Conditions: Prader-Willi Syndrome
Keywords: PWS Prader-Willi Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 127
Healthy volunteers: no

Brief summary:
The purpose of this is study is to evaluate the effects of DCCR (diazoxide choline controlled release tablets) in children and adults with Prader-Willi syndrome.

Detailed description:

Arms:
arm 1: 75 - 450 mg DCCR arm 2: 75 - 450 mg placebo for DCCR

Interventions: intervention 1: DCCR intervention 2: Placebo for DCCR
Intervention descriptions: intervention 1: Once daily oral administration intervention 2: Once daily oral administration

Protocol document:
Prot_SAP_001.pdf: 
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Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
Soleno Therapeutics, Inc. 
 
Page 2 of 132 
Confidential Information 
 
11 June 2019 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
Page 3 of 132 
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11 June 2019 
 
1.0 
TABLE OF CONTENTS 
 
CLINICAL PROTOCOL ..............................................................................................................1 
1.0 
TABLE OF CONTENTS ..................................................................................................3 
 
2.0 
STUDY SYNOPSIS .........................................................................................................10 
3.0 
LIST OF ABBREVIATIONS .........................................................................................16 
4.0 
BACKGROUND ..............................................................................................................20 
4.1 
Prader-Willi Syndrome ..........................................................................................20 
 
 
4.2.1 
Mode of Action .....................................................................................21 
4.3 
Nonclinical and Clinical Data ................................................................................21 
 
 
 
 
 
 
 
 
 
 
 
 
4.3.2.2 
Clinical Safety and Efficacy Studies ..............................................23 
 
 
 
 
 
 
 
 
4.6 
Trial Conduct .........................................................................................................26 
4.7 
Population ..............................................................................................................26 
5.0 
TRIAL OBJECTIVES.....................................................................................................26 
5.1 
Primary ...................................................................................................................26 
5.2 
Secondary ...............................................................................................................26 
 
 
6.0 
TRIAL DESIGN...............................................................................................................27 
6.1 
Study Endpoints .....................................................................................................27 


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Diazoxide Choline Controlled-Release (DCCR) 
 
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6.1.1 
Primary Study Endpoints ......................................................................27 
6.1.2 
Secondary Study Endpoints ..................................................................27 
 
 
6.1.4 
Safety Endpoints....................................................................................28 
 
 
6.2 
Study Design/Type .................................................................................................29 
6.3 
Randomization .......................................................................................................29 
 
 
6.3.2 
Additional Steps Taken to Minimize/Avoid Bias .................................30 
 
 
 
 
 
 
 
 
 
 
6.4 
Maintenance of Randomization Code ....................................................................31 
6.5 
Trial Treatment ......................................................................................................31 
6.5.1 
Dose Description ...................................................................................31 
6.5.2 
Packaging and Labeling ........................................................................31 
6.5.3 
Storage and Handling ............................................................................32 
6.6 
Duration .................................................................................................................32 
6.7 
Discontinuation of the Study .................................................................................32 
6.8 
Product Accountability ..........................................................................................33 
6.9 
Data Identification .................................................................................................33 
7.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................34 
7.1 
Screening Assessments ..........................................................................................34 
7.1.1 
Screening Inclusion Criteria ..................................................................35 
7.1.2 
Screening Exclusion Criteria.................................................................35 
 
 
 
 
 
 
7.3 
Subject Withdrawal ................................................................................................38 
 
 


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Diazoxide Choline Controlled-Release (DCCR) 
 
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8.0 
TREATMENT OF SUBJECTS ......................................................................................39 
8.1 
Treatments to be Administered ..............................................................................39 
 
 
8.3 
Dose Maintenance ..................................................................................................40 
 
 
 
 
8.6 
Medication .............................................................................................................40 
8.6.1 
Prohibited Medications and Procedures ................................................41 
8.7 
Monitoring for Subject Compliance ......................................................................41 
9.0 
STUDY PROCEDURES .................................................................................................41 
9.1 
Description of Study Procedures and Assessments ...............................................42 
9.1.1 
Informed Consent / Assent ....................................................................42 
9.1.2 
Medical History, Medications and Demographics ................................42 
9.1.3 
Physical Examination ............................................................................43 
 
 
 
 
 
 
 
 
9.1.4 
Vital Signs .............................................................................................45 
9.1.5 
Weight ...................................................................................................45 
 
 
9.1.7 
Height ....................................................................................................46 
9.1.8 
Electrocardiogram (ECG) .....................................................................47 
9.1.9 
Laboratory Tests....................................................................................47 
9.1.9.1 
Monitoring of Laboratory Results .................................................49 
 
 
 
 
 
 
9.1.12 
Urine Pregnancy Test ............................................................................51 
9.1.13 
Enrollment .............................................................................................51 
9.1.14 
Randomization ......................................................................................52 
9.1.15 
Dual-Energy Absorptiometry (DXA) ...................................................52 
9.1.16 
Clinical Global Impression Scales ........................................................52 
 
 


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Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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9.1.16.2 
Clinical Global Impression of Improvement (CGI-I) ....................53 
9.1.17 
Caregiver-Completed Questionnaires ...................................................53 
9.1.17.1 
Hyperphagia Questionnaire - Clinical Trials (HQ-CT) .................53 
 
 
9.1.17.3 
Caregiver Global Impression of Change (GI-C) ............................54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.18 
Study Drug Dispensation ......................................................................57 
9.1.19 
Study Drug Administration ...................................................................58 
9.1.20 
Study Drug Accountability ...................................................................58 
9.1.21 
Adverse Events .....................................................................................59 
9.1.22 
Concomitant Medications / Procedures ................................................59 
 
 
9.2 
Schedule of Events .................................................................................................60 
 
 
10.0 
ASSESSMENT OF EFFICACY .....................................................................................63 
10.1 
Efficacy Parameters ...............................................................................................63 
11.0 
ASSESSMENT OF SAFETY ..........................................................................................64 
11.1 
Safety Parameters ...................................................................................................64 
11.2 
Definitions..............................................................................................................65 
11.2.1 
Adverse Event .......................................................................................65 
11.2.2 
Suspected Adverse Reaction .................................................................65 
11.2.3 
Serious Adverse Event ..........................................................................65 
11.2.3.1 
Hospitalizations as Serious Adverse Events ..................................65 
11.2.4 
Unexpected Adverse Event ...................................................................66 
11.2.5 
Expected Adverse Events ......................................................................66 


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11.3 
Adverse Event Assessment ....................................................................................66 
 
 
11.3.1.1 
Adverse Event Severity..................................................................68 
11.3.1.2 
Adverse Event Relationship ...........................................................68 
11.3.1.3 
Vital Signs, Physical Examination and Clinical Laboratory 
Adverse Events ..............................................................................69 
11.3.2 
Serious Adverse Event Reporting .........................................................69 
12.0 
STATISTICAL PLAN .....................................................................................................70 
 
 
 
 
 
 
 
 
 
 
 
 
12.3 
Efficacy Analyses ..................................................................................................71 
12.3.1 
Primary Efficacy Analysis ....................................................................71 
12.3.1.1 
Multiple Comparisons - Control of the Alpha Level .....................72 
12.3.2 
Secondary Efficacy Analyses ................................................................72 
 
 
12.4 
Subgroup Analyses ................................................................................................73 
12.5 
Safety Analyses ......................................................................................................73 
12.5.1 
Adverse Events .....................................................................................73 
12.5.2 
Clinical Laboratory Evaluations ...........................................................73 
 
 
12.5.4 
ECG Parameters ....................................................................................74 
12.5.5 
Vital Signs .............................................................................................74 
 
 
 
 
 
 
 
 
 
 
12.7 
Termination Criteria...............................................................................................75 
12.8 
Deviation Reporting ...............................................................................................75 
12.9 
Interim Analysis .....................................................................................................76 


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13.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................76 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................76 
15.0 
ETHICAL CONSIDERATIONS ....................................................................................76 
16.0 
DATA HANDLING AND RECORD KEEPING ..........................................................77 
17.0 
PUBLICATION PLAN ...................................................................................................77 
18.0 
REFERENCES .................................................................................................................79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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CHANGES FROM PREVIOUS VERSION 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
Page 10 of 132 
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11 June 2019 
2.0 
STUDY SYNOPSIS 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study of Diazoxide 
Choline Controlled-Release Tablet (DCCR) in Patients with Prader-Willi 
Syndrome 
Sponsor: 
Soleno Therapeutics, Inc. 
Phase of 
Development: 
III 
Objectives: 
Primary 
The primary objective of this study is to evaluate the effects of diazoxide 
choline controlled-release (DCCR) tablet compared to placebo on hyperphagia 
in PWS patients. 
 
Secondary  
The secondary objectives of this study are to evaluate changes in body fat 
mass, Clinical Global Impression of Improvement (CGI-I), and Caregiver 
Global Impression of Change (GI-C) with DCCR compared to placebo in 
PWS patients. 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel 
arm, phase III study comparing DCCR to placebo in approximately 105 PWS 
patients with hyperphagia. This study will be conducted at approximately 
30 sites globally.  
Each subject’s expected duration of study participation is approximately 
105 days. 
 
 
   


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Study Design 
(cont): 
For subjects who are continuing on into clinical study C602, the open-label, 
long-term, safety extension study, C601 Visit 7 will also serve as Visit 1 in 
clinical study C602.  For subjects who will not enroll into clinical study C602, 
this will be their final study visit, unless they are experiencing an adverse 
event at Visit 7 that requires a follow-up visit.    
 
 
 
Randomized subjects will be titrated every two weeks with their assigned 
treatment, DCCR or placebo, until the target dose is achieved.  The target dose 
is based on subject’s weight.   
Study 
Population: 
Patients with genetically-confirmed Prader-Willi syndrome.  
Screening 
Inclusion 
Criteria: 
Potential subjects must meet all of the following inclusion criteria to be 
enrolled: 
Provide voluntary, written informed consent (parent(s) / legal guardian(s) 
of subject); provide voluntary, written assent (subjects, as appropriate) 
Male and female subjects, 4 years of age and older 
Genetically-confirmed Prader-Willi syndrome. If confirmation by a 
method other than methylation analysis, subject and caregiver consent to 
methylation analysis.   
 
In a stable care setting for at least 6 months prior to Visit 1 and 
throughout the study 
Caregiver must have been caring for the subject for at least 6 months prior 
to Visit 1 and will care for the subject throughout the study a minimum of 
4 waking hours per day 
 
 
 
 
 
 
 
 
 
 
 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Screening 
Inclusion 
Criteria 
(continued): 
 
 
 
  
 
Screening 
Exclusion 
Criteria: 
Potential subjects must not meet any of the following exclusion criteria to be 
enrolled: 
  
Have participated in an interventional clinical study (i.e., investigational 
drug or device, approved drugs or device evaluated for unapproved use) 
within 60 days prior to Visit 1 
 Entry of any subject’s information or data into a non-interventional study 
and/or observational study (e.g., PATH for PWS) or PWS registry(ies) 
during the subject’s participation in this study    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Screening 
Exclusion 
Criteria 
(continued): 
 
 
 
  
 Positive urine pregnancy test (in females of child-bearing potential) 
Females who are pregnant or breastfeeding, and/or plan to become 
pregnant or to breast-feed during or within 90 days after study 
participation 
 
 
 
 
 
 
 
 
Any other known disease and/or condition, which would prevent, in the 
opinion of the Investigator, the subject from completing all study visits 
and assessments required by the protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Efficacy 
Evaluation: 
 
Primary Endpoint 
• Hyperphagia (HQ-CT) change from Baseline (Visit 2) to Visit 7 
Secondary Endpoints 
• Body fat mass (DXA) change from Baseline to Visit 7 
• Clinical Global Impression of Improvement at Visit 7 
• Caregiver Global Impression of Change at Visit 7 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Efficacy 
Evaluation 
(continued): 
 
 
 
 
Safety 
Evaluation: 
Safety Endpoints  
• Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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3.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
AgRP 
Agouti-Related Peptide 
ALT  
Alanine aminotransferase  
ANCOVA 
Analysis of Covariance 
 
 
  
 
ATP 
Adenosine triphosphate  
 
 
C 
Celsius 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CHI 
Congenital Hyperinsulinism 
Cmax 
Maximum concentration 
cm 
Centimeters 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DBC, DBC2-P 
Developmental Behaviour Checklist, DBC Version 2 - Parent 
DCCR 
Diazoxide Choline Controlled-Release Tablet 
DXA 
Dual-Energy Absorptiometry 
dL 
Deciliter 
DMF 
N,N-Dimethylformamide 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
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Abbreviation or Term 
Definition/Explanation 
eGFR 
Estimated glomerular filtration rate 
EtOH 
Ethanol 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
g 
Gram 
g/mol 
Grams per mole 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal  
GI-C 
Global Impression of Change 
GI-S 
Global Impression of Severity 
GLP 
Good Laboratory Practices 
HbA1c 
Hemoglobin A1c or glycated hemoglobin test 
HDL 
High-Density Lipoprotein 
hERG 
Human Ether-a-go-go Related Gene 
HFD 
High-Fat Diet 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
HSP 
Hysterosalpingogram 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICH 
International Conference on Harmonization 
ID 
Imprinting Defect 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-Like Growth Factor 
IM 
Intramuscular 
IPA 
Isopropyl Alcohol 
INR 
International Normalized Ratio 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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Abbreviation or Term 
Definition/Explanation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV, i.v. 
Intravenous 
IWRS 
Interactive Web Response System 
K+ 
Potassium 
KATP 
ATP-Sensitive Potassium Channel 
kg 
Kilogram 
LDL 
Low-Density Lipoprotein 
LFT 
Liver Function Tests 
MAGEL2 
MAGE Family Member L2 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MeCN 
Acetonitrile 
MeOH 
Methanol 
MEK 
Methyl Ethyl Ketone 
mg 
Milligram 
min 
Minute 
MITT 
Modified Intent-to-Treat 
mL 
Milliliter 
µM 
Micromolar 
Mm 
Millimeter 
mrem 
Millirem 
msec 
Millisecond 
m2 
Meters Squared 
NPY 
Neuropeptide Y 
OECD 
Organisation for Economic Cooperation and Development 
P 
Placebo 
pH 
Hydrogen ion concentration 


Protocol C601 
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Abbreviation or Term 
Definition/Explanation 
PK 
Pharmacokinetic(s) 
PO 
Pes Os, By Mouth  
PP 
Per Protocol 
Pre 
Before 
PT 
Prothrombin Time 
PWS 
Prader-Willi Syndrome 
PWSP 
Prader-Willi Syndrome Profile 
QD 
Once-a-day 
QTcF 
QT Interval corrected by Fridericia’s Formula 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SNORD 
Small Nucleolar RNAs, C/D box 
TdP 
Torsades de Pointes 
TEAE 
Treatment-Emergent Adverse Events 
ULN 
Upper Limit of the Normal Range 
UPD 
Uniparental Disomy 
US 
United States 
V 
Visit 
WBC 
White Blood Cell 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
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4.0 
BACKGROUND 
Diazoxide choline, a new chemical entity, is a benzothiadiazine that acts by stimulating ion flux 
through ATP-sensitive K+ channels (KATP). It is the choline salt of diazoxide, which is currently 
used as a treatment of infants, children and adults with hyperinsulinemic hypoglycemia. 
Diazoxide choline, formulated as a once-a-day extended-release tablet or DCCR (diazoxide 
choline controlled-release) tablets, has been studied in over 210 healthy volunteers and subjects 
with obesity, hypertriglyceridemia and Prader-Willi syndrome (PWS).      
4.1 
Prader-Willi Syndrome 
Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder, which is due to the 
absence of normally active, paternally expressed genes from the chromosome 15q11-q13 
region.1, 2  PWS is an imprinted condition with 70–75% of the cases due to a de novo deletion in 
the paternally inherited chromosome 15q11-q13 region, 20–30% from maternal uniparental 
disomy of chromosome 15 (UPD), and the remaining 2–5% from either microdeletions or 
epimutations of the imprinting center (i.e., imprinting defects; IDs).3, 4  Prader-Willi syndrome 
has an has been estimated to afflict 350,000 to 400,000 individuals worldwide.1    
There are no currently-approved products to treat hyperphagia in patients with PWS.  Although 
growth hormone is approved in patients with PWS, it only addresses the short stature, and may 
reduce hypotonia, limit the accumulation of visceral fat, and reduce cognitive impairment.5  A 
global patient survey conducted by the Foundation for Prader-Willi Research (n=779), found that 
96.5% of respondents rated reducing hunger and 91.2% rated improving behavior around food as 
very important or most important symptom to be relieved by a new treatment.  Physical function 
and body composition symptoms for which a high percentage of respondents indicated were very 
important or most important included:  improving metabolic health (reduces fat / increases 
muscle 92.9%) and the related symptom of improves activity and stamina (81.3%).  Behavioral 
and cognitive symptoms rated as very or most important were:  reduces obsessive/compulsive 
behavior (85.2%), improves intellect/development (84.6%), and reduces temper outburst severity 
and frequency (83.2%).6 
4.2 
Investigational Agent 
  
 
   


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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4.2.1 
Mode of Action 
The lack of expression of the SNORD116 gene is associated with the overexpression of 
neuropeptide Y (NPY) a potent appetite stimulatory neuropeptide.7  Additionally, in PWS, 
leptin’s regulatory control of hypothalamic neurons, particularly the NPY / agouti-regulated 
peptide (AgRP) neurons, is diminished. Diazoxide choline appears to be effective in the 
treatment of the resulting hyperphagia by agonizing the KATP channels in these dysregulated 
neurons, thereby amplifying the regulatory control of leptin. This leads to reduced secretion of 
NPY by these neurons, resulting in decreased hyperphagia.  
4.3 
Nonclinical and Clinical Data 
Summaries of the studies in this section are included in the Investigator’s Brochure for DCCR.   
 
  
 
 
 
 
 
  
 
 
 
 


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Diazoxide Choline Controlled-Release (DCCR) 
 
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4.3.2 
Summary of Clinical Data 
 
 
  
 
 
 
 
 
 
 
 
 
  
4.3.2.2 
Clinical Safety and Efficacy Studies 
Clinical study PC025 in PWS was conducted using DCCR. This single-center, randomized 
withdrawal study consisted of 3 phases. The first phase of the study was open-label during which 
subjects were initiated on a DCCR dose 
 
 
  The second phase of the study was a double-blind, placebo-controlled 
phase.  Any subject who showed 
 
 would be designated a Responder, 


Protocol C601 
Diazoxide Choline Controlled-Release (DCCR) 
 
Soleno Therapeutics, Inc. 
 
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  The first dose of double-blind 
treatment was administered at the visit on Day 69. All subjects enrolled in the study were eligible 
to participate in an open-label treatment extension phase for 6 months. 
PWS subjects treated with DCCR in this clinical study showed clinically relevant, statistically 
significant and dose dependent improvements in hyperphagia from Baseline to Day 69 (open-
label phase).  
 
 
 
 
 
 
 
 
 
 
  
The adverse events associated with DCCR treatment and deemed related to DCCR by the 
Investigator in the prior PWS study in more than one subject include: peripheral edema, glucose 
tolerance impaired, and hyperglycemia.   
In all of the studies with DCCR completed to date, two serious adverse events (SAEs) have been 
reported (neither of which were deemed to be related to DCCR): a case of pneumonia and an 
overnight hospitalization of a PWS subject with poorly controlled psychiatric disease. Adverse 
events (AE) reported in these studies were typically mild to moderate in severity, self-limiting 
and were consistent with the existing diazoxide product labels and the results of previously 
published clinical studies and case reports. DCCR 
 
 was well tolerated. 
The available clinical data with DCCR as well as the nonclinical data with diazoxide choline and 
diazoxide indicate that DCCR could be used to treat multiple aspects of PWS including the 
characteristic hyperphagia, aggressive behaviors, and accumulation of excess body fat.  
 
 
 
 
 
 


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4.5 
Dose Selection and Study Duration Rationale 
4.5.1 
Dose Selection Rationale 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  


Protocol C601 
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4.5.2 
Study Duration Rationale 
 
 
 
 
   
4.6 
Trial Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board, and according to Good Clinical Practice standards.  No change to the protocol 
will be implemented without the prior review and approval of the IRB/IEC except where it may 
be necessary to eliminate an immediate hazard to a research subject.  In such case, the change 
will be reported to the Sponsor and IRB/IEC as soon as possible. 
4.7 
Population 
The population will consist of patients with genetically-confirmed Prader-Willi syndrome 
(PWS).  
5.0 
TRIAL OBJECTIVES 
5.1 
Primary 
The primary objective of this study is to evaluate the effects of diazoxide choline controlled-
release (DCCR) tablet compared to placebo on hyperphagia in PWS patients. 
5.2 
Secondary 
The secondary objectives of this study are to evaluate changes in body fat mass, Clinical Global 
Impression of Improvement (CGI-I), and Caregiver Global Impression of Change (GI-C) with 
DCCR compared to placebo in PWS patients. 
5.3 
Additional Objectives 
 
 
 
 
 
 
 


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6.0 
TRIAL DESIGN 
6.1 
Study Endpoints 
6.1.1 
Primary Study Endpoints 
• Hyperphagia (HQ-CT) change from Baseline (Visit 2) to Visit 7 
6.1.2 
Secondary Study Endpoints 
The following secondary endpoints, in order, are: 
• Body fat mass (DXA) change from Baseline to Visit 7 
• Clinical Global Impression of Improvement at Visit 7 
• Caregiver Global Impression of Change at Visit 7  
6.1.3 
Additional Study Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 


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6.1.4 
Safety Endpoints 
• Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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6.2 
Study Design/Type 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel arm, phase III 
study comparing DCCR to placebo in approximately 105 PWS subjects with hyperphagia. This 
study will be conducted at approximately 30 sites globally.
 
 
Figure 1: 
Study Design Schematic 
 
6.3 
Randomization 
 
 
 
The randomization code will be generated and maintained by an individual independent of the 
Sponsor, Soleno Therapeutics, Inc. (Soleno), and those related to the day-to-day conduct of the 
study and/or the management of the study. 


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6.3.1 
Blinding 
 
 
  
 
 
 
 
 
Study drug will be blinded. Placebo tablets matching the size, shape, and color of the respective 
DCCR tablet strengths will be used. 
6.3.2 
Additional Steps Taken to Minimize/Avoid Bias 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 


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6.4 
Maintenance of Randomization Code 
The randomization code will be generated and maintained by an individual independent of the 
Sponsor and those related to the day-to-day conduct of the study and/or the management of the 
study.   
In order to eliminate an immediate risk to a subject, Investigators will be able to obtain a specific 
subject’s treatment group assignment.   
6.5 
Trial Treatment 
6.5.1 
Dose Description 
Subjects will be randomized to one of two study treatments, diazoxide choline controlled-release 
(DCCR) or placebo.  Diazoxide choline is formulated into an extended-release tablet.  
 
  Placebo tablets matching the size, shape, and 
color of the respective DCCR tablet strengths, but not containing any diazoxide choline, will be 
used.   
6.5.2 
Packaging and Labeling 
 
  


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The Interactive Web Response System (IWRS) will indicate which cards will be assigned to each 
subject.  
6.5.3 
Storage and Handling 
 
The DCCR and placebo tablets are investigational drug products and must be stored, handled, 
and administered in accordance with this protocol, the Investigator’s Brochure and labeling, as 
well as all applicable laws, regulations, and institution requirements.   
6.6 
Duration 
Each subject’s expected duration of study participation is approximately 105 days; visit windows 
are described in Section 9.0. 
 
  
 
 
 
 
  For subjects who are continuing on into clinical study 
C602, Visit 7 will also serve as Visit 1 in clinical study C602.  For subjects who will not enroll 
into clinical study C602, this will be their final study visit, unless they are experiencing an 
adverse event at Visit 7 that requires a follow-up visit.    
6.7 
Discontinuation of the Study 
Based on studies conducted with DCCR to date, it is not expected that serious safety issues will 
arise that would require a discontinuation of the study.  The Data Safety Monitoring Board 
(DSMB) will minimally review unblinded safety data twice during the study: 
 
 
  
 
 
 
Additional unblinded safety data reviews and/or ad hoc reviews of unblinded safety data by the 
DSMB if safety signals warrant more frequent scrutiny (i.e., similar CTCAE Grade 3 or higher 
suspected adverse reactions occurring in excess in the DCCR group compared to placebo) may 
be requested at the discretion of the DSMB. 
Based on the DMSB’s review of these unblinded data, study discontinuation reasons may 
include:   


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• 
The sponsor determines that it is unsafe to continue because of an unexpected safety signal 
not otherwise clinically anticipated in randomized subjects without relevant medical history 
• 
Significant imbalance in rate of serious, unexpected adverse reactions that, independent of 
study drug, are not clinically anticipated in subjects randomized to DCCR versus placebo in 
subjects without relevant medical history 
• Significant imbalance in rate of serious adverse reactions that, independent of study drug, are 
not clinically anticipated in subjects randomized to DCCR versus placebo in subjects without 
relevant medical history 
 
 
   
 
  
6.8 
Product Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain an 
inventory record to document the receipt, dispensation and return of each blinded treatment card. 
 
 
 
 
 
 
 
 
 
 
 
6.9 
Data Identification 
 
 
 
 
 
 


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Data that are entered directly into an electronic medium (e.g., EDC, tablet, etc.) together with the 
metadata, are considered eSource data and are kept together as an electronic record (eSource 
document) for capture, transmission and/or storage. 
 
 
 
 
 
   
 
 
 
 
 
  
 
   
 
 
 
 
7.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Screening Assessments 
Potential subjects must meet all of the following inclusion criteria and none of the exclusion 
criteria to be eligible for study enrollment. Assessments of the subject or reports the subject 


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and/or caregiver provide will be used to determine eligibility at the Screening Visit (Visit 1). If 
the subject does not meet these criteria, he/she will be considered a screen failure. The 
subject/caregiver must not be informed of the reason for failure to meet the screening criteria 
until the study is completed. 
7.1.1 
Screening Inclusion Criteria 
Potential subjects must meet all of the following inclusion criteria to be enrolled: 
Provide voluntary, written informed consent (parent(s) / legal guardian(s) of subject); provide 
voluntary, written assent (subjects, as appropriate) 
 
Genetically-confirmed Prader-Willi syndrome. If confirmation by a method other than 
methylation analysis, subject and caregiver consent to methylation analysis.  
 
 In a stable care setting for at least 6 months prior to Visit 1 and throughout the study 
 Caregiver must have been caring for the subject for at least 6 months prior to Visit 1 and will 
care for the subject throughout the study a minimum of 4 waking hours per day 
 
   
 
 
 
 
 
 
 
 
 
 
 
7.1.2 
Screening Exclusion Criteria 
Potential subjects must not meet any of the following exclusion criteria to be enrolled: 
  


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 Have participated in an interventional clinical study (i.e., investigational drug or device, 
approved drugs or device evaluated for unapproved use) within 60 days prior to Visit 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  


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 Positive urine pregnancy test (in females of child-bearing potential) 
 Females who are pregnant or breastfeeding, and/or plan to become pregnant or to breast-feed 
during or within 90 days after study participation 
 
 
 
 
 
 
 Any other known disease and/or condition, which would prevent, in the opinion of the 
Investigator, the subject from completing all study visits and assessments required by the 
protocol 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 


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7.3 
Subject Withdrawal 
Subjects and/or parent (s) / legal guardian(s) are free to withdraw consent and discontinue 
participation in the study at any time without prejudice to further treatment. Female subjects who 
become pregnant will be withdrawn from the study.  
 
     
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.0 
TREATMENT OF SUBJECTS 
8.1 
Treatments to be Administered 
DCCR or placebo doses will be administered orally, once daily in the morning with water or 
other beverage.  Tablets must be swallowed whole and should not be broken, crushed or chewed.   
 
 
 
 
 
 
   
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug product will be packaged for home administration. 
 
 
 
 


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8.3 
Dose Maintenance 
Once the target dose is reached, the subject will be maintained on that dose for the remainder of 
the treatment period. 
 
  
 
 
 
 
 
 
 
 
 
 
 
8.6 
Medication 
All concomitant medications (i.e., pharmaceuticals, biologics, herbal preparation, homeopathy, 
nutraceuticals, or procedures [e.g., acupuncture, vagal stimulation]) will be approved by the 
Medical Monitor prior to Visit 2.  Once the subject is randomized, any new, chronic, 
concomitant medication given to the subject should be discussed with the Medical Monitor.  


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8.6.1 
Prohibited Medications and Procedures 
The following medications are not permitted within 3 months prior to Screening (Visit 1) and 
during the study: 
• Anti-obesity medications or other medications (including herbal preparations, over-the- 
counter products) or procedures for weight reduction 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Any investigational drugs or devices 
 
 
 
8.7 
Monitoring for Subject Compliance 
 
 
  A member of the study site personnel will review the used study medication cards and 
assess the subject’s compliance with the study drug administration.  
 
 
   
9.0 
STUDY PROCEDURES 
The following sections describe the procedures and assessments that will be performed during 
the study.  The Schedule of Events, located in Section 9.2, indicates the frequency of these 
procedures and assessments.   
  
 
 


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9.1 
Description of Study Procedures and Assessments 
9.1.1 
Informed Consent / Assent 
At the beginning of the Screening Visit, potential participants and their parents(s) or legal 
guardian(s) will be given an IRB/IEC-approved informed consent form and an IRB/IEC-
approved assent form by a member of the study site personnel (i.e., study coordinator, 
Investigator, or other study site personnel).  Parent(s) / legal guardian(s) of potential participants 
and potential participants will be provided time to read the consent and assent forms as well as 
the opportunity to ask questions and have their questions answered prior to the initiation of any 
study-specific assessments.  Parents / legal guardians of subjects must voluntarily provide 
written informed consent and subjects must voluntarily provide written consent or assent, as 
applicable, before any study-related assessments are performed.  Once signed by the parent(s) / 
legal guardian(s), subject and the study site personnel performing the consent process, a copy of 
the consent form and assent form, as applicable, will be given to the parent(s) / legal guardian(s).  
The original forms will be stored in the study site’s files.  The subject’s medical records/source 
documents must include documentation that written informed consent and written assent was 
obtained from parent(s) / legal guardian(s) and subject, and that the parent(s) / legal guardian(s) 
of subject received copies of the signed, fully-executed informed consent form and assent form.  
In the event that the caregiver is not the parent or legal guardian, the source documents will need 
to include documentation that the caregiver was designated by the parent / legal guardian to 
complete questionnaires for the subject. All of the applicable eligibility criteria for the designated 
caregiver must be met.     
9.1.2 
Medical History, Medications and Demographics 
 
 subjects will be asked about subject’s relevant medical history and any 
medication and supplements (e.g., homeopathy, natural health products, etc.) the subject is 
currently taking or has taken, or procedures performed within 3 months of the Screening Visit.  
 
 
 
   In addition, the subject’s demographic information (age, gender, race, and 
ethnicity) will be collected.  Potential fertility should be assessed.  Subjects who are considered 


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potentially fertile should receive contraception instruction as deemed necessary by the 
Investigator. Refer to Appendix 1 for additional information.  
 
 
 
 
9.1.3 
Physical Examination 
A full physical examination (exam), including all major body systems, will be performed at each 
visit 
 
 
 
 
 
 
   
Any conditions or symptoms reported after the subject is enrolled at the Screening Visit will be 
recorded as an AE on the AE eCRF.  This includes new events, conditions, disease-related signs 
or symptoms that have worsened in severity or increased in frequency, and any event or finding 
that the Investigator feels is clinically significant.   
 
 
 
 
 
 
 
    
 
 
 
 
 
 


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9.1.4 
Vital Signs 
Vital signs will be measured at every visit 
 
  Vital signs include 
temperature, systolic and diastolic blood pressure, pulse rate, and respiration.  
 
 
 
    
9.1.5 
Weight 
Body weight will be measured at every visit 
 
 
 
 


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9.1.7 
Height 
Height will be measured at the Baseline Visit 
 and the End of Study 
Visit 
 
 
 


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9.1.8 
Electrocardiogram (ECG) 
A 12-lead electrocardiogram (ECG) will be performed at the Screening Visit (Visit 1), Visit 6 
and the End of Study Visit (Visit 7).  It is not necessary for the subject to be fasting for any 
ECGs.   
 
 
.   
The ECG performed at the Screening Visit will serve as the baseline ECG to evaluate changes.  
Nurses or investigators experienced in performing ECGs will perform the ECGs.   
 
 
  
 
 
A trained cardiologist at the study site will review the ECG output and provide an assessment of 
the intervals, segments, abnormalities of T-wave or U-wave morphology, and a diagnostic 
statement to the investigator.   
9.1.9 
Laboratory Tests 
For the blood tests, subjects will need to fast overnight (at least 8, but preferably 10-12 hours 
prior to the collection of their blood).  They must not have anything to eat or drink, except water.  
The following blood tests will be performed on blood collected, prior to study drug 
administration during the study at the Visits as defined in the Schedule of Events (Section 9.2).   
•
Fasting Plasma Glucose
•
Fasting Plasma Insulin
•
HbA1c
•
IGF-1
•
Chemistry Panel


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- Total Bilirubin 
- Direct Bilirubin 
- Indirect Bilirubin (calculation) 
- Alkaline Phosphatase 
- Alanine Transaminase (ALT) 
- Aspartate Aminotransferase (AST) 
- Gamma-Glutamyl Transferase (GGT)  
- Magnesium 
- Chloride 
- Calcium 
- Phosphorus 
- Total Protein 
- Albumin 
- Globulin (calculation) 
- Uric Acid 
- Creatine Kinase 
- Blood Urea Nitrogen 
- Creatinine 
- Estimated 
glomerular 
filtration rate 
(calculated-
screening only) 
- Sodium 
- Potassium 
- Bicarbonate 
• Hematology Panel 
- Hemoglobin 
- Hematocrit 
- WBC 
- RBC 
- RBC morphology 
- MCV  
- MCH 
- MCHC 
- Platelets  
- Neutrophils (abs, %) 
- Lymphocytes (abs, %) 
- Monocytes (abs, %) 
- Basophils (abs, %) 
- Eosinophils (abs, %) 
• Coagulation Panel  
- APTT 
- PT 
- INR 
• Lipid Panel 
- 
Triglycerides 
- 
Total Cholesterol 
- 
HDL Cholesterol 
- 
Non-HDL Cholesterol 
- 
LDL Cholesterol  
• Urinalysis 
- Color and clarity 
- Specific gravity  
- pH 
- Protein  
- Glucose  
- Ketones  
- Bilirubin  
- Urobilirubin  
- Blood  
- Nitrite 
- Leukocyte esterase  
Microscopic 
 
 
 
 
 
 
 
 
 
 
 
Instructions on sample collection, processing, storage, packaging and shipping will be provided 
in the laboratory manual.   


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9.1.9.1 
Monitoring of Laboratory Results 
Each subject’s laboratory reports will be sent by the central laboratory to the Investigator, who 
will assess the results for clinical significance.  
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
  


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.12 
Urine Pregnancy Test 
At every visit 
 
, female subjects of childbearing potential will be given a urine 
pregnancy test at the clinic.  Subjects with a positive urine pregnancy test will be excluded or 
withdrawn from the study if confirmed by a serum pregnancy test.  
 
     
9.1.13 
Enrollment 
At Visit 1, subjects who meet the screening eligibility criteria will be eligible for enrollment into 
the run-in period of the study.  Subjects will be assigned a unique identification number.    


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9.1.14 
Randomization  
At Visit 2, subjects who meet the eligibility criteria for randomization will be eligible for 
randomization into the study.   
9.1.15 
Dual-Energy Absorptiometry (DXA) 
 dual-energy 
absorptiometry (DXA) will be used to measure the subjects’ body composition.  Whole body 
(with head) scans will be performed. Reports should include a breakdown of the following 
regions: left arm, right arm, trunk, left leg, right leg, and head. Each region should be evaluated 
for body fat mass (g), lean body mass (g), total mass (g) and percent (%) body fat.  If the DXA 
scan report includes Region % fat and Tissue %fat, then the Region % fat should be recorded on 
the eCRF for percent body fat.   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
9.1.16 
Clinical Global Impression Scales 
Two Clinical Global Impression (CGI) scales are completed by the Investigator:  CGI of Severity 
and CGI of Improvement.  For the these scales, it is important for the Investigator to establish the 
presence of relevant symptoms, their frequency, intensity or severity and their effect on the 
major areas of the subject’s life such as work, home, school and relationships. 


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9.1.16.2 
Clinical Global Impression of Improvement (CGI-I)  
The Clinical Global Impression of Improvement (CGI-I) for Improvement is a single statement 
designed to assess the Investigator’s overall perception of change in the subject’s condition 
across the course of the clinical trial.  The Investigator provides a response to “Compared to the 
subject’s condition at enrollment, the subject’s condition is:” by rating the subject’s behavior 
using a 7-point response scale: Very much improved, Much improved, Minimally improved, No 
change, Minimally worse, Much worse, and Very much worse. The Investigator should only take 
into account the subject’s PWS condition. 
  
9.1.17 
Caregiver-Completed Questionnaires 
Caregiver questionnaires and interviews should be administered in a relaxed, informal setting.  
 
 
 
 
  The caregiver should consider all environments and situations including, but not 
limited to, school, work, and outside activities.  In addition, nights and weekends should be 
considered.   
 
 
9.1.17.1 
Hyperphagia Questionnaire - Clinical Trials (HQ-CT) 
Hyperphagia-related behaviors will be assessed by the validated hyperphagia questionnaire for 
clinical trials (HQ-CT), an instrument designed to measure symptoms of food related 
preoccupations and behaviors that will be completed by the caregiver 
  The HQ-CT 


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consists of nine items with responses ranging from 0–4 units each (possible total score range: 
0−36).  
 
  
 
   
 
     
 
 
 
 
 
 
   
 
  
9.1.17.3 
Caregiver Global Impression of Change (GI-C) 
The Caregiver Global Impression of Change (GI-C) is a single statement designed to assess the 
caregiver’s overall perception of change in the subject across the course of the clinical trial.  The 
caregiver provides a response to “Please choose the response below that best describes the 
overall change in the person’s PWS since they started taking the study medication” using a 7-
point graded response scale: Very much better, Moderately better, A little better, No change, A 
little worse, Moderately worse, and Very much worse.   
 
 
 
 
 
 
 
 
 
 
 
   


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9.1.18 
Study Drug Dispensation 
 
 
 
  


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The subject will be provided a sufficient supply of study drug plus some overage for daily 
administration of the assigned dose until the subsequent visit.    
 
9.1.19 
Study Drug Administration 
The study drug is to be administered by mouth (PO) once daily in the morning at approximately 
the same time, with water or another beverage. 
 
  
 
 
  
 
 
 
  
 
 
   
 
 
 
 
  
9.1.20 
Study Drug Accountability 
At Screening (Visit 1), the caregiver will be instructed on how to the record the date and time 
when the study drug is taken on the study medication cards.  At each subsequent visit, a member 
of the study site personnel will review with the caregiver the recorded information on the study 
medication cards then document dosing compliance and note discrepancies, if any, in the source 
documents and on the appropriate eCRF. 
 


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9.1.21 
Adverse Events 
Subjects will be monitored for safety from the time they are enrolled at the Screening Visit 
(Visit 1) until the End of Study Visit (Visit 7).  Any conditions or symptoms reported will be 
recorded as an AE in the subject’s source documents and on the AE eCRF page.  Subjects who 
have an ongoing AE related to study drug will be followed until resolution or stabilization of the 
event.  
 
 
 
 
 
   
 
 
 
  
9.1.22 
Concomitant Medications / Procedures 
Medications taken and procedures performed,
 will be 
recorded in the subject’s source document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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9.2 
Schedule of Events 
Visit Number 
1 
2  
 
  
5  
6  
7†,  
End of 
Study 
Screening 
Pre-
Rand 
Post-
Rand 
Day
 
-14 
0 
14 
28 
42 
56 
91 
Week 
-2 
0 
2 
4 
6 
8 
13 
Informed Consent, Assent 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical History 
X 
X* 
 
 
 
 
 
 
Screening Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
Randomization Inclusion/Exclusion Criteria Review 
 
X 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
Physical Examination, 
 
 
 Vital Signs, 
Weight, Waist Circumference 
X 
X** 
 
X1 
X1 
X1 
X1 
X** 
Height 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test*** 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Hematology Panel including PT, APTT and INR, 
Chemistry Panel, LFTs 
X 
X 
 
X 
X 
X 
X 
X 
HbA1c  
X 
 
 
 
 
 
 
X 
Lipid Panel 
 
X 
 
 
X 
 
X 
X 
IGF-1 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA Scan 
 
 
X 
 
 
 
 
X 
Hyperphagia Questionnaire (HQ-CT) 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-I, 
 
 
 
X# 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dispensation 
X 
 
X 
X 
X 
X 
X 
 
Study Drug Accountability 
 
X 
 
X 
X 
X 
X 
X 


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Visit Number 
1 
2  
 
  
5  
6  
7†,  
End of 
Study 
Screening 
Pre-
Rand 
Post-
Rand 
Day
 
-14 
0 
14 
28 
42 
56 
91 
Week 
-2 
0 
2 
4 
6 
8 
13 
Study Drug Administration## 
X 
 
X 
X 
X 
X 
X 
 
Adverse Events
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications
 
X 
X 
X 
X 
X 
X 
X 
X 
† 
Visit 7 assessments will be used as the Visit 1 assessments for subjects who enroll in Study 
C602. 
 
 
   
 
 
  
 
 
 
 
 
†† 
ECG performed at the Screening Visit will be used as the baseline ECG to evaluate changes.  
 
 
  
 
 
 
  
 
 
 
 
  
Full physical examination to be conducted if needed.   
***  For females of child-bearing potential only.  A positive urine pregnancy test must be confirmed 
by serum pregnancy test. 
 
 
 
 
  
 
 
 
  
 
## At each visit, after the necessary procedures have been completed, the assigned dose of DCCR or 
placebo will be taken in the clinic with water or other beverage. All other doses will be taken 
daily in the morning as described in Section 8.1 
 
 
 
 
 
 
 
   
 
 
 


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10.0 
ASSESSMENT OF EFFICACY 
10.1 
Efficacy Parameters 
The efficacy parameters that will be assessed in this study are: 
• HQ-CT score 
• Body fat mass (DXA) 
• Clinical Global Impression of Improvement  
 
 
• Caregiver Global Impression of Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.0 
ASSESSMENT OF SAFETY 
11.1 
Safety Parameters 
The safety parameters that will be assessed in this study are:   
• Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.2 
Definitions 
The following definitions, developed in accordance with the International Committee on 
Harmonization (ICH) Clinical Safety Data Management Guidance for Industry, E2A, 21 CFR 
Part 312.32, and EU Directive 2005/28/EC and Regulation 536/2014 will be used for the purpose 
of identifying AEs in this clinical study.   
11.2.1 
Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a clinical investigation patient, 
administered a pharmaceutical product which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or increase in severity or 
frequency of a pre-existing abnormality, temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product.   
11.2.2 
Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is reasonable possibility that 
the drug caused the adverse event.  Suspected adverse reactions will consist of the adverse events 
that are evaluated by the Investigator as possibly related or probably related to the study drug.   
11.2.3 
Serious Adverse Event  
A serious adverse event (SAE) is any adverse experience occurring after enrollment at any dose 
that results in any of the following outcomes: death, life-threatening (at the time of the event), 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect (in an offspring) 
Medically significant events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
event may jeopardize the subject and/or the subject may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
11.2.3.1 
Hospitalizations as Serious Adverse Events 
All AEs requiring hospitalization or prolongation of hospitalization should be reported as SAEs.   
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate eCRF: short-term administrative hospitalization for procedures, tests 


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or treatments of conditions that would not otherwise constitute an SAE, or elective 
hospitalizations. 
11.2.4 
Unexpected Adverse Event 
Any adverse event that is not listed in the Reference Safety Information section in the 
Investigator’s Brochure or is not listed at the same specificity or severity that has been observed 
previously.   
11.2.5 
Expected Adverse Events 
 
  
 
 
 
 
 
AEs reported as related to DCCR in at least 10% of subjects include peripheral edema and 
headache.  AEs reported in 2-9% of subjects include decreased appetite, palpitations, 
hyperglycemia, fluid retention, dizziness, chest pain, fatigue, tachycardia, nausea, hirsutism, 
abdominal distension, and arthralgia.  
11.3 
Adverse Event Assessment 
As defined above, an AE is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the medicinal product.   
AEs may include increases in intensity or frequency of conditions or diseases that were pre-
existing prior to study participation.  An example might include a subject in whom routine 
headaches become more severe or begin to occur more frequently.   
Medical or surgical procedures are not in and of themselves considered AEs, but if a condition or 
disease led to the procedure, the condition or disease would be considered an AE unless it was 
present prior to entering the study and did not worsen after entering the study.   
When possible, AEs will be graded according to CTCAE criteria (CTCAE, Version 5.0, which 
can be found online at https://evs.nci.nih.gov/ftp1/CTCAE).  


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Subjects entering the trial with ongoing baseline medical conditions should have their 
signs/symptoms graded according to CTCAE criteria. Increases in CTCAE grading from 
baseline conditions (e.g., Grade 1 to Grade 2) will be considered adverse events.   
A non-serious AE is any AE that does not meet the definition of a serious adverse event.   
11.3.1 
Performing AE Assessments 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
  
 
 
 
 
 
 
 


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11.3.1.1 
Adverse Event Severity 
AEs will be assessed for severity (intensity) according to the clinical description provided in the 
CTCAE Version 5.0 (Grade 1, Grade 2, Grade 3, Grade 4, or Grade 5).  If an AE cannot be 
classified using CTCAE terminology, severity will be assessed using the following definitions 
listed in Table 8. 
Table 8: 
Adverse Event Severity 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.1  
Grade 3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limited self-care activities of daily living.2 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to the AE. 
1 
Examples of instrumental activities of daily living include: Watching television, using a computer, 
playing video games, attending school, playing outside, using the telephone, etc. 
2 
Examples of self-care activities of daily living are: bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, etc. 
 
11.3.1.2 
Adverse Event Relationship  
For each AE, the Investigator is required to assess the causal relationship (relatedness) between 
the administration of the study drug and the occurrence of the AE.  The Investigator should use 
his or her clinical judgment and the following definitions to determine relatedness. 
• Not Related: The AE is not related if exposure to the study drug has not occurred, or the 
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely to be 
related to use of the study drug, i.e., there are no facts (evidence) or arguments to suggest a 
causal relationship 
• Unlikely Related:  The AE is more or most likely explained by causes other than the study 
drug 
• Possibly Related: The administration of the study drug and AE are considered reasonably 
related in time and the AE could be explained by causes other than exposure to the study 
drug 


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• Probably Related: Exposure to the study drug and AE are reasonably related in time and 
the study drug is more likely than other causes to be responsible for the AE, or is the most 
likely cause of the AE. 
 
11.3.1.3 
Vital Signs, Physical Examination and Clinical Laboratory Adverse Events 
Laboratory abnormalities and changes in vital signs or physical examination/findings are 
considered AEs only if they are determined to be clinically significant by the Investigator, result 
in withdrawal from the study, necessitate therapeutic intervention, or for some other reason the 
Investigator considers them clinically important.  However, if any of these changes in laboratory, 
vital signs or physical examinations is attributable to a new disease or condition or a worsening 
of a condition pre-existing study enrollment, the disease or condition itself shall be the reported 
AE, not the change in laboratory, vital sign or physical examination. 
11.3.2 
Serious Adverse Event Reporting 
All SAEs must be reported to Soleno within 24 hours of first knowledge of the event.  All SAEs 
that occur from the time the subject is enrolled at Screening through the End of Study Visit are 
reportable within 24 hours.   
The procedure for reporting an SAE is as follows: 
• Within 24 hours of first knowledge of the event, the site must contact Soleno by telephone or 
facsimile to report the event. 
• The initial report should include all information known at the time of the report (additional 
information can be reported as discovered).  Initial reporting should not be delayed in order 
to obtain resolution or follow-up information. 
• The site will fax an SAE report, or similar form, which includes the following information, as 
available: 
– Study subject number 
– Basic demographic information (age, gender, weight) 
– Relationship to study drug  
– The outcomes attributed to the event (death, life-threatening, hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to prevent 
permanent impairment/damage, etc.) 
– The onset date and severity of the event 
– A brief description of the event including frequency and severity of symptoms leading to 
diagnosis 


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– A list of relevant test results and lab data 
– Any other relevant history 
– Date of study drug administration 
– Whether the study drug was discontinued prematurely  
– Investigator’s assessment of causality 
The completed SAE report should be sent electronically as soon as possible (within 24 hours) to: 
 
 
 
The Medical Monitor or another representative or designee of Soleno may contact the 
Investigator to request additional information regarding the event or to confirm information.  All 
SAEs will be entered on the AE eCRF.  The same nomenclature should be used on both the SAE 
report and the AE eCRF.   
The Investigator is responsible for the complete and timely reporting of all SAEs to Soleno, 
following up on resolution of the SAE, and expeditiously and simultaneously notifying the 
responsible IRB/IEC of the occurrence and details of the event according to institutional standard 
procedures.  In the event there is a question as to whether the experience is serious, the event 
should be reported. 
12.0 
STATISTICAL PLAN 
It is estimated that 105 subjects will be enrolled and randomized.  In this multi-center study, each 
site is anticipated to enroll 3 or more subjects.  
12.1 
Sample Size Justification 
 
 
  
 
 
 
    
 
 
 
 


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12.3 
Efficacy Analyses 
All efficacy endpoints will be summarized at each visit by treatment group as well as by 
treatment group and strata in the ITT, MITT and PP Populations using summary statistics.  
Unless otherwise stated, subjects who are randomized to the wrong hyperphagia score group or 
growth hormone status will be analyzed in the stratum they belong in (vs. stratum randomized to 
if there are errors).   
12.3.1 
Primary Efficacy Analysis 
The primary endpoint (change from Baseline to Visit 7 in the HQ-CT score) will be analyzed 
using a linear mixed model for repeated measurements in the ITT Population.  All available data 


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from each subject will be used, with no imputation of missing data.  The dependent variable will 
be the change from Baseline to Visit 7 and the model will include fixed effects for treatment 
group 
time 
 the interaction between treatment and time, and the 
randomization stratification variable for baseline growth hormone use.  The baseline value of the 
HQ-CT score will be included as a covariate and the unstructured covariance model will be used.  
This model will include 7 fixed effects 
and 6 random effects.  With a total sample size of 105 subjects
randomized in a 2:1 ratio, this model is appropriate.  The primary analysis will compare the two 
treatment groups at Visit 7 using a two-sided test at the alpha=0.05 level of significance.
12.3.1.1
Multiple Comparisons - Control of the Alpha Level
To control the alpha level for the primary and secondary efficacy analyses at 0.05, a hierarchical 
fixed sequence testing procedure will be used.  
12.3.2
Secondary Efficacy Analyses
Body fat mass will be analyzed using an ANCOVA model with change from baseline to Visit 7 
as the response, baseline as a covariate, and treatment group and the randomization stratification 
variables as factors.
The Clinical Global Impression of Improvement and Caregiver Global Impression of Change
will be compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) mean 
score test with modified ridit scores, stratified by the randomization stratification variables.


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12.4 
Subgroup Analyses 
Analyses of the primary, selected secondary and/or selected exploratory endpoints may be 
performed using the following subgroups:  gender, baseline HQ-CT score, PWS genetic 
subtype/subclass, 
 
  Other subgroup analyses may be conducted. 
12.5 
Safety Analyses 
All safety analyses will be conducted in the Safety Population. Subjects who receive the wrong 
study drug for their entire course of treatment will be analyzed in the group based on the drug 
received.   
For each safety parameter, the last assessment made prior to the first dose of study drug will be 
used as the baseline for all analyses. 
All safety data will be summarized by treatment group and also by treatment group and strata.  
12.5.1 
Adverse Events 
Adverse events will be coded using MedDRA. A treatment-emergent AE (TEAE) is defined as 
an AE that starts or worsens at or during the time of or after the first study drug administration 
through the Visit 7. 
12.5.2 
Clinical Laboratory Evaluations  
All numeric laboratory data including chemistry (including liver enzyme of ALT, AST, and 
GGT) and hematology tests will be summarized at each visit as well as changes from baseline 
using summary statistics.  In addition, the maximum post-baseline and minimum post-baseline 
values will be summarized.  
Laboratory values will be categorized as normal, high, and low, based on normal ranges.  Shift 
from baseline will be summarized at each post-baseline visit. 
 
 
 
 
 
 
 
 
 


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12.5.4
ECG Parameters
Descriptive statistics for heart rate, RR interval, PR interval, QRS interval, QT interval, and QT 
interval corrected with Fridericia’s (QTcF) formula and the change from baseline to each post-
baseline visit will be presented.  Changes in morphology will be captured in text.  
12.5.5
Vital Signs
Descriptive statistics for resting heart rate, diastolic blood pressure, systolic blood pressure, 
temperature and the change from baseline to each post-baseline visit.  The change from baseline 
to the minimum and maximum post-baseline values will also be summarized by treatment group.
Shift tables may also be presented.  Clinically significant vital signs will be identified in the 
eCRF and will be listed.


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12.7 
Termination Criteria 
The DSMB may recommend stopping or modifying the study based on safety concerns identified 
based on its review of unblinded safety data (See Section 6.7).  Potential study discontinuation 
reasons include: 
• 
The sponsor determines that it is unsafe to continue because of an unexpected safety 
signal not otherwise clinically anticipated in randomized subjects without relevant 
medical history 
• 
Significant imbalance in rate of serious, unexpected adverse reactions that, independent 
of study drug, are not clinically anticipated in subjects randomized to DCCR versus 
placebo in subjects without relevant medical history 
• Significant imbalance in rate of serious adverse reactions that, independent of study drug, 
are not clinically anticipated in subjects randomized to DCCR versus placebo in subjects 
without relevant medical history 
If such issues arise, Soleno will, in consultation with the DSMB, Investigators, appropriate 
regulatory authority(ies), and/or IRBs/IECs, take the steps necessary to modify or discontinue the 
study. 
12.8 
Deviation Reporting 
Changes made to the Statistical Analysis Plan (SAP) after it has been signed but prior to database 
lock will be documented in an amendment to the Statistical Analysis Plan.  Any important 
changes made to the analysis after database lock will be described in the clinical study report 
(CSR).   


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12.9 
Interim Analysis 
There is no interim analysis planned in this study. 
13.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Site visits will be conducted by authorized representative(s) of Soleno to inspect study data, 
subject’s medical records, and eCRFs in accordance with current GCPs and respective national 
and local government regulations and guidelines (if applicable). The Investigator and Institution 
will permit authorized representatives of Soleno, its designees, the national health authorities, 
local authorities, and IRB/IEC direct access to source data/documents, with the exception of the 
responses to the HQ-CT and Global Impression Questions during the course of the study as 
described in Section 6.3.2,  to conduct study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections. 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Soleno will ensure that the study is conducted, and data are generated, documented (recorded), 
and reported in compliance with the protocol, GCP, and applicable regulatory requirements. 
Quality control will be applied at each stage of data handling to ensure that all data are reliable 
and have been processed (e.g., monitoring to review source documents/subject’s charts against 
eCRFs, development of a monitoring plan, data management system with appropriate logic 
checks, quality control review of the database prior to database lock, quality control procedures 
to confirm accurate table, listings, etc.).    
Audits may be performed as part of implementing quality assurance. Audits will evaluate study 
conduct, data/record integrity, and/or compliance with the protocol, standard operating 
procedures, GCP, and applicable regulatory requirements.  
The study will be registered on ClinicalTrials.gov by Soleno. 
15.0 
ETHICAL CONSIDERATIONS 
This study will be conducted according to applicable national standards for protection of human 
subjects and Good Clinical Practice including but not limited to US regulations 21 CFR 50, 56, 
312, Regulation EU 536/2014, Directive 2005/28/EC, Regulation EU 2016/679, and ICH Topics 
E2A, E2B(R3), E6(R2), and E11(R1). 
IRB/IEC approval will be obtained for the protocol, informed consent form, assent form, and all 
information provided to the caregiver / subject prior to their use in the study.  No study site will 
receive study drug prior to obtaining IRB/IEC approval for the study. 


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All parent(s) / legal guardian(s) of prospective subjects for this study will be provided an 
informed consent form that describes this study and provides sufficient information for them to 
make an informed decision about their child’s participation in this study.  As applicable, 
prospective subjects will be provided an assent form that describes this study and provides 
sufficient information for them to provide assent to participate in the study.  The informed 
consent form and assent form will be submitted with the protocol for review and approval by the 
IRB/IEC.  The formal consent and assent, as applicable, of a subject’s participation, using the 
IRB/IEC-approved informed consent form, will be obtained before that subject is submitted to 
any study procedure.  The parent(s) / legal guardian(s) and subject will be given adequate time to 
review the patient information and informed consent form, given the opportunity to ask 
questions, and understand that if they decline to participate in the study, the future care of the 
subject will not change. The informed consent form must be signed by the parent(s) / legal 
guardian(s) and the assent form must be signed by the subject. The investigator-designated 
research professional obtaining the consent and assent must also sign the informed consent form 
and assent form. Copies of the signed informed consent and assent forms will be provided to the 
parent / legal guardian. 
16.0 
DATA HANDLING AND RECORD KEEPING 
The Investigator must maintain adequate records for the study including completed eCRFs, data 
correction forms, original source documents including certified copies of original source 
documents, signed ICFs, drug accountability records, AE reports, screening and enrollment logs, 
correspondence with the IRB/IEC and Soleno or designee and other pertinent data and 
information.  Essential documents must be retained for 2 years after the last approval of a 
marketing application in an International Conference on Harmonization (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 a clinical development of the study drug, 
whichever is longer. These documents should be retained for a longer period if specified through 
written agreement with Soleno. Following study closure, the Investigator must inform Soleno if 
the location for study record storage is changed (e.g. the Investigator leaves the institution where 
the study was conducted). In order to ensure that documents are not inadvertently destroyed 
prematurely, please contact Soleno prior to destruction of any study-related documents. 
Data obtained from this study, including subject identity information, will be handled, processed, 
stored, and retained in accordance with applicable laws, regulations, and guidances. 
17.0 
PUBLICATION PLAN 
The results of this clinical study may be used by Soleno in registration documents for regulatory 
authorization in the countries and/or regions participating in this study, or other countries or 
regions, or for public dissemination in the form of papers, abstracts, posters, or other information 


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materials to be presented at scientific meetings, or published in professional journals, or as a part 
of an academic thesis by an Investigator. Institution may publish the results relating solely to 
work performed at the institution for this study only after the clinical trial has been completed, 
the data have been unblinded, final data analyses have been completed. In all cases, in order to 
avoid disclosures that could jeopardize proprietary rights, to ensure accuracy of the study data, 
and to ensure integrity is maintained, all manuscripts, abstracts, and presentations related to this 
study must be submitted to Soleno for review at least 45 days before their submission or release 
or as specified in separate written agreements.  
 
 


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18.0 
REFERENCES 
 
 
(1)  Butler M, Lee P, Whitman BE. Clinical Findings and Natural History of Prader-Willi 
Syndrome. Management of Prader-Willi Syndrome. Springer New York; 2006. 3-48. 
 
(2)  Buiting K, Horsthemke B. Molecular Genetic Findings in Prader-Willi Syndrome. In: 
Butler MG, Lee PDK, Whitman BY, editors. Management of Prader-Willi 
Syndrome.New York: Springer Science+Business Media, Inc.; 2006. 58-73. 
 
(3)  McCandless SE. Clinical report-health supervision for children with Prader-Willi 
syndrome. Pediatrics 2011;127(1):195-204. 
 
(4)  Whittington JE, Holland AJ, Webb T, Butler J, Clarke D, Boer H. Population prevalence 
and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in 
one UK Health Region. J Med Genet 2001;38(11):792-798. 
 
(5)  Dykens EM, Roof E, Hunt-Hawkins H. Cognitive and adaptive advantages of growth 
hormone treatment in children with Prader-Willi syndrome. J Child Psychol Psychiatry 
2017;58(1):64-74. 
 
(6)  Foundation for Prader-Willi Research. Prader-Willi Syndrome "Patient Voices" Online 
Survey and Results.  1-80. 2014.  
 
(7)  Qi Y, Purtell L, Fu M et al. Snord116 is critical in the regulation of food intake and body 
weight. Sci Rep 2016;6:18614. 
 
  
 
 
 
 
  
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 


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Protocol C601 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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Diazoxide Choline Controlled-Release (DCCR) 
 
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STATISTICAL ANALYSIS PLAN APPROVAL
Protocol: C601
ADDENDUM