A Physician-Initiated Randomised, Multiple-Dose, Single Period, Phase II Dose Ranging Study to Examine Transdermal Human Insulin In Adult Healthy Volunteer Patients
Phase: EARLY_PHASE1
Conditions: Pharmacodynamic Response to Small Doses of Insulin
Sponsor: Transdermal Delivery Solutions Corp

Levellor ™ Phase 0 Protocol HVD1  Healthy Volunteer Dose Range Trial ver 1.0 21st April 2021 – First Draft                                      
Page  1 of 64 
 
 
 
 
 
A Physician-Initiated Multiple-Dose, Single Period, 
Phase 0-I Dose Ranging Study to Examine 
Levellor™ HypoSpray Human Insulin Adult 
Healthy Volunteer Patients 
 
 
 
Protocol No.: LEV 101-D-022521 
ClinicalTrials.gov Reference NCT04857320 
 
 
 
21st APRIL, 2021 
 
Version 1.3 
 
 
 
SPONSOR: Langford Research Institute 
  
Principal Investigator: William D. Kirsh, D.O., M.P.H. 
 
 
Approved by Langford Research Institutional Review Board April 21st, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
AMENDMENTS: 
1. 
2. 
3. 
4. 
 
 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you, which is indicated as privileged or confidential. Copyright 2020 Transdermal 
Delivery Solutions Corp dba HypoSpray Pharma. 
 
 

Levellor ™ Phase 0 Protocol HVD1  Healthy Volunteer Dose Range Trial ver 1.0 21st April 2021 – First Draft                                      
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Contents 
List of abbreviations .................................................................................................................................. 6 
1.0 Synopsis .............................................................................................................................................. 8 
2.0 
Flow Chart .................................................................................................................................... 13 
3.0     Background Information ................................................................ Error! Bookmark not defined. 
3.1      Name and description of investigational product .................. Error! Bookmark not defined. 
3.2      Introduction ................................................................................. Error! Bookmark not defined. 
3.3      Known potential risks ................................................................ Error! Bookmark not defined. 
3.4      GCP compliance ........................................................................ Error! Bookmark not defined. 
3.5      Population ................................................................................... Error! Bookmark not defined. 
4.0     Trial objectives and purpose ......................................................... Error! Bookmark not defined. 
4.1      Primary objective ....................................................................... Error! Bookmark not defined. 
4.2      Secondary objectives ................................................................ Error! Bookmark not defined. 
5.0     Trial Design ..................................................................................... Error! Bookmark not defined. 
5.1      Overall study design .................................................................. Error! Bookmark not defined. 
5.1.1 Screening .................................................................................. Error! Bookmark not defined. 
5.1.2 Pharmacokinetic Sampling & Response monitoring: Visit 2 .......... Error! Bookmark not 
defined. 
5.1.3 Pharmacokinetic Sampling& Response monitoring: Visit 3 (Day 2) .... Error! Bookmark 
not defined. 
5.1.4 Pharmacokinetic Sampling& Response monitoring: Visit 4 (Day 3) .... Error! Bookmark 
not defined. 
5.1.5 
Discharge Visit 5: ................................................................ Error! Bookmark not defined. 
5.2      Endpoints ........................................................................................ Error! Bookmark not defined. 
5.2.1   Primary Pharmacokinetic endpoints ................................... Error! Bookmark not defined. 

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5.2.2 Secondary endpoints .............................................................. Error! Bookmark not defined. 
5.3      Discussion of design ................................................................. Error! Bookmark not defined. 
5.4      Visit schedule and assessments ............................................. Error! Bookmark not defined. 
5.4.1 Visit 1 – Pre-Screening Day ................................................... Error! Bookmark not defined. 
5.4.2 Visit 2 – Baseline Screen, first dose - Day 1 ........................ Error! Bookmark not defined. 
5.4.3 Visit 3 – Day 2 .......................................................................... Error! Bookmark not defined. 
5.4.4 Visit 4 – Day 3 .......................................................................... Error! Bookmark not defined. 
5.4.5 Visit 5 – Day 4+ ........................................................................ Error! Bookmark not defined. 
5.5 
Randomization ............................................................................ Error! Bookmark not defined. 
5.5.1 
Randomization .................................................................... Error! Bookmark not defined. 
5.5.2 Subject identification ............................................................... Error! Bookmark not defined. 
5.6      Investigational therapy .............................................................. Error! Bookmark not defined. 
5.6.1 Packaging and labeling ........................................................... Error! Bookmark not defined. 
5.7      Data collection ............................................................................ Error! Bookmark not defined. 
6.0 
Selection and Withdrawal of Subjects ......................................... Error! Bookmark not defined. 
6.1 
Inclusion criteria .......................................................................... Error! Bookmark not defined. 
6.2 
Exclusion criteria ......................................................................... Error! Bookmark not defined. 
6.3      Screening failure ........................................................................ Error! Bookmark not defined. 
6.4      Withdrawals ................................................................................ Error! Bookmark not defined. 
6.5      Replacement of subjects .......................................................... Error! Bookmark not defined. 
7.0     Treatment of Subjects P.R.N. ..................................................... Error! Bookmark not defined. 
7.1      Treatments.................................................................................. Error! Bookmark not defined. 
7.2      Concomitant therapy ................................................................. Error! Bookmark not defined. 
7.3      Treatment compliance .............................................................. Error! Bookmark not defined. 
8.0     Pharmacokinetic and Therapeutic Parameters .......................... Error! Bookmark not defined. 
8.1      Concentrations over Sampling Time ....................................... Error! Bookmark not defined. 

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8.2      Primary pharmacokinetic variables ......................................... Error! Bookmark not defined. 
9.0     Safety and tolerability assessments ............................................ Error! Bookmark not defined. 
9.1      Skin evaluation at Human Insulin Levellor™ HypoSpray application site .. Error! Bookmark 
not defined. 
9.2      Vital signs .................................................................................... Error! Bookmark not defined. 
9.3      Physical examination ................................................................ Error! Bookmark not defined. 
9.4.1 Hematology .............................................................................. Error! Bookmark not defined. 
9.4.2 Blood chemistry ....................................................................... Error! Bookmark not defined. 
9.5      Adverse events .......................................................................... Error! Bookmark not defined. 
9.5.1 Definitions ................................................................................. Error! Bookmark not defined. 
9.5.2 All adverse events (AEs) ........................................................ Error! Bookmark not defined. 
9.5.3 Serious adverse events (SAEs) ............................................. Error! Bookmark not defined. 
9.5.4 Reporting procedures .............................................................. Error! Bookmark not defined. 
10.0   Statistics ........................................................................................... Error! Bookmark not defined. 
10.1    Statistical methods .................................................................... Error! Bookmark not defined. 
10.2    Sample size and power calculations ....................................... Error! Bookmark not defined. 
10.3    Level of significance .................................................................. Error! Bookmark not defined. 
10.4    Procedure for missing, unused or spurious data ................... Error! Bookmark not defined. 
10.5    Selection of subjects to be included in the analysis ............. Error! Bookmark not defined. 
10.5.2         Safety Population .......................................................... Error! Bookmark not defined. 
10.5.3    Statistical Analysis Methods ................................................. Error! Bookmark not defined. 
10.6         Safety Data ....................................................................... Error! Bookmark not defined. 
11.0   Administration ................................................................................. Error! Bookmark not defined. 
11.1    Protocol amendments ............................................................... Error! Bookmark not defined. 
11.2    Other changes in study conduct .............................................. Error! Bookmark not defined. 
11.3    End of study ................................................................................ Error! Bookmark not defined. 

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11.4    Premature discontinuation ........................................................ Error! Bookmark not defined. 
11.5    Monitoring procedures .............................................................. Error! Bookmark not defined. 
12.0   Ethics ................................................................................................ Error! Bookmark not defined. 
12.1    Ethics and Good Clinical Practice ........................................... Error! Bookmark not defined. 
12.2    Regulatory and Ethics Committee approvals......................... Error! Bookmark not defined. 
12.4    Declaration of Helsinki .............................................................. Error! Bookmark not defined. 
13.0   Data Handling ................................................................................. Error! Bookmark not defined. 
13.1    Data collection ............................................................................ Error! Bookmark not defined. 
13.2    Data management and quality control .................................... Error! Bookmark not defined. 
13.3  Recording of data and retention of documents ....................... Error! Bookmark not defined. 
13.4    Auditing procedures .................................................................. Error! Bookmark not defined. 
13.5    Handling of study medication ................................................... Error! Bookmark not defined. 
14.0   Indemnity and compensation ........................................................ Error! Bookmark not defined. 
15.0 
Publication Policy ............................................................................ Error! Bookmark not defined. 
15.1 
Publication of results .................................................................. Error! Bookmark not defined. 
16.0 
Appendices ...................................................................................... Error! Bookmark not defined. 
Appendix 1        Declaration of Helsinki 1996 ........................................ Error! Bookmark not defined. 
Appendix 2  Subject Information Sheet and Informed Consent .......... Error! Bookmark not defined. 
Appendix 3 Normal Ranges and Clinically Significant Abnormal Vital Signs Error! Bookmark not 
defined. 
Appendix 4        Skin Reaction Scoring Scale ....................................... Error! Bookmark not defined. 
Appendix 5  Blood Sampling for Serum Glucose and  Human Insulin .......... Error! Bookmark not 
defined. 
Appendix 6        Haematology and Biochemistry sample collection ... Error! Bookmark not defined. 
Appendix 7       Protocol Amendments .................................................... Error! Bookmark not defined. 
 

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List of abbreviations 
 
 
AE 
adverse event 
 
ALT 
alanine aminotransferase 
 
ANOVA 
analysis of variance 
 
AST 
aspartate aminotransferase 
 
AUC 
area under the curve 
 
BP 
blood pressure bpm
 
beats per minute 
BUN 
blood urea nitrogen 
Cmax 
maximal plasma concentration 
 
CPK 
creatinine phosphokinase 
CNS 
central nervous system 
CRF 
case report form 
EPI 
Human Insulin(Adrenalin) 
EU 
European Union 
 
GCP 
Good Clinical Practice 
 
GP 
General Practitioner 
 
HIV 
human immunodeficiency virus 
HPS 
HypoSpray® proprietary transdermal delivery system (TDS)  
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
 
IUCD 
Intrauterine Contraceptive Device 
 
LDH 
lactate dehydrogenase 
 
LFT 
Liver Function Test 
 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mm Hg 
millimeters of mercury 
NCR 
no carbon required 
 
NRS 
numerical rating scale 
 
OECD 
Organisation for Economic Co-operation and Development 
 
PI 
Principal Investigator 

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PK 
Pharmacokinetics 
RBC 
red blood cells 
 
REC 
Research ethics committee 
SAP 
Statistical analysis plan 
SAE 
Serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase (same as AST) 
SGPT 
serum glutamic pyruvic transaminase (same as ALT) 
SUSAR 
serious unexpected suspected adverse reaction 
T1/2 
plasma concentration half life 
TDS® 
Proprietary transdermal drug delivery system 
 
Tmax 
time  passed  since  administration  at  which  the  maximum  plasma 
concentration occurs 
 
WBC 
white blood cells (leukocytes) 
WHO 
World Health Organization 

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1.0 Synopsis 
Name of 
medicinal 
product/active 
substance 
Levellor™ HypoSpray Human Insulin 100 IU/mL 
Title of the 
Study 
A Multi-Dose, Cross-over, Phase 0 Dose Ranging Study to 
Compare 
Levellor 
HypoSpray 
Human 
insulin 
in 
Healthy 
Volunteers. 
Protocol 
Number/Clinical 
Phase 
Protocol No.: LEV 001-D-020521  
Phase 0-1  
Chief 
Investigator 
William Kirsh, D.O., M.P.H.  
Study Site 
Clinical Studies Unit 
Rationale 
A new formulation of Human Insulin (Levellor™ HypoSpray) utilizes the 
HDS HypoSpray® drug delivery system (HypoSpray Pharma, Florida, 
USA) which is a novel, proprietary transdermal technology, developed 
for use in pharmaceutical, cosmetic and over-the-counter products. 
Transdermal administration combines a rapid onset of action with a 
convenient and patient-friendly, and in this case needle-less method of 
administration, which, it is believed, will provide enhanced safety as a 
more rapid and long lasting physiological-response alternative to the 
traditional SC Injectable route for the administration of Insulin. 
This study will assess the volunteer response to increasing doses of 
Human Insulin Levellor HypoSpray at various doses p.r.n. compared 
against SC injection at various sites of application and under varied 
conditions. 
Objectives 
The primary objective is to determine the amount of lowering serum 
glucose and dose response to a topically applied formulation of Human 
Insulin (Levellor™ HypoSpray) administered by spraying onto adult 
Healthy Volunteer subjects as compared to no treatment.  A 2-week 
period of daily blood sugar monitoring and insulin dosing for 3 days then 
monitoring for 3 days following will form the baseline data or each 
subject. 
The secondary objective is to evaluate the tolerability and local 
and systemic effects of Levellor™ HypoSpray. 
Design: 
This is a non-randomized, open label single period, phase 0I study.

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Duration of 
treatment: 
The maximum study duration is 20 days. 
 
Study 
Population: 
Adult Male patient volunteers aged 20 to 60 years. 
Main Criteria for 
Inclusion 
1. Healthy Adult Males 
2. 20 and 60 years of age, inclusive. 
3. The subject has a serum protein A1C of less than 6. 
 
4. The  subject  is  willing  and  able  to  read,  understand  the 
Subject Information Sheet and provide written informed 
consent. 
5. The subject has a body mass index (BMI) within 18-50 kg/m2. 
6. The subject is in otherwise good health as determined by 
medical history and physical examination. 
7. The subject is a non-smoker. 
8. The subject must agree to continue with daily serum glucose 
testing by means of a wearable blood glucose for the 
pharmacokinetic assessments. 
9. The subject is willing and able to comply with all testing and 
requirements defined in the protocol. 
10. The subject is willing and able to return to the study site for all 
visits. 

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Main Criteria for 
Exclusion: 
1. The subject has any relevant deviations from normal other 
than blood glucose in physical examination, electrocardiogram 
(ECG), or clinical laboratory tests, as evaluated by the 
investigator. 
2. The subject has had a clinically significant illness within 30 
days preceding entry into this study. 
3. The subject has a history of significant neurological, hepatic, 
renal, endocrine, cardiovascular, gastrointestinal, pulmonary, 
or metabolic disease. 
4. The subject has a known allergy or history of hypersensitivity 
to Human Insulin or similar modified Insulin compounds. 
5. The subject has used any prescription medication that may 
interfere with the evaluation of study medication. 
6. The subject has donated or lost a significant volume of blood 
(>450 mL) within four (4) weeks of the study, and their 
Haemoglobin concentration and hematocrit have not returned 
to within 5% of normal. 
7. The subject has a history of substance abuse or a current 
positive urine drug screen or urine alcohol test. 
8. Alcohol consumption greater than community norms (i.e. more 
than 21 standard drinks per week for males). 
9.  Subjects who have received an investigational drug or have 
used an investigational device in the 30 days prior to study 
entry 
Concomitant 
Medication 
Restrictions 
The intake of any medications (OTC or prescription) will be 
vigorously discouraged except as required to maintain health. 
Total expected 
number of 
subjects 
Sufficient volunteers will be recruited so as to obtain 5 completed 
subjects.  Up to two additional subjects may be added. 

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Study Drug 
The investigational medicinal product is Human Insulin (Levellor 
HypoSpray L). Three dose ranges will be assessed: administered 
via sprays from a syringe.  Doses will be calculated from what the 
literature reports is the low end of Healthy Volunteer Insulin 
Sensitivity. The 3 doses will be 0.075 IU/KG body weight, 0.1 
IU/KG Body weight and 0.15 IU/KG Body Weight.  This will result 
in dose ranges of 5 to 20 IUs. 

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Randomization 
Subjects will not be randomized.  Sites of application: applied 
topically to the neck/chest arm, thigh area or inner aspect of a 
forearm. 
Dosage 
Patients will receive dosing from the investigator and document 
blood sugar with a wearable Continuous Glucose Monitor (Libre 2) 
and will be dosed for 3 days.  The monitor will be worn for 24 hours
before the first dose and longer if available up to 7 days before 
beginning the study routine and 3 days after and receive the study 
drug via topical application for three days.  
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Criteria for 
evaluation:  
Pharmacokinetics 
Primary pharmacokinetic variables 
The primary pharmacokinetic variables include: the reduction of 
serum glucose from baseline and at typical post prandial spikes 
and the amount of insulin necessary to accomplish this reduction. 
In addition to 90% confidence intervals, the data will be 
summarized by medians, and maximum and minimum values. 
The elimination half-life of Insulin will be compared using non-
transformed data and parametric techniques.  Averages for the 
serum glucose and Post prandial excursions will be compared 
against averages for experimental periods. 
Safety and 
Tolerability 
Adverse Events will be recorded throughout the study, at all visits 
and during any telephone calls. 
Details on medical history and concomitant illnesses will be 
recorded on the day of screening by conducting a medical 
interview of subject or subject relative(s) and/or review of the 
subject’s medical records. Any changes observed or reported 
during the study will be recorded. 
 
A brief physical examination will be performed at Screening and 
at the Final Visit. 
Clinical laboratory tests will be performed at Screening, and on the 
days of Human Insulin administration, serum glucose levels will be 
monitored by means of a wearable Continuous Glucose Monitor. 

 
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2.0 
Flow Chart 
 
                                          
Study Day 
 
Activity 
Visit 1 
Screening 
Visit 2  
First Dose 
Visit 3 
Second 
Dose 
Visit 4 
Last Dose 
Visit 5 
Discharge 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Brief physical examination 
X 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
Concomitant medication 
X 
X 
 
X 
 
Local skin evaluation: clinical  
 
X 
X 
 
X 
 
Hematology, biochemistry and 
urinalysis 
X 
X 
 
X 
 
Serum Glucose Profile Test* 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Topical Dose  
 
X 
X 
X 
 
Patient Questionnaires 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
 
* 
Normal pre and post meal and pre- and post bedtime Time Points as measured by the 
CGM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential 
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Page  1 of 64 
A Physician-Initiated, Multiple-Dose, Single Period, 
Phase 0-I Dose Ranging Study to Examine 
Levellor™ HypoSpray Human Insulin Adult 
Healthy Volunteer Patients 
VOLUNTEER DOCLOSURES 
Protocol No.: LEV 101-D-022521 
ClinicalTrials.gov Reference NCT04857320 
21st APRIL, 2021 
Version 1.3 
SPONSOR: Langford Research Institute 
Principal Investigator: William D. Kirsh, D.O., M.P.H. 
Approved by Langford Research Institutional Review Board April 21st, 2021 
AMENDMENTS: 
1. 
2. 
3. 
4. 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you, which is indicated as privileged or confidential. Copyright 2020 Transdermal 
Delivery Solutions Corp dba HypoSpray Pharma. 

Confidential 
 
Levellor ™ Phase 0 Protocol HVD1  Healthy Volunteer Dose Range Trial ver 1.0 25th February 2021 – First Draft                                      
Page  2 of 64 
 
 
 
Appendix 2  Subject Information Sheet and Informed Consent 
 
(Form to be on headed paper) 
 
Study Number: LEV 101-D-022521 
Subject Identification Number:  
 
Study title: 
  
A Physician-Initiated  , Multiple-Dose, Single Period, Phase 0-I Dose Ranging 
Study to Examine Levellor™ HypoSpray Human Insulin Adult Healthy Volunteer 
Patients 
 
 
IND No:       N A  P h a s e 0  
Sponsor:       Langford Research Institute 
Version number: 1.0 
 
Part 1 
Invitation 
You are being invited to take part in a research study.  Before you decide it is 
important for you to understand why the research is being done and what it will 
involve.  Please take time to read the following information carefully.  Talk to 
others about the study if you wish. 
 
 Part 1 tells you the purpose of this study and what will happen to you if 
you take part. 
 Part 2 gives you more detailed information about the conduct of the 
study. 
 
Ask us if there is anything that is not clear or if you would like more information. 
Take time to decide whether or not you wish to take part. 
 
The Langford Institute is the sponsor of this research. 
 
What is the purpose of the study? 
The purpose of the study is to measure the extent of the absorption (through the 
skin and into the blood) of several doses of Human Insulin from a new 
formulation of this well-known medicine. It is believed that the new transdermal 
route i.e. through the skin, will provide a rapid onset of action, and be more 
convenient and user-friendly than the traditional injection route for the 
administration of Human Insulin. This study will examine your blood glucose 
response  profiles to Human Insulin applied via the skin with a new delivery 

Confidential 
 
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technology as compared to injection. 
 
Why have I been approached? 
You are being asked to take part in this study because you are an adult aged 
between 20 and 60 years and in good health, particularly without Type 1 or 2 
Diabetes Mellitus. 
 
 
 
Do I have to take part? 
No. It is up to you to decide whether or not to take part.  If you do, you will be 
given this information sheet to keep and be asked to sign a consent form. You are 
still free to withdraw at any time and without giving a reason.  A decision to 
withdraw at any time, or a decision not to take part, will not affect the standard of 
care you receive. 
 
What will happen to me if I take part? 
If you agree to take part, you will be required to attend the clinic on four (4) 
occasions to see the doctor/nurse. Two (2) of these visits will last only an hour 
each. The total study period for most will be a maximum of 35 days including the 
screening visit.  A minimum of 7 volunteers will be recruited to the study. 
 
The requirements of the study and your participation are described as follows: 
 
At every visit we will check your general health and perform a brief physical 
examination, including blood pressure and pulse rate. 
 
Screening Visit 
(This will occur no more than 28 days before the first administration of study 
medication) 
 
If you agree to take part and to sign a “Consent for Study Screening” you will be 
invited  to  a  selection  session  with  the  Endocrine  Investigations  Unit. 
 
You will be examined by the study doctor, who will take a detailed medical history 
and conduct a brief physical examination, including blood pressure and pulse rate 
and we will ask you about your medication and ask about any drug and/or alcohol 
abuse. We will ask you to provide a urine sample to test for drugs of abuse. 
 
Before joining the study we will require a 30mL blood sample from your arm for 
routine safety tests (about six (6) tablespoons. 
 
With your permission we will contact your General Practitioner to advise them of 
your potential participation in this study. 
 

Confidential 
 
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Visit 2 – Baseline 
Once accepted into the study, we will ask you to come to the Clinical Trials Unit in 
the early morning.  At this time you will undergo a check-in procedure and sign a 
“Consent for Study Participation”. 
 
We will start by applying the wearable continuous glucose monitor CGM (a small 
button with a small size needle) into your arm if you haven’t already done so, by 
following the instructions on the package.  By using the CGM we will be able to 
take monitor small samples of blood without having to keep using a needle each 
time. After the last sample day, the CGM button can be removed. 
 
The Human Insulin dose will be sprayed topically by you onto the upper chest, or 
your forearm or thigh and you will be asked to rub it in gently. At 60 minutes after 
application we will poll the CGM for a reading. The blood sampling by the CGM is 
to calculate your response to Human Insulin as measured by a shift in serum 
glucose. We will also measure your heart rate and blood pressure at regular 
intervals. 
 
A digital photograph will be taken of the application site prior to administration and 
after 30 minutes. The purpose of the photograph is to both carefully assess the 
application site and to keep a record of this; you will not be identifiable from the 
photograph. 
 
We will also measure your heart rate and blood pressure. 
 
During the day you can stay within the Unit but are not required to. It is most 
important that you are relaxed and are not stressed or excited as this may alter 
your own natural Human Insulin production and confuse the study results.  You 
should plan to eat lunch at the same time each of the 3 dosing days and you 
should try to eat roughly the same thing each day. 
 
 
In between dosing visits 
We will call you by telephone at an agreed time between Visits 2 and 3 to confirm 
your continued participation, daily dose schedule and eligibility (including 
concomitant medication use) as well as the occurrence of adverse events. 
 
Visit 5 (Final dose) - Day 6+ 
We will ask you to come to the Clinical Trials Unit in the early morning.  At this 
time you will undergo a check-in procedure. 
 
We will start by polling the CGM in your arm.  The blood samples on this day are 
to calculate whether you are returning to your normal pattern of glucose rising 
before to just after and falling after meals has resumed. We will also measure your 
heart rate and blood pressure at regular intervals.  After the last polling, the CGM 
can be removed. 

Confidential 
 
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During the day you can stay within the Unit or leave to work or read quietly. It is 
most important that you are relaxed and are not stressed or excited as this may 
alter your own natural Human Insulin production and confuse the study results. 
 
A digital photograph will be taken of the application site prior to the final 
administration of the Human Insulin spray and again after 60 minutes. 
 
After the last blood collection, the CGM can be removed, you will be assessed and 
then may go home. 
 
 
What do I have to do? 
If you choose to take part in this study you must not be taking part in other study. 
You must also not have taken part in any other study within the last 30 days. 
 
You will need to come to the Clinical Trials Center at the times requested and 
remain there for the duration of time required for each visit. 
 
You must inform your research doctor of all other medications you are taking 
including over the counter medications. You should not take any medications 
without first consulting the research doctor or nurse. 
 
If you experience any changes in your health whether or not you feel that this is 
related to your study medication, then you must inform your research doctor. 
 
 
 
What is the drug, device or procedure that is being tested? 
The HypoSpray Pharma System (HypoSpray®) is a combination of harmless 
chemicals at very low doses, which are balanced to deliver drugs through the skin 
without a needle, pain or irritation. These chemicals are usually used in 
cosmetics foods and food supplements. The HDS® system releases the drug 
where it is intended to have its effect without changing the drug in any way. 
 
Human Insulin is the hormone that the body creates to stimulate the conversion of 
fat to sugars the body needs for energy.  The hormone is critical in helping the 
body manage dietary glucose metabolism.    
 
What are the alternatives for diagnosis or treatment? 
There are no alternative treatments to Human Insulin except the injectable form. 
In the unlikely event of a reaction, you will be treated with the appropriate remedy 
which might be a dose of glucose or other sugar by means of eating or drinking a 
sugary foodstuff or drink like a soft drink.  The medicines being used in the study 
are believed to be the easiest and least invasive to use. 
 
 
 

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What are the side effects of any treatment received when taking part? 
Most Common: Application site reaction, abnormal lab test results.  The severity 
of these side effects usually depends on the size of the dose of Human Insulin 
and may continue throughout the study. 
 
Less common: Headache, dizziness, hypoglycemia and problems passing water. 
 
Very Rare: Heart attack or stroke.  We do not expect this, but it is possible. 
 
What are the other possible disadvantages and risks of taking part? 
The chemicals used in all of the HypoSpray® system are mainly used in the 
cosmetics and foods industries and are known to be safe for skin application. 
Additionally, we will be using them at very low concentrations compared to other 
products. We have recently finished two studies using HypoSpray ® with local 
anesthetics in 100 volunteers HypoSpray ® with Testosterone in a further 17 
volunteers and  HypoSpray ® with Diazepam in 12 volunteers, a skin safety study 
in 32 volunteers with no side effects. 
 
There are very few risks involved in inserting a continuous glucose monitor 
probe into a vein in the arm. You  may feel some discomfort and  sometimes 
there may be  a small bruise around the area, which may be sore and last for a 
couple of days. 
 
Harm to the unborn child 
The effects of Human Insulin on the unborn child may be harmful.  You should be 
careful to avoid making skin-to-skin contact while the skin is still wet after dosing, 
with anyone who is or might be pregnant while you are participating in this trial.  
 
What are the possible benefits of taking part? 
This study may not benefit you directly; however it may lead to the development 
of a more effective transdermal (delivery through the skin) version of Human 
Insulin. 
 
What happens when the research study stops? 
You will be free to go home. 
 
What if there is a problem? 
Any complaint about the way you have been dealt with during the study or any 
possible harm you might suffer will be addressed.  The detailed information on 
this is given in part 2. 
 
If you have a complaint, please contact the following person:  Dr. William Kirsh. 
 
If you feel any discomfort or distress during the investigations, you must say so 
and we will stop the tests immediately at any time. 
 
If you are employed by Langford Research, non-participation or dropping out of the 

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study will not affect your training or career. 
 
Any complaint about the way you have been dealt with during the study or any 
possible harm you might suffer will be addressed. The detailed information on this 
is given in Part 2. 
 
A contact number for complaints will be given. 
 
Will my taking part in the study be kept confidential? 
Yes. All the information about your participation in this study will be kept 
confidential. The details are included in Part 2. 
 
Contact Details: 
If you require any further information, please 
contact:  
 
Name of Doctor: Dr. William Kirsh 
Tel Number: 786-382-3310 
 
 
Or: 
 
After-hours number: 786-382-3310 
 
This completes Part 1 of the Information Sheet. 
 
If the information in Part 1 has interested you and you are considering 
participation, please continue to read the additional information in Part 2 before 
making any decision. 

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Part 2 
 
What if relevant new information becomes available? 
Sometimes, during the course of a research project, new information becomes 
available about the treatment/drug that is being studied.  If this happens, your 
research doctor will tell you about it and discuss whether you want to or should 
continue in the study.   If you decide not to carry on, your research doctor will 
make arrangements for your care to continue. If you decide to continue in the 
study, you will be asked to sign an updated consent form. 
 
Also, on receiving new information your research doctor might consider it to be in 
your best interests to withdraw you from the study.  He/she will explain the 
reasons and arrange for your care to continue. 
 
If the study is stopped for any other reason, you will be told why, and your 
continuing care will be arranged. 
 
What will happen if I don’t want to carry on with the study? 
If you withdraw from the study, we will need to use the data collected up to your 
withdrawal. We would ask you to keep in contact with us to let us know your 
progress.  Information collected may still be used.  Any stored blood or tissue 
samples that can still be identified, as yours will be destroyed if you wish. 
 
If your participation in the study is discontinued after you have started taking the 
study drug you will be asked to undergo a final examination for your own safety. If 
the reason for ending the study is, for example, an adverse event or a side-effect 
of the drug, you will be asked to give information on these in order to protect the 
other patients taking part in this clinical study. 
 
What if there is a problem? 
If you are harmed by taking part in this research project, there are no special 
compensation arrangements. If you are harmed due to someone’s negligence, 
then you may have grounds for a legal action, but you may have to pay for it. 
Regardless of this, if you wish to complain, or have any concerns about any 
aspect of the way you have been approached or treated during the course of this 
study, the normal National Health Service complaints mechanisms should be 
available to you. 
 
Complaints: 
If you have a concern about any aspect of this study, you should ask to speak 
with the Research Doctor who will do their best to answer your questions (Dr. 
William Kirsh, telephone: 786-382-3310).  If you remain unhappy and wish to 
complain formally you can do this by contacting: 
The Complaints Officer: c/o Chief Operating Officer for the Clinical Unit Center. 
 

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Will my taking part in this study be kept confidential? 
All the information obtained about you in the course of the study is confidential 
according to rules and will be kept in a secure locked room. The investigators 
performing the study and a study Monitor will have access to the data collected in 
this study.  They may also be looked at by representatives of regulatory 
authorities and by authorised people from the Institute to check that the study is 
being carried out correctly. All will have a duty of confidentiality to you as a 
research participant and nothing that could reveal your identity will be disclosed 
outside the research site. 
 
Involvement of the General Practitioner/Family doctor (GP) 
With your permission we will contact your General Practitioner to advise them of 
your potential participation in this study. 
 
What will happen to any samples I give? 
All your blood and urine samples taken for safety screening and for drugs of 
abuse will be tested immediately in the clinical lab and once the results are 
obtained, they will be destroyed.  
 
Will any genetic tests be done? 
 
No genetic tests will be done for this study. 
 
What will happen to the results of the research study? 
The results of this study may be published or presented at meetings.  You will not 
be identified in any report / publication or presentation. 
 
Who is organizing and funding the research? 
This research is being sponsored by HypoSpray Pharma. 
 
Who has reviewed the study? 
This study has been given a favorable ethical opinion for conduct in the Research 
Ethics Committee of the Langford Research Institute.   
 
Before you sign this consent form, please ask any questions you have about 
the study.  Thank you for taking the time to read this information sheet. 

 
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Study Number: LEV 101-D-022521 Phase 0  
Subject Identification Number: _______ 
SCREENING CONSENT FORM 
 
Title of Project: 
 
A  Multiple-Dose, Single Period, Phase 0-I Dose Ranging Study to Examine 
HDS®-Human Insulin in Adult Subjects 
 
Name of Researcher: Dr. William Kirsh 
Please initial box 
 
1.  I confirm that I have read and understand the information sheet 
dated ............................ , (version .......................) for the above study. I 
have had the opportunity to consider the information, ask questions and 
have had these answered satisfactorily. 
 
2.  I understand that my participation is voluntary and that I am free to 
withdraw at any time, without giving any reason, without my medical care or 
legal rights being affected. 
 
3. I understand that relevant sections of any of my medical notes and data 
collected during the study, may be looked at by responsible individuals from 
Clinical Studies Center and from regulatory authorities, where it is relevant to
my taking part in this research.  I give permission for these individuals to 
have access to my records and understand that my records will be 
maintained confidential. 
 
4.  I agree to my GP being informed of my participation in the study if 
necessary. 
 
5. I agree to take part in the above study. 
 
 
 
 
Name of Patient 
Date 
Signature 
 
Name of Person Taking Consent 
Date 
Signature 
 
Name of Researcher 
Date 
Signature 

 
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Study Number: LEV 101-D-022521 Phase 0 
Subject Identification Number: ______ 
 
STUDY CONSENT FORM 
 
A  Multiple-Dose, Single Period, Phase 0-I Dose Ranging Study to Examine 
Human Insulin HypoSpray in Adult Subjects 
 
Name of Researcher: Dr. William Kirsh 
Please initial box 
 
1.  I confirm that I have read and understand the information sheet 
dated ............................ , (version .......................) for the above study. I 
have had the opportunity to consider the information, ask questions and 
have had these answered satisfactorily. 
 
2.  I understand that my participation is voluntary and that I am free to 
withdraw at any time, without giving any reason, without my medical care or 
legal rights being affected. 
 
3. I understand that relevant sections of any of my medical notes and data 
collected during the study, may be looked at by responsible individuals from 
Clinical Research Center and from regulatory authorities, where it is relevant 
to my taking part in this research.  I give permission for these individuals to 
have access to my records. 
 
4.  I agree to my GP being informed of my participation in the study. 
 
5. I agree to take part in the above study. 
 
 
 
 
Name of Patient 
Date 
Signature 
 
Name of Person Taking Consent 
Date 
Signature 
 
Name of Researcher 
Date 
Signature