3.9, 3.3, 
and 2.8 mmol/L, 
respectively) by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average daily 
duration, 
Average daily 
percent time, 
cohort 
8 Weeks 
/EOT 
Average daily 
hypoglycemia incidence 
(event rate) at each of the 
specified glucose 
thresholds by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average daily 
hypoglycemia 
incidence, 
cohort  
8 Weeks 
/EOT 
Average 8h overnight 
percent time in glucose 
target range of 70-180 
mg/dL (3.9-10 mmol/L) by 
CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 8h 
overnight 
percent time, 
cohort  
8 Weeks 
/EOT 


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Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Occurrence of hypoglycemia 
during a 12h fasting 
challenge. (Percentage of 
patients able to complete a 
fast) 
 
Count and 
percentage, 
Comparison of 
proportions 
using 
McNemar 
Test. 
PP 
Population 
and ITT 
Population 
No 
imputation 
eCRF 
Week 7 
Occurrence of 
hypoglycemia during a 
12h fasting challenge. 
(Time to termination of fast, 
Glucose nadir during fast, 
Ketone levels at the 
conclusion of fast) 
 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
eCRF 
Week 7 
Additional Exploratory Endpoints 
Average 8h overnight duration 
(min) and percent time with 
hypoglycemia at thresholds of 
<70, <60, and <50 mg/dL 
(3.9, 3.3, and 2.8 mmol/L, 
respectively) by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 8h 
overnight 
duration, 
Average 8h 
overnight 
percent time, 
cohort 
8 Weeks 
/EOT 


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Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Average 8h overnight 
hypoglycemia incidence 
(event rate) at each of the 
specified glucose 
thresholds by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 8h 
overnight 
hypoglycemia 
incidence, 
cohort 
8 Weeks 
/EOT 
Average daily and 8h 
overnight area over and 
under the glucose curve 
(AUC, AOC) for each of 
the specified glucose 
thresholds by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average daily 
and 8h 
overnight 
AUC & AOC, 
cohort  
8 Weeks 
/EOT 
Average glucose level 
between midnight and 
8:00 AM (or nearest pre-
breakfast time point) by 
CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 
glucose level 
between 
midnight and 
8:00 AM, 
Cohort 
8 Weeks 
/EOT 


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Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Average weekly 
hypoglycemia incidence 
(event rate) at each of the 
specified glucose 
thresholds by SMBG 
Descriptive 
statistics 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 
weekly 
hypoglycemia 
incidence, 
cohort 
8 Weeks 
/EOT 
Glycemic efficacy of 
RZ358 as evaluated by the 
average daily percent time 
within a glucose target 
range of 70-250 mg/dL 
(3.9-13.9 mmol/L) by 
CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average daily 
percent time, 
cohort  
8 Weeks 
/EOT 
Average 8h overnight 
percent time in glucose 
target range of 70-250 
mg/dL (3.9-13.9 mmol/L) 
by CGM 
Descriptive 
statistics, 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 8h 
overnight 
percent time, 
cohort  
8 Weeks 
/EOT 


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Endpoint 
Statistical 
Method / Test 
Analysis 
Population 
Missing 
Data 
Imputation 
Approach 
Parameters/Va
riables in the 
analysis (Stat. 
test/Model) 
Analysis 
Time point 
Average weekly 
hyperglycemia incidence 
(event rate) at each of the 
specified glucose 
thresholds of >180, >250, 
and >300 mg/dL (10.0, 
13.9 and 16.6 mmol/L, 
respectively) by SMBG 
 
Descriptive 
statistics 
Paired T-test 
(analyzing post 
baseline visits 
with baseline 
visit) 
PP 
Population 
and ITT 
Population 
No 
imputation 
Average 
weekly 
hyperglycemia 
incidence, 
cohort 
8 Weeks 
/EOT 
Incidence of fasting blood 
glucose values >200, 
>250, and >300 mg/dL 
(>11.1, >13.9, and >16.6 
mmol/L, respectively) 
Count and 
percentage 
PP 
Population  
No 
imputation 
eCRF 
8 Weeks 
/EOT 
PD Markers of RZ358 
activity including fasting 
levels of glucose, insulin, 
c-peptide, glucagon, FFAs, 
and ketones (beta-
hydroxybutarate). 
Descriptive 
statistics 
PP 
Population  
No 
imputation 
eCRF 
8 Weeks 
/EOT 
 
 
7.1.8. Safety Analysis 
The analysis of primary safety endpoints will include assessments of AEs, vital signs, 12-lead ECGs, 
infusion-site observations, physical examination, hepatic ultrasound results, and clinical laboratory 
evaluations including glucose values. All safety analyses will be performed using the Safety 
Population. 
 


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Adverse Events: 
Adverse Events will be coded using (MedDRA version 25.0 Mar 2022) AE coding system for the 
purpose of summary tables. Treatment-emergent adverse events (TEAE) will be summarized by 
cohorts and RZ358 Total and AEs that are non-TEAE will be identified. 
 
For each cohort, AEs will be summarized with frequency count and percentage by MedDRA SOC and 
PT, with all patients treated in that cohort as the denominator, unless otherwise specified. In addition, 
AEs will also be summarized by severity and relationship to study drug. 
All AEs and TEAEs during the study will be summarized for the respective cohorts. A patient 
experiencing the same AEs and TEAEs multiple times will be counted only once for that PT. Similarly, 
if a patient experiences multiple AEs and TEAEs (preferred terms) within the same SOC then that 
patient will be counted only once for that SOC. When summarizing by severity, the event with highest 
severity will be counted. All AEs will be listed in chronological order of the events occurred. 
For purposes of this study, TEAEs for summary tabulation will be further defined as those events 
which occur within a period of time through the +42 days follow-up visit after the final dose of study 
drug.  Adverse events with onset after ICF but before first dose of study drug or after last dose of study 
drug +42 days will be identified separately from TEAEs.  
Summary tables of the following AEs will be provided: 
An overview of TEAE summary will be presented by cohorts, and it will include: 
ᇏ Number of Subjects with any TEAEs  
ᇏ Number of subjects with any TEAEs related to study drug 
ᇏ Number of subjects with any TEAEs leading to treatment/study discontinuation 
ᇏ Number of subjects with TEAEs by maximum severity grade 
ᇏ Number of Subjects with any serious TEAEs  
ᇏ Number of Subjects with any serious TEAEs related to study drug 
ᇏ Number of Subjects with any serious TEAEs leading to treatment/study discontinuation  
ᇏ Number of Subjects with any serious TEAEs leading to death 


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ᇏ Number of subjects with any non-TEAEs 
A summary of the frequency (number and percentage of patients) of TEAEs and serious TEAEs by 
cohort will be presented by SOC, PT, and non-TEAEs will be separately identified.  
Similarly, summary results will be generated for TEAEs by SOC, PT for severity grade>=3. 
A summary of the frequency (number and percentage of patients) of TEAEs by cohort will be 
presented by SOC, PT and by related to study drug.  
A summary of the frequency (number and percentage of patients) of TEAEs leading to treatment/study 
discontinuation by cohort will be presented by SOC and PT. 
All AEs reported during the study will be present in a by-patient listing.  Separate by-patient listings 
will be generated to present AEs, SAEs leading to discontinuation from treatment and the study and 
TEAEs leading to death. 
 
Infusion Site Reactions: 
A local infusion site reaction is any local reaction occurring at the site of injection following study 
drug administration. A local infusion site reaction, including, but not limited to, erythema, induration, 
and pain, should be reported as an adverse event. 
Infusion site reactions will be summarized by cohort and RZ358 Total using frequency count and 
percentage for safety population. 
All infusion site reactions will be presented in listing for safety population. 
(b) (4)


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Vital signs:  
Vital signs measurement will include systolic and diastolic blood pressure (mmHg), temperature 
(degree Celsius), pulse rate (beats/minute) and respiratory rate (breaths/minute).  
The actual and change from baseline values at each scheduled time-point will be summarized by visit, 
cohort and RZ358 Total (pediatric and adult patients) using descriptive statistics (n, Mean, SD, 
Median, Minimum, and Maximum) for Safety population. For categorical shift summaries, any 
available pre-treatment values (screening or pre-treatment baseline) may be used to define baseline, 
for the categorical assignment. 
 
All vital signs data will be presented in listings for Safety population. 
 
The below table will be referred to for the vital signs abnormalities. 
 
Table 2: Vitals Abnormality 
(b) (4)


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VS Ranges 
1-3 
Years 
4-5 
Years 
6-8 
Years 
9-12 
Years 
13-16 
Years 
17- 
Onwards 
≤12 
≥13 
Min Max 
Systolic BP 
  
  
  
  
  
  
80-
120 
90-
140 
  
  
Diastolic BP 
  
  
  
  
  
  
50-
80 
55-
90 
  
  
Temperature 
  
  
  
  
  
  
  
  
36.0 38.0 
Respiratory 
Rate 
  
  
  
  
  
  
18-
30 
12-
20 
  
  
Pulse Rate 
94-179 
72-195 
61-116 
54-111 
47-108 
60-100 
  
  
  
  
 
 
12-Lead ECG: 
The 12-lead ECG measurements will include heart rate (bpm), QRS (msec), QT (msec), corrected QT 
(msec), RR (msec), and PR (msec) intervals, as well as an overall interpretation. 
 
Actual and change from baseline value of quantitative ECG parameters will be summarized using 
descriptive statistics (n, Mean, SD, Median, Minimum, and Maximum) by visit, cohort and RZ358 
Total (pediatric and adult patients) for safety population.  
 
Overall assessment of safety ECGs (Normal, Abnormal - NCS, Abnormal – CS) will be summarized 
using frequency counts and percentage by visit, cohort and RZ358 Total for safety population. In 
addition, a shift table comparing overall interpretation (Normal, Abnormal - NCS, Abnormal - CS) of 
the ECG parameters at baseline vs treatment-emergent post-baseline (worst treatment-emergent 
category) will also be presented by cohort for safety population. For categorical shift summaries, any 
available pre-treatment values (screening or pre-treatment baseline) may be used to define baseline, 
for the categorical assignment. 
 
Individual data listings of ECG results along with the Investigator-identified ECG abnormalities will 
be presented for each patient.  
 
Clinical Laboratory Data 
The Clinical Laboratory test category will include assessments of Hematology, Chemistry, Urinalysis, 
HbA1c, ADA Blood Collection. 


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Quantitative parameters of hematology, chemistry, and urinalysis, actual and change from baseline 
values at each scheduled time-point will be summarized by visit, cohort and RZ358 Total (pediatric 
and adult patients) using descriptive statistics (n, Mean, SD, Median, Minimum, and Maximum) for 
safety population. All qualitative result parameters at each scheduled time-point will be summarized 
by visit, cohort and RZ358 Total using frequency counts and percentage for safety population. 
Additionally, comparing the changes in categorical laboratory variables from baseline (Low, Normal, 
and High) / (Positive, Negative) vs treatment-emergent post-baseline (worst treatment-emergent 
category) will be presented by cohort using a shift table for safety population. For categorical shift 
summaries, any available pre-treatment values (screening or pre-treatment baseline) may be used to 
define baseline, for the categorical assignment. 
A summary table will be presented for HbA1c by visit, cohort and RZ358 Total for safety population. 
Anti-drug Antibody (ADA): Anti-drug Antibody (ADA) with categories ADA Negative, Pre-
existing Immunoreactivity, Treatment Boosted, and Treatment-emergent. Positive will be summarized 
by cohort, and RZ358 Total using frequency count and percentage for safety population.  
 
Definitions: 
 
ADA Negative: defined as negative response in the ADA assay at all time points and those that 
exhibit a pre-existing response, regardless of any missing samples. 
 
Pre-existing Immunoreactivity: defined as either a positive response in the ADA assay at baseline 
with all post first dose ADA results negative OR a positive response at baseline with all post dose 
ADA response less than 4-fold of baseline titer levels. 
(b) (4)


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Treatment Boosted ADA: defined as a positive response post first dose that is greater than or equal 
to 4-fold over baseline titer level, when baseline results are positive. 
 
Treatment-emergent Positive (D): defined as an ADA positive response post first dose when 
baseline results are negative or missing, OR ADA positive response more than 4-fold of a positive 
baseline titer. 
 
Additionally, comparing the changes in categorical ADA Blood Collection from baseline (Positive, 
Negative) to post baseline visit will be presented by cohort using a shift table for safety population. 
 
Individual data listings of laboratory results will be presented for hematology, chemistry, urinalysis 
HbA1c and ADA Blood Collection separately. 
Physical examination: 
The investigator or qualified designee will perform a complete physical examination (genitourinary 
examination not required) and targeted abbreviated physical examinations. 
 
A full physical examination will include, at a minimum, assessment of the following systems: skin, 
head, ears, eyes, nose and throat, respiratory system, cardiovascular system, gastrointestinal system, 
neurological condition, blood and lymphatic systems, and the musculoskeletal system. An abbreviated 
physical examination is inclusive of neurological, cardiac, gastrointestinal, and pulmonary 
assessments. 
The physical examination findings (Normal, Abnormal NCS, Abnormal CS) will be summarized using 
counts and percentages by visit, cohort and RZ358 Total for each body system using safety population. 
 
Additionally, for each body system, changes in physical examination findings from baseline vs 
treatment-emergent post-baseline (worst treatment-emergent category) will be presented using a shift 
table for each cohort using safety population. For categorical shift summaries, any available pre-
treatment values (screening or pre-treatment baseline) may be used to define baseline, for the 
categorical assignment. 
 
All physical examination findings will also be presented in listing for safety population. 
 
Hepatic Ultrasound 
Hepatic ultrasound will be performed at the specified time points as listed in the Schedule of 
Assessments, and per the Investigator’s institution’s standard practice methodology. The results will 
be interpreted by qualified personnel. 
 


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The overall interpretation of hepatic ultrasound (Normal, Abnormal NCS, Abnormal CS) will be 
summarized using counts and percentages by visit, cohort and RZ358 Total for safety population. 
 
Additionally, changes in overall interpretation of hepatic ultrasound from baseline vs treatment-
emergent post-baseline (worst treatment-emergent category) will be presented using a shift table for 
each cohort using safety population. All hepatic ultrasound results will also be presented in listing for 
safety population. 
 
7.1.9. PK Analysis 
PK analysis plan development and performance of PK analysis will be managed by another vendor.  
Therefore, the reporting will be described in a supplementary PK analysis plan and report. 
Following are the details of PK analysis: 
The individual and mean RZ358 serum concentrations will be summarized by treatment cohort and 
planned sample times in tables and figures. Serum concentrations for samples collected within 30 min 
after the dosing infusion will be reported as the observed concentration at the end of infusion (CEOI). 
Concentrations will be summarized using descriptive statistics. The study design and planned PK 
sample collection are not suitable for the calculation of PK parameters by noncompartmental methods. 
Specifically, the number of PK samples within dosing intervals is insufficient to support 
noncompartmental estimation of AUC; and due to the long half-life of RZ358, steady state is not 
expected to be achieved by the end of the 8-week Treatment Period. Therefore, the observed serum 
RZ358 concentration-time data will be used to develop a population PK (popPK) model to describe 
the PK of RZ358 in patients with CHI. PopPK modeling will also investigate the effects of selected 
covariates on RZ358 PK such as age, body weight, gender and race, as data permit.  
The popPK model will be used to estimate PK parameters for each treatment cohort, including but not 
limited to the following:  
• AUCss: steady state area under the concentration-time curve.  
• Cmaxss: steady state maximum concentration.  
• Cavgss: steady state average concentration.  
• t1/2: effective half-life.  
• CL: total drug clearance.  
• V: volume of distribution of the central compartment.  
Descriptive statistics will be presented for PK parameters, including but not limited to Cmax, Tmax, 
t1/2, and AUC. The relationships between dose and Cmax and AUC will be analyzed for dose 
proportionality. The PK results of this study may be combined with those of other studies for analysis 
and modeling (e.g., population PK and PK-PD), and reported separately Detailed methods for the PK 
modeling will be provided in a separate PK modeling analysis plan. 


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7.1.10. Pooled Analyses 
No pooled analyses will be conducted in this trial. 
7.1.11. Subgroup Analyses 
The subgroup analyses will be evaluated for the below mentioned primary, secondary, and exploratory 
endpoints of this study using Per-Protocol (PP) population.  
 
x 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 CGM 
x Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose 
(SMBG) 
x Average daily percent time with hypoglycemia at thresholds of <70, <60, and <50 mg/dL 
(3.9, 3.3, and 2.8 mmol/L, respectively) by CGM 
x Average weekly hypoglycemia incidence (event rate) at each of the specified glucose 
thresholds by SMBG 
x Average weekly hyperglycemia incidence (event rate) at each of the specified glucose 
thresholds by SMBG 
 
 
(b) (4)


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specified glucose thresholds by SMBG”. 
 
7.1.12. Interim Analysis 
No interim analyses planned for this trial. 
7.1.13. Changes to Analyses Specified in Protocol 
x Glycemic efficacy of RZ358 as evaluated by the average daily percent time within a glucose 
target range of 70-250 mg/dL (3.9-13.9 mmol/L) by CGM 
Above mentioned endpoint will be derived as below: 
 
Daily percent time within a glucose target range of 70-250 mg/dL (3.9-13.9 mmol/L) by CGM 
will be derived by, 
 
Daily percent time (%) = (Actual number of readings satisfying glucose target range of 70-250 
mg/dL (3.9-13.9 mmol/L) / Total number of readings obtained in 24h period from 12 AM to 12 AM) 
× 100. (Note: The day (24 hours) will be derived using date and time). 
 
Above mentioned endpoint will be summarized and analyzed as below: 
 
The endpoint of actual and change from baseline values will be summarized by visit, cohort and RZ358 
Total using descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum, and 95% CI for 
Mean). Within cohort comparative analysis will be performed using paired t test by comparing each 
post baseline visits with baseline visit, p-value from the test will be reported and analysis will be 
performed using ITT and PP Populations.  
x Average 8h overnight percent time in glucose target range of 70-250 mg/dL (3.9-13.9    
mmol/L) by CGM 
Above mentioned endpoint will be derived as below: 
 
8h overnight percent time within a glucose target range of 70-250 mg/dL (3.9-13.9 mmol/L) by 
CGM will be derived by, 
 
8h overnight percent time (%) = (Actual number of readings satisfying glucose target range of 70-
250 mg/dL (3.9-13.9 mmol/L) / Total number of readings obtained in 8h overnight period from 12 
AM (midnight) to 8 AM) × 100.  
 
Above mentioned endpoint will be summarized and analyzed as below: 
 
The endpoint of actual and change from baseline values will be summarized by visits, cohort and 
RZ358 Total using descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum and 95% CI 


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for Mean). Within cohort comparative analysis will be performed using paired t test by comparing 
each post baseline visits with baseline visit, p-value from the test will be reported and analysis will be 
performed using ITT and PP Populations.  
x Average weekly hyperglycemia incidence (event rate) at each of the specified glucose 
thresholds of >180, >250, and >300 mg/dL (10.0, 13.9 and 16.6 mmol/L, respectively) by 
SMBG 
 
Above mentioned endpoint will be derived as below: 
 
Weekly incidence of hyperglycemia (event rate) >180 mg/dL = The number of unique, discrete, 
and non-continuous hyperglycemia events (>180 mg/dL threshold) per week over the evaluable 
period.  
 
Weekly incidence of hyperglycemia (event rate) >250 mg/dL = The number of unique, discrete, 
and non-continuous moderate hyperglycemia events (> 250 mg/dL threshold) per week over the 
evaluable period.  
 
Weekly incidence of hyperglycemia (event rate) >300 mg/dL = The number of unique, discrete, 
and non-continuous severe hyperglycemia events (>300 mg/dL threshold) per week over the 
evaluable period. 
 
 
 
 
 
 
 
(Note: The week (7 days) will be derived using date and time.)  
 
Above mentioned endpoint will be summarized and analyzed as below: 
 
The endpoint of actual and change from baseline values will be summarized by visit, cohort and RZ358 
Total using descriptive statistics (n, Mean, SD, SE, Median, Minimum, Maximum and 95% CI for 
Mean). Within cohort comparative analysis will be performed using paired t test by comparing each 
post baseline visits with baseline visit, p-value from the test will be reported and analysis will be 
performed using ITT and PP Populations.  
 
 
 
(b) (4)


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REFERENCE 
 
x ICH E3: Structure and Content of Clinical Study Reports. 
x Clinical Study Protocol (RZ358-606 version amendment 5.0 dated 17MAY2021 
x eCRF Version and Date: version 3.40 dated 04JUN2021 
x Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in 
diagnosis and therapy. Orphanet J Rare Dis 2011;6:63. 
 
x Buraczewska M, Szymanska E, Brandt A, et al. Congenital hyperinsulinism in Polish 
patients—how can we optimize clinical management? Endokrynol Pol 2015;66(4):322-8. 
9. APPENDIX 
9.1.1. AUC and AOC Derivation 
Daily glucose AOC and AUC at each of the specified glucose thresholds by CGM 
The figure below is presented only to show the idea of the calculation of glucose AUC and AOC 
parameters and the shape of the curve is based on dummy data. The parameters will be calculated 
using Linear Trapezoidal Rule over the specified time range. 
 
Daily glucose AOC (area over the curve) less than 70 mg/dL (3.9 mmol/L) and AUC (area under the 
curve) greater than 70 mg/dL (3.9 mmol/L) will be calculated using Trapezoidal rule, 
 
ܣܷܥ/ܣܱܥ= න݂(ݔ)݀ݔ≈(ܾ−ܽ) ∗݂(ܽ) + ݂(ܾ)
2
௕
௔
 
 


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x From the above figure, the horizontal reference line is the glucose threshold of 70 mg/dL (3.9 
mmol/L) 
x Area over the curve (AOC) < 70 mg/dL will be calculated as sum of AOC parts (Lavender) 
using Linear Trapezoidal Rule 
x Area under the curve (AUC) > 70 mg/dL will be calculated as sum of AUC parts (Yellow) 
using Linear Trapezoidal Rule 
 
AUC0-t (mg/dL × Hours) for plasma glucose > 70 mg/dL  
From the yellow region of the example figure, the glucose AUC (area under the curve) > 70 mg/dL is 
calculated as follows: 
 
 
AUC0-12h>70mg/dL = [(2-1) (0+60)/2] + [(4-2) (60+30)/2] + [(6-4) (30+0)/2]  
                           = 30 + 90 + 30  
                           = 150
௠௚
ௗ௅∙ℎݎ 
 


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AOC0-t (mg/dL × Hours) for plasma glucose < 70 mg/dL 
From the lavender region of the example figure, the glucose AOC (area over the curve) < 70 mg/dL is 
calculated as follows: 
 
AOC0-12h<70mg/dL = [(1-0) (70+0)/2] + [(8-6) (0+20)/2] + [(10-8) (20+50)/2] + [(12-10) (50+60)/2]   
          = 35 + 20 + 70 + 110 
          = 235
௠௚
ௗ௅∙ℎݎ 
Similarly, these methods will be used to derive other endpoints, such as 8h overnight glucose AOC 
and AUC at each of the specified glucose thresholds <70, <60 and <50 mg/dL (3.9, 3.3 and 2.8 
mmol/L, respectively) and >70, >60 and >50 mg/dL (3.9, 3.3 and 2.8 mmol/L, respectively) 
respectively by CGM. 
 
9.1.2. 
 
 
 
 
(b) (4)
(b) (4)
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(b) (4)