Conditions: Type 1 Diabetes Mellitus
Keywords: Humalog - Insulin lispro Citrate Infusion Site Pain Excipients
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 40
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the effect of excipients sodium citrate and treprostinil without insulin on local infusion site pain in participants with type 1 diabetes mellitus (T1DM) on continuous subcutaneous insulin infusion (CSII). The study may last up to 36 days including a screening period and 3 visits.

Detailed description:

Arms:
arm 1: Participants had cannulas inserted into each of the designated infusion sites (6 millimeter (mm) for all the sites. Additionally for the abdominal area only, a 9 mm cannula was also inserted into the opposite side of the lower abdomen), and the first infusion site was initiated subcutaneously (SC) with 15 millimolar (mM) sodium citrate and 1 microgram per milliliter (μg/mL) treprostinil in Humalog diluent with 5 mM magnesium chloride (without insulin) solution at a basal infusion rate of 1 unit per hour (U/h). The same procedure occurred at subsequent infusion sites with an approximately 30-minute (min) interval between each initiation. Approximately 3, 6, and 9 hours after the start of the basal infusion, a bolus dose of 15 U was delivered at quick bolus speed (15 U/min) to each infusion site according to the treatment sequence with an approximately 30-minute interval between infusion sites. arm 2: Participants had cannulas inserted into each of the designated infusion sites (6 mm for all the sites. Additionally for the abdominal area only, a 9 mm cannula was also inserted into the opposite side of the lower abdomen), and the first infusion site was initiated with 15 mM sodium citrate and 1 μg/mL treprostinil in Humalog diluent with 5 mM magnesium chloride (without insulin) solution at a basal infusion rate of 1 U/h. The same procedure occurred at subsequent infusion sites with an approximately 30-minute interval between each initiation. Approximately 3, 6, and 9 hours after the start of the basal infusion, a bolus dose of 15 U was delivered at quick bolus speed (15 U/min) to each infusion site according to the treatment sequence with an approximately 30-minute interval between infusion sites. arm 3: Participants had cannulas inserted into each of the designated infusion sites (6 mm for all the sites. Additionally for the abdominal area only, a 9 mm cannula was also inserted into the opposite side of the lower abdomen), and the first infusion site was initiated with 15 mM sodium citrate and 1 μg/mL treprostinil in Humalog diluent with 5 mM magnesium chloride (without insulin) solution at a basal infusion rate of 1 U/h. The same procedure occurred at subsequent infusion sites with an approximately 30-minute interval between each initiation. Approximately 3, 6, and 9 hours after the start of the basal infusion, a bolus dose of 15 U was delivered at quick bolus speed (15 U/min) to each infusion site according to the treatment sequence with an approximately 30-minute interval between infusion sites. arm 4: Participants had cannulas inserted into each of the designated infusion sites (6 mm for all the sites. Additionally for the abdominal area only, a 9 mm cannula was also inserted into the opposite side of the lower abdomen), and the first infusion site was initiated with 15 mM sodium citrate and 1 μg/mL treprostinil in Humalog diluent with 5 mM magnesium chloride (without insulin) solution at a basal infusion rate of 1 units per U/h. The same procedure occurred at subsequent infusion sites with an approximately 30-minute interval between each initiation. Approximately 3, 6, and 9 hours after the start of the basal infusion, a bolus dose of 15 U was delivered at quick bolus speed (15 U/min) to each infusion site according to the treatment sequence with an approximately 30-minute interval between infusion sites. arm 5: Participants had cannulas inserted into each of the designated infusion sites (6 mm for all the sites. Additionally for the abdominal area only, a 9 mm cannula was also inserted into the opposite side of the lower abdomen), and the first infusion site was initiated with 15 mM sodium citrate and 1 μg/mL treprostinil in Humalog diluent with 5 mM magnesium chloride (without insulin) solution at a basal infusion rate of 1 U/h. The same procedure occurred at subsequent infusion sites with an approximately 30-minute interval between each initiation. Approximately 3, 6, and 9 hours after the start of the basal infusion, a bolus dose of 15 U was delivered at quick bolus speed (15 U/min) to each infusion site according to the treatment sequence with an approximately 30-minute interval between infusion sites.

Interventions: intervention 1: Sodium Citrate intervention 2: Treprostinil intervention 3: Humalog diluent intervention 4: Magnesium Chloride
Intervention descriptions: intervention 1: Administered SC infusion. intervention 2: Administered SC infusion. intervention 3: Administered SC infusion. intervention 4: Administered SC infusion.

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I8B-MC-ITTC(c) 
 
 
A Study to Investigate Local Infusion Site Pain after Infusion of Excipients across Infusion Sites 
and Infusion Depths 
  
 
NCT05067270 
 
Approval Date: 14-Oct-2021 
 
 
 
 
 
 


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli n i c al 
i n v e sti g ati o n u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al 
i nfor m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y 
p u bli c r el e a s e. I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e 
r epr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title: A S t u d y t o In vest i gate L ocal  Inf usi o n S ite P ai n after Inf u sio n  of Exci pie nts 
acr oss Inf usi o n S ites a n d I nfusi o n D e pt hs
Pr ot oc ol N u m ber: I 8 B-M C -I T T C
A me n d me nt N u m ber: ( c)
C o m p o u n d : Cit rate, Tre pr osti nil ( L S N 3 3 2 6 7 7 7 )
St u d y P h ase: 1
S h ort Title: I n vesti gati on of I nf usi o n Si te Pai n after I nf usi on of E xci pie nts acr oss I nf usi on Si tes 
a n d I nf usi on De pt hs
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na, U S A 4 6 2 8 5
Re g ul at or y A ge nc y I de ntifier N u m ber(s)
E u dr a C T : 2 0 2 1- 0 0 1 9 8 7- 1 8
A p pr o v al D ate: Pr ot oc ol A me n d me nt ( c) El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date 
pr o vi de d bel o w . 
A p pr o v al D at e: 1 4- O ct- 2 0 2 1 G M T


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I8B-MC-ITTC (c)
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Medical Monitor Name and Contact Information will be provided separately 


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
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Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt ( b)
2 8 -Se pte m ber -2 0 2 1
A me n d me nt (a)
0 8 -Se pte m ber -2 0 2 1
Ori gi nal Pr ot oc ol
1 8- M a y - 2 0 2 1
A me n d me nt ( c)
T his a me n d me nt is c o nsi dere d t o be n o n- s u bsta ntial.
T he pr ot oc ol is a me n de d t o e ns ure t hat t he i nf usi on site l ocati o n is d oc u me nte d f o ll owi n g 
sta n dar d me d ical practice.
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
6. 1 . St u d y I nter ve nti o ns 
A d mi nistere d; 6. 1. 1. 
A d mi nistrati o n Details
P u m ps will be use d t o e val uate i nf usi o n 
sites 
 
T o e ns ure t hat t he 
i nf usi o n site l ocati o n is 
d oc u me nte d f oll o wi n g 
sta n dar d me dical practice .
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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................12
2.
Introduction..............................................................................................................22
2.1.
Study Rationale ..........................................................................................................22
2.2.
Background ................................................................................................................22
2.3.
Benefit/Risk Assessment ............................................................................................24
3.
Objectives and Endpoints.........................................................................................25
4.
Study Design .............................................................................................................26
4.1.
Overall Design............................................................................................................26
4.2.
Scientific Rationale for Study Design .........................................................................29
4.3.
Justification for Dose..................................................................................................30
4.4.
End of Study Definition..............................................................................................30
5.
Study Population ......................................................................................................31
5.1.
Inclusion Criteria........................................................................................................31
5.2.
Exclusion Criteria.......................................................................................................31
5.3.
Lifestyle Considerations .............................................................................................33
5.3.1.
Meals and Dietary Restrictions ...................................................................................33
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................33
5.3.3.
Activity ......................................................................................................................33
5.4.
Screen Failures...........................................................................................................33
6.
Study Intervention....................................................................................................35
6.1.
Study Interventions Administered...............................................................................35
6.1.1.
Administration Details................................................................................................36
6.1.2.
Pump Occlusion Alarms and Accidental Infusion Set 
Discontinuations.........................................................................................................37
6.2.
Preparation/Handling/Storage/Accountability.............................................................37
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................38
6.4.
Study Intervention Compliance...................................................................................38
6.5.
Concomitant Therapy .................................................................................................39
6.6.
Dose Modification......................................................................................................39
6.7.
Intervention after the End of the Study........................................................................39
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................40
7.1.
Discontinuation of Study Intervention ........................................................................40
7.1.1.
Hepatic Criteria for Discontinuation ...........................................................................40
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................40
7.3.
Lost to Follow-Up ......................................................................................................40
8.
Study Assessments and Procedures .........................................................................42
8.1.
Efficacy Assessments .................................................................................................42
8.2.
Safety Assessments ....................................................................................................42


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8.2.1.
Physical Examinations................................................................................................42
8.2.2.
Vital Signs..................................................................................................................42
8.2.3.
Electrocardiograms.....................................................................................................43
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................43
8.2.5.
Safety Monitoring.......................................................................................................43
8.2.6.
Local Pain Measurements Using the Visual Analog Scale...........................................44
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................45
8.3.1.
Timing and Mechanism for Collecting Events ............................................................45
8.4.
Treatment of Overdose ...............................................................................................47
8.5.
Pharmacokinetics........................................................................................................49
8.6.
Pharmacodynamics.....................................................................................................49
8.7.
Genetics .....................................................................................................................49
8.8.
Biomarkers.................................................................................................................49
8.9.
Immunogenicity Assessments.....................................................................................49
8.10.
Medical Resource Utilization and Health Economics..................................................50
9.
Statistical Considerations.........................................................................................51
9.1.
Statistical Hypotheses.................................................................................................51
9.2.
Analyses Sets .............................................................................................................51
9.3.
Statistical Analyses.....................................................................................................51
9.3.1.
General Considerations...............................................................................................51
9.3.2.
Primary Endpoints......................................................................................................51
9.3.3.
Secondary Endpoints ..................................................................................................52
9.3.4.
Exploratory Endpoints................................................................................................52
9.3.5.
Safety Analyses ..........................................................................................................52
9.4.
Interim Analysis .........................................................................................................52
9.5.
Sample Size Determination.........................................................................................53
10.
Supporting Documentation and Operational Considerations ................................54
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................54
10.1.1.
Regulatory and Ethical Considerations........................................................................54
10.1.2.
Informed Consent Process ..........................................................................................55
10.1.3.
Data Protection...........................................................................................................55
10.1.4.
Committees Structure .................................................................................................55
10.1.5.
Dissemination of Clinical Study Data .........................................................................56
10.1.6.
Data Quality Assurance ..............................................................................................56
10.1.7.
Source Documents......................................................................................................57
10.1.8.
Study and Site Start and Closure.................................................................................58
10.1.9.
Publication Policy.......................................................................................................58
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................59
10.2.1.
Blood Sampling Summary..........................................................................................61
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................62
10.3.1.
Definition of AE.........................................................................................................62
10.3.2.
Definition of SAE.......................................................................................................63
10.3.3.
Definition of Product Complaints ...............................................................................64


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10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................64
10.3.5.
Reporting of SAEs......................................................................................................66
10.3.6.
Regulatory Reporting Requirements ...........................................................................66
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................68
10.5.
Appendix 5: Genetics .................................................................................................71
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................72
10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting........................................................................73
10.8.
Appendix 8: Country-Specific Requirements..............................................................74
10.9.
Appendix 9: Provisions for Changes in Study Conduct During  
COVID-19 Pandemic .................................................................................................75
10.10.
Appendix 10: Abbreviations .......................................................................................78
10.11.
Appendix 11: Protocol Amendment History ...............................................................81
11.
References.................................................................................................................84


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
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1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title: A St u d y  t o I n vesti gate L ocal I nf usi on Si te Pai n after I nf usi on of E xci pie nts 
acr oss I nf usi on Si tes a n d I nfusi o n De pt hs
S h ort Title: I n vesti gati on of I nf usi o n Si te Pai n after I nf usi on of E xci pie nt s acr oss I nf usi on Si tes 
a n d I nf usi on De pt hs
R ati o n ale :
L ocal  inf usi o n site pai n ma y var y  bet wee n a nat o mical sites of i nf usi o n a n d bet wee n de pt hs of 
i nf usi on . T his st u d y will assess t he c o ntri b ut i on of  i nf usi on site a n d de pt h, as well as e xci pie nts 
s uc h as s o diu m  citrate a n d tre pr osti nil, o n l ocal i nf usi o n site pai n i n patient s wit h t ype 1 di a betes 
mellit us ( T 1 D) o n c o nti n u o us s u bc uta ne o us i ns uli n i nf usi o n ( C SII) .
O bjecti ves a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
P art A
Pri m ar y
T o i n vesti gate l ocal i nf usi o n site pai n f or i nf usi o ns of 
s o di u m citrate a n d tre pr osti nil i n H u mal o g dil ue nt wit h
ma g nesi u m c hl ori de ( wit h o ut i ns uli n) i n t he 
a b d o mi nal, ar m, t hi g h , a n d b utt oc k area s i n partici pa nts
wit h T 1 D o n C SII .
V A S pai n sc ore
Sec o n d ar y
T o i n vesti gate l ocal i nf usi o n site pai n of 2 differe nt 
ca n n ula i nserti o n de pt hs ( 6 m m a n d 9 m m) i n 
pa rtici pa nts wit h T 1 D o n C SII
V A S pai n sc ore
A b bre viati o n s: C SII = c o nti n u o us s u bc uta ne o us i ns uli n i nf usi o n ; V A S = vis ual a nal o g scale ; T 1 D = t ype 1 dia betes 
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I 8 B-M C -I T T C (c)
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O ver all Desi g n
St u d y  I 8 B-M C -I T T C is a 1-/ 2- ce nter, partici pa nt -( Part A  
) a n d i n vest i gat or-
bli n d, 2 -part ra n d o mize d cr oss o ver st u d y i n a d ults ( 1 8 t o 6 9 years of  a ge, i nclusi ve ) wit h T 1 D o n 
C SII .
Part A of t his st u d y  will be a 1-/ 2- ce nter, ra n d o mize d, 1 da y  5-p eri o d cr oss o ver base d o n t he 
or der of i nf usi on sites a n d de pt hs, bli n de d ( bet wee n i nf usi on de pt hs) , o pe n -lab el si n gle-treat me nt 
st u d y c o n d ucte d i n parti ci pa nt s wit h T 1 D.
N u m ber of P artici p a nts:
A p pr o xi matel y 4 6 parti ci pa nts will be ra n d oml y assig ne d t o st u d y int er ve nt i on s uc h t hat 
a p pr o xi matel y 4 0 e val ua ble partici pa nts c o m plete Part A  
 of t he st u d y. 
 
I nter ve nti o n Gr o u ps a n d D ur ati o n :
I nterve nti o ns gr o u ps
Part A

F o ll owi n g a n i nf or me d c o nse nt a n d a scree ni n g visit, partici pa nts will c o me t o t he 
cli nical researc h u nit ( C R U ) t he e ve ni n g pri or t o Da y 1 f or Part A . Parti ci pa nt s will 
c o nti n ue use of  t heir pers o nal p u m p t o a d mi nister i ns uli n at t he c urre nt ly e m pl o ye d 
i nf usi on sit e a n d i nf usi o n setti n gs . Parti ci pa nts will be i nstr ucte d t o a v oi d t he use of t he 
ce ntral a b d o mi nal area f or t heir pers o nal inf usi o n  s et (f or at least 3 da ys) pri or t o arri v al  
at t he C R U. T hic k ness of t he s u bc uta ne o us ( S C) fat la yer at t he a b d omi nal, ar m, t hi g h ,
a n d b utt oc k areas will be assesse d b y ul tras o u n d.

Eac h Me dtr o nic ™
Mi ni Me d ™7 7 0 G
p u m p reser v oir will be fille d wi t h st u d y treat me nt
(s o diu m  citr at e a n d tre pr osti nil i n H u mal o g dil ue nt wit h ma g nesi u m c hlori d e [wi t ho ut 
i ns uli n]) b y a q ualifie d site staff me m ber, a Mi ni M e d™
Mi o ™A d va nce i nf usi on set will 
be attac he d t o t he reser v o ir, t he reser v o ir l oa de d i nt o t he p u m p, a n d t he i nf usi on set 
t u bi n g pri me d u nt il dr o ps are see n at t he tip. S i x m m ca n n ula will be i nserte d i nt o eac h of 
t hese areas (a b d o me n [at le ast 5 c m a wa y fr o m t he u m bilic us i n t he left or rig ht l o wer 
q ua dra nts ], p osteri or as pect of t he u p per ar m, a nteri or or lateral t hig h , a n d u p per b utt oc k) , 
a v o i di n g areas of li p o h y pertr o p h y a n d s ur gical scars. At  t he a b d o mi nal area o nl y, a 9 m m 
ca n n ula will als o be i nserte d i nt o t he o p p osite si de of t he l ower a b d o me n. T he i nf usio n  
set ca n n ula will  be fille d wi t h 0.6 u nit f or b ot h 6 m m a n d 9 m m ca n n ula (w hile n o i ns uli n 
will be i nf use d b y  t he st u d y p u mps, f or si m plici t y, v o l umes a n d rates will be descri be d i n 
u nit s a n d u nits/ h o ur w here 1 u ni t = 1 0 µ L). 

P arti cipa nt s will be ra n d oml y assi g ne d t o a treat me nt se q ue nce t o i n dicate t he or der of  t he
i nf usi on site s bei n g e val uate d.
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I 8 B-M C -I T T C (c)
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
T he first i nf usi on site will be i nitiate d acc or di n g t o t he treat me nt se q ue nce a n d a basal 
inf usi o n rate of 1 U/ h will be starte d. T he sa me pr oce d ure will occ ur at t he s u bse q ue nt
i nf usi on sites acc or di n g t o t he treat me nt se q ue nce wi t h an a p pr o xi mate 3 0- mi n ute 
i nter val bet wee n i nitiat i on of t he pre vi o us i nf usi o n site .

A p pr o xi matel y  3 h o urs after start of t he basal i nf usi on rate, a b olus d ose of  1 5 U gi ve n at 
q ui c k s pee d ( 1 5 U/ mi n) will  be deli vere d t o eac h i nf usi on site acc or di n g t o t he treat me nt 
se q ue nce wi t h an a p pr o xi mate 3 0- mi n ute i nter val bet wee n i nf usi o n sites . 

A sec o n d b o l us d ose of 1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d 
a p pr o xi matel y 6 h o urs after t he start of t he basal i nf usi o n t o eac h i nf usi on site acc or di n g 
t o t he treat me nt se q ue nce wi t h an a p pr o xi mate 3 0 -mi n ute i nter val bet wee n i nf usi o n sites .

A t hi r d b ol us d ose of 1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d
a p pr o xi matel y 9 h o urs after t he start of  t he basal i nf usi on t o eac h i nf usi on site acc or di n g 
t o t he treat me nt se q ue nce wi t h an a p pr o xi mate 3 0- mi n ute i nter val bet wee n i nf usi o n sites.

P arti cip a nts will rate t he pai n at eac h i nf usi o n site wi t h eac h b o l us d ose at  t he f oll owi n g 
a p pr o xi mate ti me p oi nts : 5 mi n utes bef ore t he a d mi nistrati o n of a b o l us d ose a n d 1 a n d 
1 5 mi n utes aft er t he start of  eac h b olus d ose . St u d y i nf usi on sets a n d p u m ps will  be 
r e mo ve d, t he i nf usi o n sites will be e valu at e d f or ac ute i nf usio n react i ons , a n d t he 
parti ci pa nt will be disc har ge d .
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C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 0
D ur ati o n
T he a p pr o xi mate d urati o n of st u d y  p artici patio n f or eac h parti ci pa nt ma y be u p t o 3 6 da ys, acr oss 
t he f o ll owi n g st u d y  int er vals:

Scree ni n g, a p pr o xi matel y  2 8 da ys

Treat me nt peri o d, 2 visit s o ver 5 da ys ( 1 da y for Part A
 
)

F o ll ow -u p peri o d 
D at a M o nit ori n g C o m mittee: N o
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C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
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1. 2.
Sc he m a
 
Fi g ure 1
Sc he m atic o ver vie w of t he c hr o n ol o gic al str uct ure of t he tri al .
I nf or me d 
C o nse nt
I nf usi o n sites
P art A
Scree ni n g
Visit 0
Visit 1
Visit 2
Visit 3
Scree ni n g Peri o d 
St u d y Peri o d 
≥1 d a y 
bef ore Visit 1
≤2 8 d a ys 
bef ore Visit 2
At le ast 3 d a ys bet wee n Visit 2 
a n d Visit 3
Fi n al 
e x a mi n ati o n
Visit 4
F oll o w -u p -
Tele visit
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 2
1. 3.
Sc he d ule of Acti vities ( S o A)
T a ble 1
Tri al Fl o w C h art
Tri al Peri o d
Scree ni n g Peri o d
St u d y Peri o d
F oll o w -u p -
Tel e visit /earl y 
disc o nti n u ati o n
C o m me nts
Visit n o.
0
1
2 ( P art A) 
4
Ti mi n g
≥1 da y bef ore 
Visit 1
≤2 8 da ys pri or 
t o Visit 2
at least 3 da y s bet wee n Visit 2
a n d Visit 3
I n-h o use Visit/ Peri o d
see Ta ble 2
I nf or me d c o nse nt
X
X
At Visit 1, c hec k t hat i nf or me d 
c o nse nt has bee n si g ne d a n d 
date d
Fasti n g
X
I ncl usi o n/e xcl usi o n criteria
X
At Visit 2, c o nfir m partici pa nt 
c o m plia nce
De m o gra p hic data
X
S m o ki n g a n d alc o h ol 
c o ns u m pti o n ha bits
X
M e dical hist or y/ Pr e-
e xisti n g C o n diti o ns
X
Wei g ht 
X
X
H ei g ht
X
Alc o h ol breat h test /ur i ne 
dr u g scree n
X
X
P h y sical e xa mi nati o n
X
Vital si g ns
X
X
1 2 -lea d E C G
X
Hae mat ol o g y
X
Bi oc he mistr y
X
C oa g ulati o n
X
Ur i nal ysis
X
I nfecti o us ser ol o g y 
X
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 3
Tri al Peri o d
Scree ni n g Peri o d
St u d y Peri o d
F oll o w -u p -
Tel e visit /earl y 
disc o nti n u ati o n
C o m me nts
Visit n o.
0
1
2 ( P art A) 
4
Ti mi n g
≥1 da y bef ore 
Visit 1
≤2 8 da ys pri or 
t o Visit 2
at least 3 da y s bet wee n Visit 2
a n d Visit 3
I n-h o use Visit/ Peri o d
see Ta ble 2
Pre g na n c y test 
X
X
O nl y  re q uire d f or wo m en of 
chil d beari n g p ote ntial
S er u m at t he scree ni n g visit a n d 
uri ne at Visits 2 a n d 3 
F S H
X
T his is o nl y  for  w o me n wit h 
b ot h m ore t ha n 1 2 m o nt hs of 
a me n orr hea a n d a ge of ≤5 5 (see
Secti o ns 1 0. 2 a n d 1 0. 4 ) 
H b A 1c
X
Ultras o u n d
X
T hic k ness of t he s u bc uta ne o us 
( S C) fat la yer will be assesse d 
at t he a b d o mi nal areas (l o wer 
ri g ht a n d left), ar m, t hi g h, a n d 
b utt oc k .
L ocal I nf usi o n site pai n 
( V A S)
X
See Ta ble 2 a n d Ta ble 3 f or 
c ollecti o n ti mes
L ocal I nf usi o n site 
reacti o ns
X
After re m o val of eac h i nf usi o n 
set
 
Platf or m
X
C ollect i ma ge of eac h l ocal 
i nf usi o n site pri or t o i nserti o n 
a n d after re m o val of eac h 
i nf usi o n set
A Es/ Pr o d uct C o m plai nts
X
X
X
C o nc o mita nt Me dicati o ns
X
X
X
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 4
Tri al Peri o d
Scree ni n g Peri o d
St u d y Peri o d
F oll o w -u p -
Tel e visit /earl y 
disc o nti n u ati o n
C o m me nts
Visit n o.
0
1
2 ( P art A) 
4
Ti mi n g
≥1 da y bef ore 
Visit 1
≤2 8 da ys pri or 
t o Visit 2
at least 3 da y s bet wee n Visit 2
a n d Visit 3
I n-h o use Visit/ Peri o d
see Ta ble 2
Meals ( brea kfast, l u nc h ,
a n d di n ner)
X
Br ea kfast will be pr o vi de d pri or 
t o st u d y acti vities. L u nc h will 
be pr o vi de d after c o m pleti o n of 
t he first b ol us assess me nts. 
Di n ner will be pr o vi de d after 
c o m pleti o n of t he sec o n d b ol us 
assess me nts
A b bre viati o ns: A E = a d verse e ve nt ; B MI = b o d y mass i n de x; E C G = electr ocar di o gra m; H b A 1c = he m o gl o bi n A 1c ; n o. = n u m ber; V A S = vis ual a nal o g scale .
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 5
T a ble 2
Assess me nt Sc he d ule f or Visit 2 ( P art A)
A p pr o x. h o ur
N o mi n al 
ti mi n g
Acti vit y
Ot her
D a y - 1
Partici pa nt arri ves after di n ner f or o ver ni g ht sta y
at t he trial site a n d c o nti n ue d eli gi bilit y will be 
c hec ke d. T he partici pa nt will c o nti n ue pers o nal 
dia betes ma na ge me nt care. Partici pa nts will be 
i nstr ucte d t o a v oi d t he use of t he ce ntral 
a b d o mi nal area f or t heir pers o nal i nf usi o n set 
(f or at least 3 da ys) pri or t o arri val at t he C R U
a n d co nti n ue i ns uli n i nf usi o n wit h t heir pers o nal
i ns uli n p u m p.
S A R S -C o V - 2 test ma y be perf or me d acc or di n g t o 
t he site ge neral pr oce d ures
A Es, c o nc o mita nt me dicati o n, alc o h ol breat h test, 
vital si g ns, uri ne pre g na nc y test
D a y 1
Br ea kfast
Meas ure a n d rec or d a di p ose t hic k ness b y 
ultras o u n d at i nf usi o n sites
C ollect i ma ge of eac h l ocal i nf usi o n site pri or t o 
i nserti o n of t he c orres p o n di n g i nf usi o n set usi n g 
 Platf or m
T h ese meas ure me nt s m a y  be perf or me d at a n y ti me 
after t he s u bject’s arri val on D a y -1 u ntil i nf usi o n 
set i nserti o n.
Eac h l ocal i nf usi o n site s h o ul d be la bele d a n d ha ve 
a u ni q ue i de ntifier f or 
 Platf or m
i ma ge ac q uisiti o n    
St u d y p u m ps l oa de d wit h st u d y treat me nt
+ 0 h
I nsert i nf usi o n set ca n n ula i nt o i nf usi o n site 1 
a n d start p u m p at a basal rate of 1 U/ h
+ 0 . 5 h ( ±5 mi n)
I nsert i nf usi o n set i nt o i nf usi o n site 2 a n d start 
p u m p at a basal rate of 1 U/ h
+ 1 h ( ±5 mi n)
I nsert i nf usi o n set i nt o i nf usi o n site 3 a n d start 
p u m p at a basal rate of 1 U/ h
+ 1 . 5 h ( ±5 mi n)
I nsert i nf usi o n set i nt o i nf usi o n site 4 a n d start 
p u m p at a basal rate of 1 U/ h
+ 2 . 0 h ( ±5 mi n)
I nsert i nf usi o n set i nt o i nf usi o n site 5 a n d start 
p u m p at a basal rate of 1 U/ h
+ 3 . 0 h ( ±3 mi n)
-5 mi n b
C ollect V A S sc ore f or i nf usi o n site 1
0 mi n
A d mi nister 1 5 U b ol us t o i nf usi o n site 1 at q uic k 
b ol us s pee d ( 1 5 U/ mi n)
+ 1 mi n a
C ollect V A S sc ore f or i nf usi o n site 1
+ 1 5 mi n b
C ollect V A S sc ore f or i nf usi o n site 1
+ 3 . 5 h ( ±3 mi n)
-5 mi n b
C ollect V A S sc ore f or i nf usi o n site 2
C CI
C CI


CONFIDENTIAL
I8B-MC-ITTC (c)
16
Approx. hour
Nominal 
timing
Activity
Other
0 min
Administer 15 U bolus to infusion site 2 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 2
+15 minb
Collect VAS score for infusion site 2
+4.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 3
0 min
Administer 15 U bolus to infusion site 3 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 3
+15 minb
Collect VAS score for infusion site 3
+4.5 h (±3 min)
-5 minb
Collect VAS score for site 4
0 min
Administer 15 U bolus to infusion site 4 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 4
+15 minb
Collect VAS score for infusion site 4
+5.0 h (±3 min)
-5 minb
Collect VAS score for site 5
0 min
Administer 15 U bolus to infusion site 5 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 5
+15 minb
Collect VAS score for infusion site 5
Lunch
+6.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 1
0 min
Administer 15 U bolus to infusion site 1 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 1
+15 minb
Collect VAS score for infusion site 1
+6.5 h (±3 min)
-5 minb
Collect VAS score for site 2
0 min
Administer 15 U bolus to infusion site 2 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 2
+15 minb
Collect VAS score for infusion site 2
+7.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 3
0 min
Administer 15 U bolus to infusion site 3 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 3
+15 minb
Collect VAS score for infusion site 3
+7.5 h (±3 min)
-5 minb
Collect VAS score for infusion site 4


CONFIDENTIAL
I8B-MC-ITTC (c)
17
Approx. hour
Nominal 
timing
Activity
Other
0 min
Administer 15 U bolus to infusion site 4 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 4
+15 minb
Collect VAS score for infusion site 4
+8.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 5
0 min
Administer 15 U bolus to infusion site 5 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 5
+15 minb
Collect VAS score for infusion site 5
Dinner
+9.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 1
0 min
Administer 15 U bolus to infusion site 1 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 1
+15 minb
Collect VAS score for infusion site 1
+9.5 h (±3 min)
-5 minb
Collect VAS score for infusion site 2
0 min
Administer 15 U bolus to infusion site 2 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 2
+15 minb
Collect VAS score for infusion site 2
+10.0 h (±3 min)
-5 minb
Collect VAS score for site 3
0 min
Administer 15 U bolus to infusion site 3 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 3
+15 minb
Collect VAS score for infusion site 3
+10.5 h (±3 min)
-5 minb
Collect VAS score for infusion site 4
0 min
Administer 15 U bolus to infusion site 4 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 4
+15 minb
Collect VAS score for infusion site 4
+11.0 h (±3 min)
-5 minb
Collect VAS score for infusion site 5
0 min
Administer 15 U bolus to infusion site 5 at quick 
bolus speed (15 U/min)
+1 mina
Collect VAS score for infusion site 5
+15 minb
Collect VAS score for infusion site 5


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 8
A p pr o x. h o ur
N o mi n al 
ti mi n g
Acti vit y
Ot her
+ 1 1 . 5 h ( ±3 mi n)
Re m o ve i nf usi o n sets, e val uate l ocal i nf usi o n 
sites
C ollect i ma ge of eac h l ocal i nf usi o n site after 
re m o val of t he c orres p o n di n g i nf usi o n set usi n g 
 Platf or m
Eac h l ocal i nf usi o n site s h o ul d be la bele d a n d ha ve 
a u ni q ue i de ntifier f or 
 Platf or m
i ma ge ac q uisiti o n t hat is t he sa me as pri or t o 
i nf usi o n   
+ 1 2 . 5 h ( ±3 0 mi n)
Pa rtici pa nt d isc har ge fr o m C R U
F oll o wi n g t he fi nal e val uati o n, t he partici pa nts will 
ha ve t he o pti o n t o s pe n d t he ni g ht or be disc har ge d 
fr o m t he C R U
A b bre viati o ns:  A E = a d verse e ve nt; A p pr o x. = a p pr o xi matel y; C R U = cli nical researc h u nit; S A R S -C o V - 2 = se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 ; 
V A S = vis ual a nal o g scale.
a
T he V A S ti me p oi nt of 1- mi n ute (+ 1 mi n ) is t o be c ollecte d fr o m t he start of b ol us i nf usi o n .
b
T he V A S ti me p oi nts of - 5 ( ± 2 mi n), a n d 1 5 ( ± 2 mi n) mi n utes are t o be c ollecte d fr o m start of b ol us i nf usi o n .
.
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
1 9
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 0
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 1
C CI


CONFIDENTIAL
I8B-MC-ITTC (c)
22
2.
Introduction
LY900014 (Lyumjev®) is an ultra-rapid-acting formulation of insulin lispro for subcutaneous 
(SC) and intravenous use that employs excipients, citrate and treprostinil, to accelerate time 
action, along with magnesium to enhance insulin stability, resulting in improved glycemic 
control in participants with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus.
2.1.
Study Rationale
In the Phase 3 pivotal multiple daily injection studies (Blevins et al. 2020; Jinnouchi et al. 2020;
Klaff et al. 2020), LY900014 dosed at the start of a meal demonstrated noninferior overall 
glycemic control (hemoglobin A1c [HbA1c]) in patients with T1D and type 2 diabetes mellitus,
and superior overall glycemic control in patients with T1D, and consistently better postprandial 
glucose (PPG) control, compared to Humalog. Injection site reactions occurred at a higher 
incidence with LY900014 compared to Humalog (2.7% versus 0.1%, respectively), but had an 
overall low incidence.
LY900014 was efficacious, providing superior PPG control and less time in hypoglycaemia but 
with more frequent infusion site reactions (ISRs) compared with Humalog when administered by 
continuous subcutaneous insulin infusion (CSII) (Warren et al. 2021). Infusion site reactions
were reported by 37.7% of T1D patients treated with LY900014 using CSII for 16 weeks in the 
PRONTO-Pump-2 study (Warren et al. 2021). Typically, local infusion site pain is noted 
immediately after infusion of a bolus dose, subsiding over 20-30 minutes thereafter.
This study aims to investigate whether local infusion site pain is dependent on the site of infusion
and/or the depth of the infusion. In addition, the study will investigate the contribution of two of 
the excipients of LY900014 to local infusion site pain.
2.2.
Background
Type 1 diabetes mellitus is an autoimmune disease resulting in destruction of beta cells, and 
lifelong dependency on exogenous insulin. The prevalence of T1D is near 1 in 300 and its 
incidence is steadily increasing worldwide (3% per year) (Gan et al. 2012). 
Many advances in the treatment of T1D have occurred in the last 20 years; however, reaching 
and maintaining glycemic goals remains challenging even under intensive insulin therapy 
regimens. Rapid-acting insulin analogs, such as insulin lispro, aspart, and glulisine, were 
developed to be absorbed more rapidly and have a faster onset of insulin action compared with 
regular human insulin. Despite these improvements, the current formulations are not rapid 
enough to match carbohydrate absorption, limiting their efficacy in controlling PPG. LY900014 
is a novel insulin lispro formulation developed to more closely match physiological insulin 
secretion and improve PPG control. In a recent publication comparing the pharmacokinetics and 
glucodynamics of LY900014 with Humalog, Fiasp®, and NovoRapid®, LY900014 showed 
greater numeric glucose lowering during a mixed meal tolerance test in patients with T1D and 
more closely matched the early glucose lowering of endogenous insulin secretion in healthy 
individuals (Heise et al. 2020; Leohr et al. 2020). Phase 3 clinical studies of LY900014 have 
demonstrated superiority of LY900014 to Humalog in controlling PPG excursions, with a similar 


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 3
o verall safet y pr ofile i n pat ient s wit h T 1 D (Klaff et al. 2 0 2 0) a n d T 2 D (Ble vi ns et al. 2 0 2 0; 
Ji n n o uc hi et al. 2 0 2 0).
L Y 9 0 0 0 1 4 i s c om p ose d of t he acti ve i n gre die nt i ns uli n lis pr o a n d t wo l ocall y acti n g e xci pie nts,
tre pr osti nil t o i n d uce lo c al  vas o dilat i on a n d citr at e t o i ncrease vasc ular per mea bility, t here b y 
accelerati n g i ns uli n lis pr o a bs or pti o n. T he L Y 9 0 0 0 1 4 f or m ulat i on als o dif fers fr o m t he H u malo g 
f or mulat i on i n t hat it i ncl u des ma g nesi u m t o sta bilize t he i ns uli n. Tre pr osti nil is a pr ostac y cli n 
a nal o g use d i n t he tr e at me nt of p ul m o nar y  art erial h y perte nsi on. Treat m e nt wit h hig h -d ose 
c o nti n u o us S C or i ntra ve n o us i nf usi on of tre pr osti nil wit h clear s yste mic effects is k n o w n t o be 
ass ociat e d wit h inject i on /i nf usio n site pai n a n d i njectio n /i nf usio n site reactio ns (Re m o d uli n S P C 
2 0 1 6). T he cli nicall y rele va nt d oses of L Y 9 0 0 0 1 4 a d mi nistere d via t he S C r o ute c o nt ai n 
micr o d oses of t re pr osti nil t hat are n ot detecta ble i n t he s yste mic circ ulati on or ass ociate d wit h 
a n y s yste mic effects. H o we ver, l ocal vas o dilat i on at t he i nject i on site c o ul d p ote nti all y be a 
c o ntri b uti n g fact or t o l ocal er yt he ma or di sc omf o rt. I n a d diti on, pr ostac ycli ns ma y be i n v o l ve d as 
e n d o ge n o us me diat ors of i nfla m mat i on a n d pai n (M urata et al . 1 9 9 7).
 
 
 
 
C itrate has bee n ass ociate d wit h i njecti on site pai n i n ot her i njecta ble pr o d ucts ( H u mira 
Prescri bi n g I nf or mat i on 2 0 2 1; Kaiser et al. 2 0 1 2; Nas h et al. 2 0 1 6). T he s pecific r ole o f citrate i n 
L Y 9 0 0 0 1 4 i nject i on/ i nf usi on site reactio n e ve nts is u n k n o w n, b ut i ncrease d l ocal vasc ular 
p er m ea bilit y wi t h injecti o n /i nf usio n of  L Y 9 0 0 0 1 4 c o uld p ote ntiall y c o ntri b ute t o 
i njecti on /i nf usio n sit e reactio ns . F urt her, e vi de nce s u g gests t hat citrate c helat i on of e n d o ge n o us 
di vale nt meta l i ons ma y lea d t o i njecti on/ i nf usi on site pai n, a n d rei ntr o d ucti o n of ma g nesi u m ca n 
mit i gate t his disc o mf ort ( Kras ner et al. 2 0 1 2).
 
 
 
I n t he P R O N T O-P u m p - 2 st u d y, most I S Rs wi t h L Y 9 0 0 0 1 4 starte d i n t he first 4 wee ks after 
ra n d omizat i on ( Warre n et al. 2 0 2 1). T he re p orte d I S Rs were p ri maril y mil d i n se verity 
(a p pr o xi matel y 7 5 %) a n d l aste d a me dia n of 2 t o 6 da ys i n t his st u dy . W hile i n di vi d ual  I S Rs 
res ol ve d d uri n g t he st u d y, ot her e ve nts c o uld occ ur wi t h a differe nt i nf usi on set/site . A d dit i onal 
a nal ysis deter mi ne d t here were n o si g nifica nt treat me nt - b y-s u b gr o u p i nteracti o ns f or t he 
i nci de nce of I S Rs f or se x, a ge, b o d y  mass in de x ( B MI), et h nicit y , race, i nf usi on set m o del , b o l us 
s pee d, t otal dail y d ose, d urati o n of dia betes , or d urati o n of  C SII use. 
T he I n vesti gat or’s Br oc h ure (I B) descri bes t he cli nical a n d n o ncli nical de vel o p me nt of 
L Y 9 0 0 0 1 4 . A d dit i on al  detail s are als o a vaila ble i n t he L Y 9 0 0 0 1 4 pac ka ge i nsert ( L y u mje v S P C 
2 0 2 0 ).
C CI
C CI
C CI


CONFIDENTIAL
I8B-MC-ITTC (c)
24
2.3.
Benefit/Risk Assessment
There is no direct clinical benefit anticipated from participation in this trial. 
The treatments (sodium citrate, magnesium chloride, Humalog diluent, or treprostinil) within this 
study are administered below approved therapeutic levels and are considered placebo treatments.
No known potential risks are associated with the use of small amounts of treprostinil, sodium 
citrate, magnesium chloride, or Humalog diluent. Furthermore, these study treatments are well 
characterized, and the description of each treatment relative to a therapeutic use is described in 
Section 8.4.
Potential risks associated with CSII pump use

Minor skin irritation, sensitization, or localized inflammatory response can occur if skin 
contacts bioincompatible materials.

Pain, bruising, swelling, redness, and bleeding at the infusion set insertion site.
The occurrence and severity of these events are not expected to be different from routine use of 
the Medtronic™MiniMed™770G pump. More detailed information about the known and 
expected risks and potential adverse events may be found in the manufacturer’s instructions. 


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 5
3.
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
P art A
Pri m ar y
T o i n vesti gate l ocal i nf usi o n site pai n f or i nf usi o ns of 
s o di u m citrate a n d tre pr osti nil i n H u mal o g dil ue nt wit h 
ma g nesi u m c hl ori de ( wit h o ut i ns uli n) i n t he 
a b d o mi nal, ar m, t hi g h , a n d b utt oc k area s i n partici pa nts 
wit h T 1 D o n C SII .
V A S pai n sc ore
Sec o n d ar y
T o i n vesti gate l ocal i nf usi o n site pai n of 2 differe nt 
ca n n ula i nserti o n de pt hs ( 6 m m a n d 9 m m) i n 
pa rtici pa nts wit h T 1 D o n C SII
V A S pai n sc ore
E x pl or at or y:
T o assess l ocal i nf usi o n site reacti o ns usi n g t he 
e x pl orat or y
 Platf or m
C haracterizati o n a n d meas ure me nt of i nci de nce a n d 
se verit y of l ocal i nf usi o n site reacti o n data
A b bre viati o n s: C SII = c o nti n u o us s u bc uta ne o us i ns uli n i nf usi o n; V A S = vis ual a nal o g scale; T 1 D = t y pe 1 dia betes 
mellit us.C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 6
4.
St u d y Desi g n
4. 1.
O ver all Desi g n
St u d y  I 8 B-M C -I T T C is a 1-/ 2- ce nter, partici pa nt -( Part A 
) a n d i n vest i gat or-
 
bli n d, 2 -part ra n d o mize d cr oss o ver st u d y i n a d ults ( 1 8 t o 69 years of  a ge, i nclusi ve ) wit h T 1 D o n 
C SII . Ap pr o xi matel y 4 6 parti ci pa nts will be ra n d o ml y assi g ne d t o st u d y int er ve nt i on s uc h t hat 
a p pr o xi matel y 4 0 e val ua ble partici pa nts c o m plete Part A  
 of t he st u d y.
 
Part A of t his st u d y  will be a 1-/ 2- ce nter, ra n d o mize d, 1 da y  5-p eri o d cr oss o ver base d o n t he 
or der of i nf usi on sites a n d de pt hs, bli n de d ( bet wee n i nf usi o n de pt hs), o pe n -label si n gle-treat me nt 
st u d y c o n d ucte d i n a d ults wi t h T 1 D.
 
F or 
 Part  A  
, the partici pa nt will c o nti n ue usi n g his or her pers o nal i ns uli n p u m p 
s yste m at t he c urre ntl y e mpl o y e d i nf usi on sit e a n d will be res p o nsi ble f or perf or mi n g t he
re q uire d actio ns t o m ai ntai n its f uncti o nali t y. Partici pa nts will  be i nstr ucte d t o a v oid t he use of 
t he ce ntral a b d omi nal area f or t heir pers o nal inf usi o n sets d uri n g t he 
 
a n d pri or t o arri val at t he cli nical researc h u nit ( C R U ).
F o r P art A
1. F oll o wi n g a n i nf or me d c o nse nt a n d a scree ni n g visit, partici pa nts will c o me t o t he C R U i n t he 
e ve ni n g ( after di n ner) of  D a y -1 f or Part A . 
2. Pri or t o t he i nserti o n of t he first i nf usi o n set, the t hic k ness of t he S C a di p ose tiss ue la yer at t he 
a b d o m e n, ar m, t hig h , a n d b utt oc k areas will be assesse d b y ultras o u n d a n d rec or de d i n t he 
ele ctr o nic case re p ort f or m ( e C R F). T he e val uate d site s h o uld be i de ntifie d wi t h a u niq ue 
i de ntifier.
3. T he i nf usi o n sites will be assesse d , a n d a n i ma ge of eac h l ocal i nf usi o n site will  be c ollecte d
usi n g t he 
 Plat f or m ( Sectio n 8. 2. 5. 3. 1 ) pri or t o i nsert i on of t he c orres p o n di n g
i nf usi on set.
4. Eac h Me dtr o nic ™
Mi ni Me d ™
7 7 0 G p u m p reser v oi r will be fille d b y a q ualifie d site staff 
me m ber wi t h 3 mL of  st u d y treat me nt (s odi u m citrate a n d tre pr osti nil i n H u mal o g dil ue nt wi t h 
ma g nesi u m c hl ori de [wi t ho ut i ns uli n ]). T he p u m p a n d i nf usi on set will be set u p as descri be d i n 
Secti o n 6. 1. 1 .
5 . Fi ve p u m ps will  be use d f or eac h partici pa nt t o assess i nf usio n s i nt o t he a b do mi nal, ar m , 
t hig h, a n d b utt oc ks area s. Parti ci pa nts will be ra n d o ml y assi g ne d t o 1 of 5 i nf usi on sit e 
se q ue nces as s h o w n i n Ta ble 4 to i n dicate t he or der of t he i nf usi on sites bei n g e val uate d.
6. Si x m m ca n n ula will be i nserte d i nt o eac h of t he desi g nate d areas (a b d o m e n [at least 5 c m 
a wa y fr o m t he u m bilic us i n t he left or rig ht l o wer q ua dra nts ], p osteri or as pect of t he u p per ar m, 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 7
a nterior or lateral t hig h , a n d u p per b utt oc k), a v oi di n g areas of li p o h y pertr o p h y or s ur gi cal scars. 
At  t he a b d omi nal area o nl y, a 9 m m ca n n ula will als o be i nserte d i nt o t he o p p osite si de of t he 
l ower a b d o me n.
7. T he first i nf usi o n site will be i nit iate d, a n d a basal i nf usi o n rate of 1 U/ h will be starte d. T he 
sa me pr oce d ure will occ ur at t he s u bse q ue nt i nf usi o n sites acc or di n g t o t he ra n d o ml y assi g ne d 
se q ue nce wi t h an a p pr o xi mat el y 3 0- mi n ute i nter val bet wee n i nit iati on of t he pre vi o us i nf usi o n 
sit e. I n case of i m me diate i nf usi on set i nt olera nce, a ne w i nf usi o n set ca n be i nserte d wit hi n t he 
first 1 0 mi n utes of i nit iati on of t he i nf usi o n site. 
T a ble 4
I nf usi o n Site Se q ue nce s f or P art A
I nf usi o n 1
I nf usi o n 2 
I nf usi o n 3 
I nf usi o n 4 
I nf usi o n 5
Se q ue nce 1
Ar m
T hi g h
A b d o me n 6 m m  
A b d o me n 9 m m
B utt oc k
Se q ue nce 2
A b d o me n 6 m m  
A b d o me n 9 m m
T hi g h
B utt oc k
Ar m
Se q ue nce 3
A b d o me n 9 m m
Ar m
B utt oc k
A b d o me n 6 m m
T hi g h
Se q ue nce 4
T hi g h
B utt oc k
A b d o me n 9 m m
Ar m
A b d o me n 6 m m
Se q ue nce 5
B utt oc k
A b d o me n 6 m m
Ar m
T hi g h
A b d o me n 9 m m
N ote: T his is a n e xa m ple ta ble base d o n a 5 x 5 L ati n s q uare desi g n ; partic ipa nts will be assi g ne d a n i nf usi o n
se q ue nce acc or di n g t o t he act ual sc he d ule pr o vi de d t o t he site.
8. A p pr o xi matel y 3 h o urs after t he start of t he basal i nf usi on at 1 U/ hr , a b ol us d ose of  1 5 U will 
be deli vere d at q uic k b ol us s pee d (1 5 U/ mi n) t o eac h i nf usi on site acc or di n g t o t he treat me nt 
se q ue nce wi t h an a p pr o xi mate l y 3 0- mi n ute i nter val bet wee n i nf usi o n sites . 
9 . A sec o n d b ol us of  1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d a p pr o xi matel y
6 h o urs after t he start of t he basal i nf usi o n t o eac h i nf usi o n site acc or di n g t o t he treat me nt 
se q ue nce wi t h an a p pr o xi mate l y 3 0- mi n ute i nter val bet wee n i nf usi o n sites . 
1 0 . A t hir d b ol us d ose of 1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d a p pr o xi matel y
9 h o urs after t he start of t he basal i nf usi o n t o eac h i nf usi o n site acc or di n g t o t he treat me nt 
se q ue nce wi t h an a p pr o xi mate l y 3 0- mi n ute i nter val bet wee n i nf usi o n sites .
1 1. Parti cipa nts will rate t he pai n at eac h i nf usi o n site after eac h b ol us d ose at t he f o ll owi n g 
a p pr o xi mate ti me p oi nts : 5 mi n utes bef ore t he a d mi nistrati o n of a b ol us d ose a n d 1 a n d 1 5 
mi n utes after t he start of eac h b o l us d ose.
1 2 . St u d y  i nf usi on sets wit h ca n n ula a n d p u mps will  be r e mo v e d.
1 3. I nf usi on sites will be e val uate d f or ac ute l ocal i nf usi on sit e reactio ns as descri be d i n 
Secti o n 8. 2. 5. 3 a n d a n i ma ge of eac h l ocal i nf usi on si t e wil l be c ollecte d usi n g t he 
 
 Platf or m ( Sectio n 8. 2. 5. 3. 1 ).
1 4 . F oll o wi n g t he fi nal e val uat io n , t he partici pa nt s will ha ve t he o pti o n t o s pe n d t he ni g ht or be
di sc har ge d fr o m t he C R U.
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
2 8
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C ( c)
2 9
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
Eac h st u d y  part c o nsists of a cr oss-o ver desi g n t o all o w eac h parti ci pa nt act as his/ her o w n 
c o ntr ol. T he t otal n u m ber of partici pa nt s nee de d f or t his d esi g n is less t ha n t he n u m ber nee de d 
f or a parallel gr o u p desi g n.
T he b o l us d ose is deli vere d t o eac h i nf usi on site 3 ti mes a n d pr o vi des i ntr a-s u bject varia bility i n 
t he l ocal i nf usi on pai n sc ore i n eac h st u d y p art.
Ra n d o mi z atio n a n d bli n di n g are use d t o a v oi d bias i ntr o d uce d t h r o u g h a n ass ociati on bet wee n 
all ocat i on or der of 
 i njecti on site .
C CI
C CI


CONFIDENTIAL
I8B-MC-ITTC (c)
30
4.3.
Justification for Dose
The concentrations of these excipients were based on the formulation of LY900014. Basal and 
bolus doses were selected based on what is typically used for LY900014 and Humalog in 
participants with T1D. 
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Activities (SoA; Section 1.3) for the last 
participant in the trial.


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I8B-MC-ITTC (c)
31
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiograms (ECGs). The 
nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. Screening may occur up to 28 days prior to enrollment. 
Participants who are not enrolled within 28 days of screening may undergo an additional medical 
assessment and/or clinical measurements to confirm their eligibility.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1. Capable of giving signed informed consent as described in Section 10.1 Appendix 1, 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
Age and Sex
2. Participant must be between 18 and 69 years of age, inclusive, at the time of signing the 
informed consent.
3. Male or Female

Male: no contraception required.

Female: contraceptive use should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. Contraception 
requirements for participants are provided in Section 10.4.
Type of Participant and Disease Characteristics
4. Have been clinically diagnosed with T1D for at least 1 year before screening and have 
continuously been using intensive insulin therapy for at least 1 year. 
5. Have been using an insulin pump for at least 6 months.
6. Have an HbA1c value ≤9.0% at screening.
7. Have a BMI of 18.5 to 35.0 kg/m2, inclusive.
8. Have clinical laboratory test results within normal reference range with acceptable 
deviations that are judged to be not clinically significant by the investigator.
9. Have venous access sufficient to allow for blood sampling.
10. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
11. Hemophilia or any other bleeding disorder.


CONFIDENTIAL
I8B-MC-ITTC (c)
32
12. A condition, which in the opinion of the investigator or designee, would put the 
participant or study at risk.
13. Have a pathologic tuning fork test as assessed with a Rydel-Seiffer tuning fork.
14. Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance 
due to neurologically disabling hypoglycemia) within the last 90 days before screening.
15. Have had more than 1 emergency room visit or hospitalization due to poor glucose 
control (hyperglycemia or diabetic ketoacidosis) within 6 months before screening (Visit 
1).
16. Have a scheduled surgery during the study.
17. Have cardiovascular disease within 6 months prior to screening, defined as stroke, 
decompensated heart failure (New York Heart Association Class III or IV), myocardial 
infarction, unstable angina pectoris, or coronary arterial bypass graft.
18. Renal:
a.
History of renal transplantation
b. Currently receiving renal dialysis
c.
Serum creatinine >2.0 mg/dL (177.0 µmol/L) at screening.
19. Hepatic: Have obvious clinical signs or symptoms of liver disease (excluding 
nonalcoholic fatty liver disease), acute or chronic hepatitis, cirrhosis, or elevated liver 
enzyme measurements as indicated below at screening (Visit 1):
a.
Total bilirubin level (TBL) ≥2× the upper limit of normal (ULN) (except for 
Gilbert’s syndrome) or
b. Alanine aminotransferase (ALT) ≥3× ULN or
c.
Aspartate aminotransferase (AST) ≥3× ULN.
20. Malignancy: Have active or untreated malignancy, have been in remission from clinically 
significant malignancy (other than basal cell or squamous cell skin cancer) for less than 
5 years, or are at an increased risk for developing cancer or a recurrence of cancer in the 
opinion of the investigator.
21. Have any hypersensitivity or allergy to any of the diluents or excipients used in this trial.
22. Hematologic: Have had a blood transfusion or severe blood loss within 90 days prior to 
screening (Visit 1) or have known hemoglobinopathy, hemolytic anemia, sickle cell 
anemia, or any other traits known to interfere with the measurement of HbA1c.
23. Have any other condition (including known drug or alcohol abuse [consuming more than 
an average 24.0 grams alcohol/day for males and 12.0 grams alcohol/day for females], or 
psychiatric disorder including eating disorder) that precludes the participant from 
following and completing the protocol at the investigator’s discretion or positive alcohol 
and/or urine drug screen at the screening visit.
24. Show evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies.
25. Show evidence of hepatitis C and/or positive hepatitis C antibody (Presence of hepatitis 
C antibodies will not lead to exclusion if liver function tests are normal and a hepatitis C 
polymerase chain reaction is negative).
26. Show evidence of hepatitis B and/or positive hepatitis B surface antigen.
27. Inability or unwillingness to refrain from smoking, vaping and any use of nicotine 
substitute products one day before and during the inpatient period.


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I8B-MC-ITTC (c)
33
Prior/Concomitant Therapy
28. Are taking anesthetics or pain medication regularly or intermittently which could 
interfere with interpretation of pain scale.
29. Have used or are currently using Lyumjev® as part of their standard insulin therapy.
Prior/Concurrent Clinical Study Experience
30. Have participated, within the last 30 days, in a clinical trial involving an investigational 
product. If the previous investigational product has a long half-life, 3 months or 5 half-
lives (whichever is longer) should have passed.
Other Exclusions
31. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted.
32. Are Eli Lilly and Company (Lilly) employees or representatives (including employees, 
temporary contract workers, or designees responsible for the conduct of the study).
5.3.
Lifestyle Considerations
Participants must adhere to lifestyle restrictions as outlined by the CRU throughout the duration 
of the stay in the CRU. 
While in the CRU, participants will use their own insulin pump and glucose sensor and bring 
extra supplies including insulin, infusion set and reservoir, glucose sensor, batteries, blood 
glucose monitor and test strips, insulin syringe in case of pump failure, and fast-acting glucose 
tablets or gel to treat hypoglycemia. Participants should avoid hypoglycemia and prolonged 
hyperglycemia during the study procedures.
5.3.1.
Meals and Dietary Restrictions
Meals and snacks will be provided in the CRU at appropriate times.
5.3.2.
Caffeine, Alcohol, and Tobacco
Caffeine will be permitted during the study. No alcohol will be allowed at least 24 hours before 
CRU admission, including screening, and throughout the duration of the stay in the CRU. No
tobacco, vaping and any nicotine products use will be permitted while in the CRU.
5.3.3.
Activity
Participants may be required to remain recumbent or sitting throughout the duration of the stay in 
the CRU.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention or enrolled in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number. When 


CONFIDENTIAL
I8B-MC-ITTC (c)
34
rescreening, the screening tests and procedures should be repeated based on the exclusion 
criteria. Individuals may be rescreened 1 time at the discretion of the principal investigator. The 
interval between the screenings should be at least 2 weeks. Before rescreening is performed, the 
individual must sign a new ICF. Repeating of laboratory tests during the screening period or 
repeating screening tests to comply with the protocol designated screening period does not 
constitute rescreening.


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
3 5
6.
St u d y I nter ve nti o n
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol . 
6. 1.
St u d y I nter ve nti o ns A d mi nistere d
Part A of t his st u d y i n v ol ves a d mi nistrati o n of s o di u m citrate a n d tre pr osti nil i n H u mal o g dil ue nt 
wi t h ma g nesi u m c hlori de ( wit ho ut i ns uli n) t o eac h parti ci pa nt at  4 differe nt i nf usi o n sites 
(a b d o me n [at l east 5 c m a wa y fr o m t he u m bilic us i n t he left or rig ht l o wer q ua dra nt ], p osteri or 
as pect of t he u p p er ar m, a nterior or lateral t hig h, a n d u p per b utt oc k ) a n d at 2 differe nt ca n n ula 
i nsertio n de pt hs ( 6 m m a n d 9 m m i n a b d ome n o nl y ) (see Ta ble 6 f or details).
T a ble 6
Tre at me nt A d mi nistere d
A R M N a me
Part A 
I nter ve nti o n N a me
S o di u m citrate a n d tre pr osti nil i n 
H u mal o g dil ue nt wit h ma g nesi u m 
c hl ori de ( wit h o ut i ns uli n)
T y pe 
E xci pie nts
D ose F or m ul ati o n
S ol uti o n
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
3 6
U nit D ose Stre n gt h(s)
1 5 m M s o di u m citrate a n d 1 µ g/ m L
tre pr osti nil i n H u mal o g dil ue nt wit h 
5 m M ma g nesi u m c hl ori de ( wit h o ut 
i ns uli n)
D os a ge Le vel(s)
1 U/ hr basal i nf usi o n rate at eac h 
i nf usi o n site (a b d o me n [at least 5 c m 
a wa y fr o m t he u m bilic us i n t he left a n d 
ri g ht l o wer q ua dra nts], p osteri or as pect 
of t he u p per ar m, a nteri or or lateral 
t hi g h, a n d u p per b utt oc k ).
1 5 U b ol us d ose at q uic k b ol us spee d of
1 5 U/ mi n 3 ti mes ( 3-hr, 6 -hr, a n d 9 -hr 
i nter vals) at eac h i nf usi o n site
R o ute of A d mi nistr ati o n
S C i nf usi o n usi n g 6 m m ca n n ula i n 
a b d o me n, ar m, t hi g h, a n d b utt oc k.
S C i nf usi o n usi n g 9 m m ca n n ula i n 
a b d o me n o nl y
Use
E x peri me ntal
I M P a n d NI M P
I M P
S o urci n g
Pr o vi de d b y t he sp o ns or
P ac k a gi n g a n d L a beli n g
St u d y int e r ve nti o n will be pr o vi de d i n 
c o ntai ner . Eac h c o ntai ner will be 
la bele d as re q uire d per c o u ntr y 
re q uire me nt
A b bre viati o ns: I M P = in vesti gati o nal m e dici nal p r od uct; NI M P = n o n -i n vesti gati o nal me dici nal pr o d uct; 
S C = s u bc uta ne o us.
6. 1. 1.
A d mi nistr ati o n Det ails
St u d y  treat me nt will be a d mi nistere d via C SII at a basal i nf usi on r at e of 1 U/ hr a n d 1 5 U b ol us 
d oses will be deli vere d at q uic k b o l us s pee d ( 1 5 U/ mi n) per t he S o A ( Secti o n 1. 3 ). Me dtr o ni c ™
Mi ni Me d ™7 7 0 G
p u m ps will  be use d i n ma n ual m o de f or i nf usi o n of all st u d y  treat me nts. T he 
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
3 7
p u m p re q ui res 1 ne w A A ( 1. 5 V) batter y . F or best res ults, use a ne w A A lit hi u m ( F R 6) batter y . 
T he p u m p als o acce pts a n A A al kali ne ( L R 6) . Mi ni Me d ™3- m L reser v oirs a n d Mi ni Me d ™
Mi o ™A d va nce i nf usi on set s will be use d wi t h t he p u mps .
P u m ps will be pr o gra m me d wi t h t he f oll ow i n g setti n gs: 

Preferre d la n g ua ge

C urre nt date a n d ti me

S i n gle basal patter n of 1 U/ hr wi t h start ti me 1 2: 0 0 AM
a n d e n d ti me 1 2: 0 0 AM

B ol us i ncre me nt of  0. 1 U

B ol us s pee d q uic k ( 1 5 U/ mi n)

B ol us t ype n or m al

B ol us e ntr y met h o d m a n ual
I n Part A, 5 p u m ps will be use d f or eac h partici pa nt. F or eac h p u m p , a 3-m L reser v oir will b e 
fille d b y a q ualifie d site staff me m ber wit h 3 m L of st u d y tr e at me nt, a Mi ni Me d ™
Mi o ™
A d va nce i nf usi on set will be attac he d t o t he fille d reser v oir a n d t he reser v oir will be l oa de d i nt o 
t he p u m p. T he i nf usi on set t u bi n g will be pri me d, an d a ca n n ula fill wit h 0. 6 u nit f or b ot h 6 m m 
a n d 9 m m ca n n ula will be c o m plete d . Si x m m ca n n ula will be i nserte d i n t o eac h of t he
desi g nate d areas (a b d o me n, ar m, t hig h , a n d b utt oc k), a v oi di n g a n y areas o f li p o h y pertr o p h y or 
s ur gical scars. At  t he a b d omi nal area o nl y, 9 m m ca n n ula will be use d i n a d dit i on t o t he 6 m m 
ca n n ula. I n case of i m me diate i nf usi on set i nt olera nce or i ns uli n fl o w bl oc k alar m occ urs , a ne w 
i nf usi on set ca n be i nserte d wi t hi n t he first 1 0 mi n utes of  init iati on of t he i nf usi o n  sit e. 
 
 
 
A p pr o pri atel y trai ne d staff m ust be a vaila ble u nt il t he partici pa nts c o m plete t he i nf usi o n s. T he 
p u m p c a n be re use d after disi nfect i on, acc or di n g t o t he l ocal pr oce d ure.
6. 1. 2.
P u m p Occl usi o n A l ar ms a n d A cci de nt al Inf usi o n S et D isc o nti n u ati o ns
If a p u mp o c cl usi o n alar m occ urs d uri n g basal i nf usi o n , t he i nf usi o n set t u bi n g s h o uld be 
i ns pecte d f or ki n ks or cri m ps a n d t he basal i nf usi o n restarte d. If t he occ l usio n  alar m persists , t he
i nf usi on sit e will be disc o nt i n ued, a n d dat a relate d t o t his site will not be use d i n t he a nal ysis . If a 
p u m p o c cl usi o n  alarm occ urs d uri n g a b o l us i nf usi o n, t he i nf usi o n site will be disc o nt i n ue d, a n d 
data relate d t o t his site will n ot be use d i n t he a nal ysis. If a n i nf usi on set ca n n ula is acci de ntall y  
p ulle d o ut of a n i nf usi on site , t he i nf usi o n sit e will be disc o nt i n ue d, a n d data relate d t o t hat site 
will n ot be use d i n t he a nal y sis. Data rel ate d t o t hese e ve nts will be rec or de d o n t he e C R F. 
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d a n y  discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.
2.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y int er ve nt i on . O nl y  a ut h orize d 
st u d y pers o n nel ma y s u p pl y, pre pare, or a d mi nister st u d y  int er ve nt i on . All st u d y  
i nter ve nt i on m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( m a n u al 
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or a ut o mate d) area i n acc or da nce wit h t he l a bele d st ora ge c o n dit i ons wit h access li mite d t o 
t he i n vest i gat or a n d a ut h orize d st u d y pers o n nel.
3.
T he i n vest i gat or or a ut h ori ze d st u d y pers o n nel are res p o nsi ble f or st u d y int er ve ntio n 
acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce (i . e., receipt, rec o nciliat i on, a n d 
fi nal dis p ositi on rec or ds).
4.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p osit i on of u n use d st u d y  int er ve ntio ns are 
pr o vi de d i n t he St u d y  Refere nce Ma n ual.
N ote:  I n s o me cases, sites ma y destr o y  t h e mat erial if, d uri n g t he i n vesti gati ve site selecti on, t he 
e val uat or has verifie d a n d d oc u me nte d t hat t he site has a p pr o priate facilit ies a n d writte n 
pr oce d ur es t o dis p ose of cli nical materials.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
Ra n d o mizati o n a n d bli n di n g will  be use d i n or der t o a v o i d bias i ntr o d uce d t hr o u g h a n ass ociati on
bet wee n all ocat i on or der a n d partici pa nt c haracteristics.
I n Part A of  t his st u d y, parti ci pa nts will be ra n d o ml y assi g ne d t o 1 of 5 i nf usi o n site se q ue nces t o 
i n dicate t he or der of t he i nf usi o n sites bei n g e val uate d . T he i nf usi o n de pt hs will be bli n de d.
 
 
T he C R U pers o n nel w h o will pre pare t he p u m p reser v o irs for eac h treat m e nt perio d will n ot be 
bli n de d a n d will be se pa rate a n d disti nct fr om t hose w h o are i n v o l ve d i n s u bject care. T he 
s p o ns or i ncl u di n g t he Lill y st u d y t e a m will be u n bli n de d. Bli n di n g will be mai ntai ne d t hr o u g h o ut 
t he c o n d uct of t he st u d y.
Treat me nt assi g n me nt will be ke pt strict l y c o nfi de ntial a n d accessi ble o nl y t o a ut h orize d pers o ns
u nt il after t he ti me of u n bli n di n g. C o des wit h treat me nt assi g n me nt will, h o we ver, be rea dil y 
a vaila ble t o t he bli n de d pers o n nel i n case of a n e mer ge nc y.
If a n i n vesti gat or, site pers o n nel perf or mi n g assess me nts, or partici pa nt is u n bli n de d, t he 
parti ci pa nt must be di sc o nti n ue d fr om t he st u d y. I n cases w here t here are et hical reas o ns t o ha ve 
t he partici pa nt re mai n i n t he st u d y, t he i n vesti gat or m ust o btai n s pecific a p pr o val fr o m a s p o ns or 
c li nical p har mac ol ogist or cli nical researc h p h ysicia n ( C R P)/cli nical researc h scie ntist ( C R S) f or 
t he partici pa nt t o c o nti n ue i n t he st u d y .
6. 4.
St u d y I nter ve nti o n C o m pli a nce
W he n t he i n di vi d ual d ose f or a partici pa nt is pre pare d fr o m a b ul k s u p pl y, t he pre parati o n of t he 
d ose will be c o nfi r me d b y a sec o n d me m ber of t he st u d y site staff. 
T he i nf usi o n of t he e xci pie nts will be a d mi nistere d i n t he C R U u n der m e dical s u per visi o n b y t he 
i n vesti gat or or desi g nee. T he st u d y e xci pie nts a n d i nf usi o n de pt hs a n d st u d y p artici pa nt 
i de ntificati on will b e c o nfir me d prior t o t he ti me of i nf usi on . T he date a n d ti me of eac h i nf usi on
a d mi nistere d will be rec or de d i n t he s o urce d oc u me nts a n d i n t he case re p ort f or m ( C R F ). 
A rec or d of t he n u m ber of e xci pie nts a d mi nistere d t o eac h partici pa nt m ust be mai ntai ne d a n d 
rec o ncile d with st u d y  int er ve ntio n a n d c o m plia nce rec or ds. I nf usi on start a n d st o p dates, 
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including dates for infusion delays and/or infusion rate reductions, will also be recorded in the 
CRF.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with:
●
Reason for use
●
Dates of administration including start and end dates
●
Dosage information including dose and frequency for concomitant therapy of 
special interest
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants taking analgesics including non-steroidal anti-inflammatory drugs within 24 hours 
before the first infusion will be rescheduled.
The investigator must check if any pre-medications affect the participants’ current ongoing 
treatment for T1D.
6.6.
Dose Modification
Dose modification for the excipients or infusion rate are not planned in this study. 
6.7.
Intervention after the End of the Study
Not applicable.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
Participants discontinuing from the study prematurely for any reason must complete adverse 
event (AE) and follow-up procedures per Section 1.3 of this protocol. 
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity reaction has occurred related to the excipients administration, the 
participant should be permanently discontinued from the infusion of the excipients.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
If an infusion site is unable to be initiated after several attempts, the participant should be 
discontinued from the study and a replacement subject may be enrolled.
7.1.1.
Hepatic Criteria for Discontinuation
Not applicable.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:
●
at any time at his/her own request 
●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons
●
if the participant becomes pregnant during the study
●
if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3). See the SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued both from the study intervention and from the 
study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records. 
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 


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expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not receive investigational product. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as described in
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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). 

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Unless otherwise stated in subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test 
results. Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
●
A physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and peripheral nervous system’
systems. Height and weight will also be measured and recorded.
●
Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs
●
For each participant, vital signs measurements should be conducted according to 
the SoA (Section 1.3).
Blood pressure and pulse rate should be measured after at least 5 minutes in a supine position.
If orthostatic measurements are required, participants should be supine for at least 5 minutes and 
stand for at least 3 minutes. 
If the participant feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Additional vital signs may be measured during each study period if 
warranted. 


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8.2.3.
Electrocardiograms
For each participant, a single 12-lead ECG will be collected according to the SoA (Section 1.3).
Electrocardiograms must be recorded before collecting any blood samples. Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. Electrocardiograms may be obtained at additional times when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee).
If a clinically significant finding is identified the investigator will determine if the participant can 
be enrolled in the study. 
8.2.4.
Clinical Safety Laboratory Assessments
●
See Section 10.2 Appendix 2 for the list of clinical laboratory tests to be 
performed and the SoA for the timing and frequency.
●
The investigator must review the laboratory results and document this review. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings or other abnormal safety assessments are those that are not 
associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Section 10.2
Appendix 2, must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual.
●
If laboratory values from non-protocol-specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the investigator 
(e.g., serious adverse event [SAE] or AE or dose modification), then report the 
information as an AE.
●
If a central vendor is used for the study, Lilly or its designee will provide the investigator 
with the results of laboratory tests analyzed by a central vendor, unless the safety 
laboratory test results may unblind the study. 
8.2.5.
Safety Monitoring
The Lilly clinical pharmacologist or CRP/CRS will monitor safety data throughout the course of 
the study. 
8.2.5.1.
Hepatic Safety
Not applicable.


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8. 2. 5. 2.
H y perse nsiti vit y Re acti o ns
Ma n y  dr u gs, or t heir e xci pie nts partic ularl y bi o l ogic a ge nts , carr y t he ris k of s yste mic 
h y perse nsit i vity reacti ons. If s uc h a reactio n occ urs, a d di tio nal data descri bi n g eac h s y m pt o m 
s h o uld be pr o vi de d t o t he s p o ns or i n t he e C R F. 
Si tes s h o uld ha ve a p pr o pri atel y trai ne d me dical staff a n d a p pr o priate me dical e q ui p me nt 
a vaila ble w he n st u d y p artici pa nts are recei vi n g st u d y dr u g. It is rec o m me n de d t hat partici pa nts
w h o e x perie nce a s yste mic h y perse nsiti vity reacti on be treate d per nati o nal a n d i nter nat i onal 
g ui deli nes. 
I n t he case of ge neralize d urticaria or a na p h yla xis, a ddi tio nal bl o o d a n d uri ne sa m ples s h o uld be 
c ollecte d as descri be d i n Secti o n 1 0. 2 A p pe n di x 2 . La b orat or y  res ults are pr o vide d t o t he s p o ns or 
via t he ce ntral l a b orat or y.
8. 2. 5. 3.
L oc al I nf usi o n Site Re acti o ns
S y m pt o ms or si g ns of  l ocal i nf usi o n sit e reacti ons ma y i ncl u de er yt he ma, i n d urat i on, pai n, 
pr uri t us, a n d e de ma.
Pre -s pecifie d l ocal inf usi o n  site reactio n assess me nts will be perf or me d a n d c ollecte d at t he ti me
p oi n ts i n dicate d i n t he S o A ( Secti o n 1. 3 ).
I n a d diti on, if a s p o nta ne o us I S R is re p orte d b y a partici pa nt or site staff at a n o n-pres pecifie d 
ti me p oi nt, t he l ocal inf usi o n site react i on e C R F will be use d t o ca pt ure a d dit i onal i nf or mati on 
a b o ut t his reacti o n ( e. g. , i nf usi o n site pai n, er yt he ma, i n d urati on, pr urit is, a n d e de ma).
L ocal  inf usi o n sit e r e a ctio ns, w het her rec or de d as a res ult of t he pres pecifie d ( or s olici te d)
assess me nt or s p o nta ne o usl y re p orte d reacti o ns, will be rec or de d as A Es as cli nicall y i n dicate d.
I n vesti gati onal site staff will be pr o vi de d wit h se parate i nstr ucti o ns/trai ni n g o n h o w t o e val uate 
l ocal i nf usio n  site reactio ns a n d t heir se verit y in a c o nsiste nt ma n ner . 
8. 2. 5. 3. 1.
E x pl or at ory Assess me nt usi n g 
 Pl atf or m
8. 2. 6.
L oc al P ai n Me as ure me nts Usi n g t he Vis u a l A n al o g Sc ale
L ocal  pai n meas ure me nts d uri n g b o l us a p plicati o n will be assesse d usi n g t he 1 0 0-m m vali date d 
V A S f or pai n. T he V A S is a well -vali date d t o ol ( Willia ms o n a n d H o g gart 2 0 0 5) t o assess 
cat heter i nsert i on site pai n. T he V A S i s prese nte d as a 1 0- c m ( 1 0 0-m m) li ne, a nc h ore d b y  ver bal 
descri pt ors, us uall y  “ n o pai n” a n d “ w orst i ma gi na ble pai n.” T he partici pa nt is as ke d t o mar k t he 
1 0 0- m m li ne t o i n dicate pai n i nte nsity. T he pa rtici pa nt will be as ke d t o rate a n y  pai n ass ociate d 
d uri n g eac h i n pat ien t i nf usi on o n a scale of 0 t o 1 0 0 m m at ti mes s pecifie d i n t he S o A 
( Sectio n 1. 3 ). 
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8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study.
The definitions of the following events can be found in Section 10.3 Appendix 3:

AEs

SAEs

Product complaints
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up on events 
that are serious, considered related to the study intervention or study procedures, or that caused 
the participant to discontinue the excipients infusion (see Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For 
product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Section 10.3 Appendix 3.
8.3.1.
Timing and Mechanism for Collecting Events
This table describes the timing, deadlines, and mechanism for collecting events.
Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Adverse Event
AE
Signing of 
the 
informed 
consent 
form (ICF)
Follow-up 
visit
As soon as possible 
upon site awareness
AE eCRF
N/A


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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Serious Adverse Event
SAE and SAE 
updates – prior to 
start of study 
intervention and
deemed reasonably 
possibly related 
with study 
procedures
Signing of 
the 
informed 
consent 
form (ICF)
Start of 
intervention
Immediately, without 
undue delay
SAE paper form
SAE paper 
form
SAE and SAE 
updates – after 
start of study 
intervention
Start of 
intervention
Participation 
in study has 
ended
Immediately, without 
undue delay
SAE paper form
SAE paper 
form
SAE – after 
participant’s study 
participation has 
ended and the 
investigator 
becomes aware
After 
participant’s 
study 
participation 
has ended
N/A
Immediately, without 
undue delay
SAE paper form
N/A
Pregnancy
Pregnancy in 
female participants 
After the 
start of 
study 
intervention
10 hours after 
the last dose
Within 24 hours of 
learning of the 
pregnancy
SAE paper form
SAE paper 
form
Product Complaints
Product complaint
associated with an 
SAE or might have 
led to an SAE
Start of 
study 
intervention
End of study 
intervention
Within 24 hours of 
awareness
Product Complaint 
form
N/A
Product complaint
not associated with 
an SAE
Start of 
study 
intervention
End of study 
intervention
Within 1 business day 
of awareness
Product Complaint 
form
N/A


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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Updated product 
complaint
information
—
—
As soon as possible 
upon site awareness
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator
N/A
Product complaint
(if investigator 
becomes aware)
Participation 
in study has 
ended
N/A
Promptly
Product Complaint 
form
Abbreviations:  AE = adverse event; N/A = not applicable; SAE = serious adverse event.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
8.4.
Treatment of Overdose
There is a low risk of an overdose from either sodium citrate, magnesium chloride, Humalog 
diluent or treprostinil within this study.
The largest planned total dose of study treatment will be administered in Part A of the study 
when each participant will have 5 pumps and will receive a total dose of 270 U/day. The total 
amount of study treatment (sodium citrate, magnesium chloride, Humalog diluent or treprostinil)
provided would be comparable to Humalog or Lyumjev administration to individuals with 
diabetes who are highly-insulin resistant and require more than 200 U of insulin per day.
Likewise, Reznik (2010) reviewed the data from 4 patients with type 2 diabetes with insulin 
resistance who were placed on CSII therapy with a concentrated insulin to address their daily 
insulin requirements (192U-630U). Although rare, patients with extreme insulin resistance
requiring 10,000 U of insulin per day have been reported (Lalej-Bennis et al. 1997).
Additionally, the total dose for each study treatment is well below any therapeutic level:

Sodium citrate as it is listed in the FDA Generally Recognized as Safe (FDA 2015a) food 
additives database and total amount given (11.9 mg as trisodium citrate dihydrate) is
within the limits identified for approved drug products in the FDA Inactive Ingredients in 
Approved Drugs database (FDA 2015b).

Magnesium chloride is a cation primarily intracellular. The total planned dose in Part A is 
13.5 µmol magnesium (or 2.74 mg magnesium chloride hexahydrate) and is below the 
therapeutic use (Lavoisier magnesium chloride 2004): 


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Therapeutic Indication
Administration
Curative treatment of torsades de pointe (TdP)
Intravenous bolus in 8 mmol of 
magnesium cation
Treatment of acute hypokalemia associated 
with hypomagnesemia
Intravenous infusion from 24 to 32 
mmol of magnesium cation daily
Magnesium supplement during electrolyte 
rebalance and parenteral nutrition
Intravenous infusion from 6 to 8 mmol 
of magnesium cation over 24 hours
Preventive and curative treatment of eclampsia 
crisis
Intravenous infusion of 16 mmol of 
magnesium cation, i.e. 3.5 g of 
magnesium chloride for 20 to 30 
minutes.
Based on the drug label (Lavoisier magnesium chloride 2004), the first signs of overdose 
of hypermagnesemia include inhibition of knee jerks, feeling of heat, drowsiness, spoken 
speech disorders, muscular paralysis with respiratory disorders and at the most, 
respiratory and cardiac arrest.

Treprostinil is approved in many European Member States for use in the treatment of 
pulmonary arterial hypertension (PAH) and is known as Remodulin® for SC
administration (Remodulin SPC 2016). In Part A, participants will be administered a
planned total dose of treprostinil of 2700 ng. The maximum total daily dose of 
treprostinil in the study will be a small fraction of the average Remodulin® therapeutic 
dose (53- to 1707-fold less; Table 7). Based on the drug label, the signs and symptoms of 
overdose with Remodulin® during clinical trials are extensions of its dose-limiting 
pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, 
and diarrhea. Most events were self-limiting and resolved with reduction or withholding 
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Table 7
Maximum Estimated Treprostinil Dose in Diabetes Relative to Treprostinil 
Doses for Pulmonary Arterial Hypertension
Treprostinil Therapeutic 
Indication
Treprostinil Dose
Treprostinil dose in PAH patients
vs Treprostinil Dose in studyb
ng/kg/min
ng/kg/day
Total Dose in Part A

Maximum dose a
-
33.75
-
PAH (Remodulin®)c

Lowest starting dose

Average dose

High dose
1.25
1800
53-fold
9.3
13392
397-fold
40
57600
1707-fold
Abbreviations:  PAH = pulmonary arterial hypertension.
a
Total Treprostinil dose in Part A (2700ng/80kg) assuming 80 kg body weight for an adult with T1DM
b
Treprostinil dose in study vs PAH patients = treprostinil dose for PAH maximum treprostinil dose in study 
(Part A)
c
Remodulin SPC 2016.
The sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Turn off all study pumps immediately.
2. Contact the medical monitor immediately.
3. Closely monitor the participant for any AE/SAE until study infusion no longer has a clinical 
effect or at least until the end of each visit. Refer to Section 10.3 Appendix 3 for reporting 
details.
4. Document the quantity of the excess dose, as well as the duration of the overdose, in the 
CRF.
8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Immunogenicity assessments are not evaluated in this study.


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8.10.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not evaluated in this study.


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
5 1
9.
St atistic al C o nsi der ati o ns
9. 1.
St atistic al H y p ot heses
T he h y p ot heses bei n g teste d are as f o ll ows :

Part A:  T o test f or differe nces bet wee n i nf usi on sites a n d de pt h of i nf usi o n i n pai n as 
meas ure d b y t he V A S pai n sc ore.

 
9. 2.
A n al yses Sets
T he f oll owi n g a nal ysis sets are defi ne d:
P artici p a nt A n al ysis Set
Descri pti o n
F ull a nal ysis set
All ra n d o mize d partici pa nts . Partici pa nts will be i ncl u de d i n t he a nal yses 
acc or di n g t o t he ra n d o ml y assi g ne d se q ue nces.
Safet y a nal ysis set
All ra n d o mize d partici pa nts w h o recei ve at least 1 i nf usi o n. Partici pa nts will 
be a nal yze d acc or di n g t o t he i nf usi o ns t he y act uall y recei ve d.
Data relate d t o a site w here a n i nf usi on set ca n n ula is acci de ntall y p ulle d o ut of a n i nf usi o n site 
will n ot be use d i n t he a nal ysis. 
9. 3.
St atistic al A n al yses
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  Lill y or its desig nee.
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q uire a n a me n d me nt 
o nl y  if it c ha n ges a pri ncip al  feat ure of t he pr ot oc ol. A n y ot her c ha n ge t o t he data a nal ysis 
met h o ds descri be d i n t he pr ot oc ol, a n d t he j ust ificati o n f or ma ki n g t he c ha n ge, will be descri be d 
i n t he statistical a nal ysis pla n ( S A P) a n d t he cli nical st u d y re p ort. A d dit i onal e x pl orat or y  
a nal yses o f t he data will be c o n d ucte d as dee me d a p pr o priate.
9. 3. 1.
Ge ner al C o nsi der ati o ns
U nless ot her wise s pecifie d, t hese ge neral c o nsi derati o ns will a p pl y t o all a nal yses . C o nti n u o us 
varia bles will be s u m marize d b y  t he n u m ber of o bser vati ons, m ea n, sta n dar d de viat i on, 
mi ni m u m, me dia n, a n d ma xi m u m val ues . Cate g orical varia bles will be s u m marize d b y c o u nts 
a n d perce nta ges. S u m maries will be pr o vi de d b y i nf usi on site l ocatio ns, i ncl u di n g ca n n ula 
de pt hs, a n d st u d y  treat me nts ( e xci pie nts). 
9. 3. 2.
Pri m ar y E n d p oi nt s
I nf usi on site pai n assesse d usi n g t he V A S pai n sc ore will be liste d a n d s u m marize d usi n g 
sta n dar d descri pti ve statistics b y b o l us ti me ( 3, 6, a n d 9 h o urs after i nitiati on of basal i nf usi o n ) 
a n d V A S assess me nt ti me p oi nt ( 5 mi n utes pri or t o b ol us a n d 1 a n d 1 5 mi n utes after b ol us ). F or 
Part A, t he s u m mar y  will als o be b y i nf usi on site l ocati o n . T he 5 i nf usi on site l ocati o ns i ncl u de 
t he assess me nt of 2 ca n n ula de pt hs at t he a b d o mi nal site . 
 
 
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
5 2
 
A mi xe d effects mo d el  will be use d t o a nal yze fr o m t he l o g tra nsf or me d V A S pai n sc ore f or eac h 
b o l us ti me a n d V A S ti me p o i nt. T he statist ical mo d el  f or Part A will i ncl u de ter ms f or i nf usi on 
sit e lo c ati o n , p eri o d ( or der of i nf usi ons) , b o l us ti me, V A S ti me p oi nt, t he 2- a n d 3-wa y 
i nteract i ons bet wee n i nf usi o n site l ocati o n, b o l us ti me, a n d V A S ti me p oi nt as fi xe d effects a n d 
parti ci pa nt as a ra n d o m effect. C o m par is o ns will be ma de bet wee n i nf usi o n site l ocat i ons a n d 
bet wee n ca n n ula i nsertio n de pt hs f or t he a b d omi na l i nf usi on site f or eac h b ol us ti me a n d V A S 
ti me p oi nt. 
 
 
 
 Least -s q uares mea ns 
( LS M ea ns), i nf usi on site l ocati o n/ tr e at me nt differe nces i n L S M ea ns, a n d t he c orres p o n di n g 9 5 % 
c o nfi de nce i nter vals ( CIs) f or t he i nf usi on site l ocati o n/ treat me nt differe nces will be esti mate d 
a n d bac k-tra nsf or me d fr o m t h e lo g scal e t o pr o vide esti mates of t he rati o of ge o metric L S M ea ns 
a n d 9 5 % CI f or t he rati o of t hese mea ns. It is p ossi ble t hat V A S sc ores will be 0; if s o, all sc ores
ma y be u p date d t o l o g ( V A S + 1) t o all o w f or t he i ncl usi o n o f t he 0 val ues i n t he a nal ysis. 
T he sa me m o del will als o be use d t o a nal y ze t he c ha n ge fr om t he pre-b ol us ti me p o i nt ( 5 mi n utes 
pri or t o t he b o l us) t o t he p ost-b ol us t i me p oi nts of ( 1 a n d 1 5 mi n utes after b ol us). 
9. 3. 3.
Sec o n d ar y E n d p oi nt s
T he c o m paris o n o f ca n n ula de pt hs at t he a b d o mi nal i nf usi o n site l ocat i on will be a nal yze d as 
part of t he mi xe d effects m o del descri be d i n Sect i on 9. 3. 2 . 
9. 3. 4. 
E x pl or at or y E n d p oi nts
L ocal  inf usi o n site reacti on data will be liste d a n d s u m marize d b y i nf usi o n site l ocat i on ( Part A) 
 i n fre q ue nc y ta bles. 
9. 3. 5. 
S afet y A n al yse s
All tr e at me nt - a n d pr ot oc ol  pr oce d ure-relate d A Es will be liste d, a n d if t he fre q ue nc y of e ve nts 
all o ws, safet y data will be s u m mari ze d usin g descri pt i ve met h o d ol o g y . 
 
 
 S y m pt o ms re p orte d t o occ ur pri or t o e nr ol me nt will be 
di sti n g uis he d fr o m t hose re p orte d as ne w or i ncrease d i n se verit y d uri n g t he st u d y . Eac h 
s y m pt o m will be classifie d b y t h e most s ui ta ble ter m fr om t he Me dic al Dicti onar y  for Re g ulat or y  
Act i vities.
9. 4.
I nteri m A n al ysis 
N o i nt eri m a nal yses are pla n ne d f or t his st u d y. If a n u n pla n ne d i nteri m a nal ysis is dee me d 
necessar y  for reas o ns ot her t ha n a safet y c o ncer n, t he pr ot oc ol m ust be a me n de d.
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
5 3
9. 5.
S a m ple Size Deter mi n ati o n
A p pr o xi matel y 4 6 parti ci pa nts wit h T 1 D will be e nr olle d i n St u d y I 8 B-M C -I T T C s o t hat 
a p pr o xi matel y 4 0 partici p a nts c o m plete Part A  
 of t he st u d y. 
 
F ort y  c o m plet i n g parti ci pa nts will pr o vi de 
a p pr o xi matel y 8 0% p o wer t o de m o nstrate a p pr o xi matel y a 5 5 % i ncrease i n t he V A S pai n sc ore 
bet wee n t he i nf usi o n site l ocati ons i n Part A 
. Testi n g 
will be d o ne at al p ha -le vel of 0.0 5 wi t h a 2-side d CI. T he vari a bilit y was esti mate d b y a nal yzi n g 
a Lill y int er nal st u d y t hat s h o we d a lo g -scale sta n dar d de viati o n of wi t hi n-s u bject differe nce i n 
V A S pai n sc ores o f 0. 9 5 . 
P arti cipa nts w h o di sc o nti n ue t he st u d y b efore c o m pl et i n g t he assess me nt s ma y be r e place d at t he 
di scretio n of  t he s p o ns or a n d i n vesti gat or t o e ns ure t hat a p pr o xi matel y 4 0 parti ci pa nts c o mplete 
t he st u d y. T he re pl ace me nt partici pa nt will be assi g ne d t o t he sa me treat me nt se q ue nce as t he 
di sc o nti n ue d partici pa nt.
C CI
C CI
C CI


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
●
This study will be conducted in accordance with the protocol and with the 
following:
○
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines
○
Applicable International Conference for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
●
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.
●
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.
●
The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
○
Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
●
Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement (CTA).


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10.1.2.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.
●
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.
●
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
●
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.
●
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
●
Participants who are rescreened are required to sign a new ICF.
10.1.3.
Data Protection
●
Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information that would make the 
participant identifiable will not be transferred.
●
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for his/her data to be used as described in the informed consent. 
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
10.1.4.
Committees Structure
No committees are planned for this study. 


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10.1.5.
Dissemination of Clinical Study Data
Communication of suspended for terminated dosing
If a decision is taken to suspend or terminate infusion of the excipients in the trial due to safety 
findings, this decision will be communicated by the sponsor to all investigators (e.g., through 
phone and/or email) as soon as possible. It will be a requirement that investigators respond upon 
receipt to confirm that they understand the communication and have taken the appropriate action 
prior to further dosing any participants with study intervention. Any investigator not responding 
will be followed up by the sponsor personnel prior to any further planned dosing. If an infusion
is planned imminently, the sponsor personnel will immediately, and continually, use all efforts to 
reach investigators until contact is made and instructions verified.
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
10.1.6.
Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.
●
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. Source data may include laboratory 
tests, medical records, and clinical notes.
●
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.
●
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-
based monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques, are provided in the 
Monitoring Plan.
●
The sponsor or designee is responsible for the data management of this study,
including quality checking of the data.
●
Source data may include laboratory tests, medical records, and clinical notes.
●
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).


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●
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the CTA
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.
●
In addition, the sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the study site. The study 
may be audited by the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture systems will be stored by third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
Source Documents
●
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.


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●
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available.
●
Definition of what constitutes source data can be found in Section 10.1.6.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include, but are 
not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines
●
Inadequate recruitment of participants by the investigator
●
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures
appropriate participant therapy and/or follow-up.
10.1.9.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.


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10.2.
Appendix 2: Clinical Laboratory Tests
●
The tests detailed in the Safety Laboratory Tests table below will be performed by 
the central laboratory or by the local laboratory.
●
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
●
In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations.
●
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.
●
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
●
Pregnancy Testing will occur as indicated in the SoA (Section 1.3).
Investigators must document their review of the laboratory safety results.
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel.


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Safety Laboratory Tests
Hematology a
Clinical Chemistry a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium (ionized/total)
Mean cell hemoglobin concentration 
Phosphorus/Phosphate
Leukocytes (WBC)
Magnesium
Absolute counts of:
Glucose
Neutrophils
Blood urea nitrogen (BUN)
Lymphocytes
Creatinine 
Monocytes
Uric acid
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Urinalysis a
Alkaline phosphatase (ALP)
Specific gravity
Aspartate aminotransferase (AST)
pH
Alanine aminotransferase (ALT)
Protein
Glucose
Ketones
Hepatitis B surface antigena
Bilirubin
Hepatitis C antibodya
Urobilinogen
HIV a
Blood
Pregnancy test
Nitrite
FSHa, b
Coagulation
HbA1ca
International normalized ratio (INR)
Abbreviations:  FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HIV = human immunodeficiency 
virus; RBC = red blood cells; WBC = white blood cells.
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered as a 
protocol violation.
a
Performed at screening only.
b
Follicle-stimulating hormone test must be performed at screening for a woman who is less than 55 years of age 
with an intact uterus, not on hormone therapy and has had 12 months of spontaneous amenorrhea.


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10.2.1.
Blood Sampling Summary
Approximately 100 mL blood sampling per participant is expected in this study. Blood sampling 
estimate will be provided in the ICF.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).


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
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Pain experienced at the infusion site during scheduled VAS assessments is not to be 
documented as an AE.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Definition of Product Complaints
Product Complaint

A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints:
o
Deficiencies in labeling information, and
o
Use errors for device or drug-device combination products due to ergonomic 
design elements of the product.

Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. Adverse event/SAE information is reported on the appropriate CRF
page and product complaint information is reported on the Product Complaint Form.


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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the CRF page for AE/SAE 
and the Product Complaint Form for product complaints.

There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:

Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.

Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.


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
The investigator will also consult the IB and Product Information in his/her 
assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor or designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
10.3.5.
Reporting of SAEs
SAE Reporting via SAE Report

Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the sponsor or designee.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE Report.
10.3.6.
Regulatory Reporting Requirements
SAE Regulatory Reporting
●
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met.


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●
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/IECs, and investigators.
●
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:

12 months of amenorrhea for women >55, with no need for follicle-stimulating 
hormone (FSH)

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and no 
other medical condition such as anorexia nervosa and not taking medications during 
the amenorrhea (e.g. oral contraceptives, hormones, gonadotropin releasing hormone, 
anti-estrogens, selective estrogen receptor modulators [SERMs], or chemotherapy 
that induced amenorrhea). 
Contraception Guidance:
Male Participants:
No male contraception is required except in compliance with specific local government study 
requirements.


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Female Participants:
Females of childbearing potential agree to either remain abstinent or use at least one effective 
contraception until study completion.
Examples of Different Forms of Contraception:
Highly effective contraception

combination oral contraceptive pill and mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women <198 lb or 90 kg)

total abstinence

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by hysterosalpingogram)

combined contraceptive vaginal ring, or intrauterine devices
Effective contraception

male or female condoms with spermicide

diaphragms with spermicide or cervical sponges

barrier method with use of a spermicide

condom with spermicide

diaphragm with spermicide, or

female condom with spermicide
Note: The barrier method must include use of a spermicide (i.e., condom with spermicide,
diaphragm with spermicide, female condom with spermicide) to be considered effective.
Ineffective forms of contraception

spermicide alone

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, temperature method, combination of above 2,
cervical mucus, symptothermal)

withdrawal

post-coital douche

lactational amenorrhea
Collection of Pregnancy Information
Male participants with partners who become pregnant
●
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive excipients 
infusion.


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●
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant
●
The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy. 
●
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate,
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies), or indication for the procedure.
●
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
●
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 
●
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
●
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study intervention, follow the standard discontinuation process and continue 
directly to the follow-up phase. The follow-up on the pregnancy outcome should 
continue independent of intervention or study discontinuation. 


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10.5.
Appendix 5: Genetics
Not applicable.


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments
Not applicable.


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10.7.
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Not applicable.


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10.8.
Appendix 8: Country-Specific Requirements
Not applicable.


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10.9.
Appendix 9: Provisions for Changes in Study Conduct During 
COVID-19 Pandemic
Implementation of this appendix
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator.
COVID-19 pandemic
Individual, site, or regional restrictions due to the COVID-19 pandemic may cause disruptions to 
the conduct of the study. These disruptions may limit the ability of the investigators, participants, 
or both to attend on-site visits or to conduct planned study procedures.
Implementing changes during the COVID-19 pandemic
The sponsor will first submit a substantial amendment to IRB/IEC, regulatory bodies, and any 
other relevant local authorities for approval, should there be a need to implement the provisional 
changes outlined in this appendix. Should these measures need to be implemented immediately 
to protect the safety of study participants, then they will be implemented as urgent safety 
measures, and reported as soon as possible following implementation. All approvals and 
notifications must be retained in the study records.
After receiving the sponsor’s written approval, sites may implement changes if permitted by 
local regulations. If the sponsor grants written approval for changes in study conduct, the sponsor 
will also provide additional written guidance, if needed.
Considerations for making a change
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study, and maintaining the integrity of the study.
Informed consent
Additional consent from the participant will be obtained for the following reasons, if required:

a change in the method of study intervention administration,

alternate delivery of study intervention and ancillary supplies, and

provision of their personal or medical information required prior to implementation of
these activities.
Changes in study conduct during the COVID-19 pandemic
Changes in study conduct not described in this appendix, or not consistent with applicable local
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations. 
To ensure the quality of data and the well-being of participants, it will be ensured that the 
investigator sites and their staff are following GCP principles and are meeting the sponsor 
responsibilities of Section 5 of ICH-GCP. Throughout these activities the participant remains 
under the care of the primary investigator.


C O N FI D E N TI A L
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7 6
S af et y m o nit ori n g will  be fol l owe d as per t he Sc he d ule of Act i vities.
Scree ni n g peri o d g ui d a nce 
T o e ns ure safet y of  st u d y partici pa nts, la b orat or y v alues a n d ot her eli gi bilit y assess me nts ta ke n 
at t he scree ni n g visit are vali d f or a ma xi m u m o f 4 2 d a y s. T he f oll owi n g r ul es will be a p plie d f or 
acti ve, n o nra n d o mize d partici pa nts w h ose partici pati o n i n t he st u d y  must be pa use d d ue t o t he 
C O VI D - 1 9 pa n de mic :

If scree ni n g is pa use d f or less t ha n 4 2 da ys fr o m scree ni n g visit t o ra n d o mizat i on 
visit: t he partici pa nt will pr ocee d t o t he ne xt st u d y  visit per t he us ual Sc he d ule of 
Act i vities, pr o vi de d t hat t he ra n d o mizati o n visit is c o n d ucte d wit hi n 4 2 da ys fr o m t he
first scree ni n g visit. 
o
T he site s h o ul d c o n d uct t he ne xt visit if t he partici pa nt’s eli gi bilit y cri t eria are 
c o nfir me d, a n d t he site s h o ul d d oc u me nt t he reas o n f or dela y.
o
D ue t o t he pa use i n scree ni n g, si tes s h o uld als o rec o nfir m t he i m pacte d 
parti ci pa nt’s c o nse nt a n d d oc u me nt t his c o nfir mat i o n i n t he s o urce 
d oc u m e nt atio n.

If scree ni n g is pa use d f or m ore t ha n 4 2 da ys fr o m scree ni n g visit t o ra n d o mizat i on 
visit: the partici pa nt m ust u n der g o a n a d dit i on al m e dical assess me nt a n d/ or cli nical 
meas ure me nts t o c o nfir m t heir eli gi bilit y. T he scree ni n g pr oce d ures per t he us ual 
Sc he d ule of Act i vities s h o ul d be f oll owe d, starti n g at t he scree ni n g visit t o e ns ure 
parti ci pa nt eli gi bilit y b y t he ra n d omizat i on visit.
A dj ust me nts t o visit wi n d o ws
A d j ustme nt s t o visit wi n d o ws will n ot be c o nsi dere d pr ot oc ol de viat i ons . Missi n g data
will be 
ca pt ure d as pr ot oc ol de viat i ons . 
W he ne ver p ossi ble a n d safe t o d o s o, as deter mi ne d b y t he i n vest i gat or’s discreti o n, partici pa nts
s h o uld c o m plete t he us ual S o A . T o m a xi mize t he p ossi bilit y t hat t he st u d y  visits ca n be
c o n d ucte d as o n-site visits, t he wi n d o ws f or visit s ma y be a djuste d, u p o n f urt her g ui da nce fr o m 
t he s p o ns or . T hi s mi ni mizes missi n g data a n d preser ves t he i nte n de d c o n duct of t he st u d y .
Tri al Peri o d
Scree ni n g Peri o d
St u d y Peri o d
F oll o w -
u p -
Tele visit
Visit I nter v al 
T oler a nce
Visit n o.
0
1 
2 ( P art A) 
4
Ti mi n g
≥ 1 da y  
bef ore Visit 1
≤2 8 da ys 
pri or Visit 2
A t least 3 da ys bet wee n 
Visit 2 a n d Visit 3
I n-h o use 
Visit/ Peri o d
S ee Ta ble 2
O n -site o nl y
O n -site o nl y
O n -site 
o nl y
Tele visit
Sa me as s h o w n i n S o A, 
b ut fle xi bilit y ca n be 
c o nsi dere d f oll o wi n g 
c o ns ultati o n wit h, a n d 
wit h pri o r a p pr o val b y, 
t he s p o ns or
A b bre viat i ons: n o. = n u m ber; S o A = Sc he d ule of Act i vities.
C CI
C CI
C CI


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Documentation
Changes to study conduct will be documented
Sites will identify and document the details of how participants and conducted activities were 
affected by the COVID-19 pandemic. Relevant communications, including delegation, should be 
filed with site study records.


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10.10.
Appendix 10: Abbreviations
Term
Definition
ADE
adverse device effects
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not.
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CRS
clinical research scientist
CRU
clinical research unit
CSII
continuous subcutaneous insulin infusion
CTA
Clinical Trial Agreement
device deficiencies
equivalent to product complaints
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture


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enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
ethical review board
FSH
follicle-stimulating hormone
GCP
good clinical practice
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISR
infusion site reaction
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
Interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
LSMeans
Least-squares means
PAH
pulmonary arterial hypertension
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PPG
postprandial glucose
product complaint
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention.


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SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SERM
selective estrogen receptor modulator
SoA
Schedule of Activities
T1D
type 1 diabetes mellitus
TBL
total bilirubin
ULN
upper limit of normal
VAS
visual analog scale
WOCBP
woman/women of childbearing potential


C O N FI D E N TI A L
I 8 B-M C -I T T C (c)
8 1
1 0. 1 1.
A p pe n di x 1 1 : Pr ot oc ol A me n d me nt Hist or y
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt ( b)
2 8- Se pte m ber - 2 0 2 1
A me n d me nt (a)
0 8- Se pte m ber - 2 0 2 1
Ori gi nal Pr ot oc ol
1 8- M a y - 2 0 2 1
A me n d me nt ( a)
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial.
T he a m e n d me nt is c o nsi dere d t o be s u bsta ntial beca use i t is li kel y t o ha ve a si g nifica nt i m pact o n 
t he
●
scie ntific val ue of t he trial,
●
c o n d uct or ma na ge me nt of t he trial
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1. 1. S y n o psis; 4. 1. 
O verall desi g n; 9. 5. 
S a m ple Size 
Det er mi nati o n
A me n de d state me nt “a p pr o xi matel y 4 0 
e val ua ble partici pa nts c o m plete b ot h 
Part A a n d Part B of t he st u d y ”. 
Re m o ve d w or d “ b ot h” t hr o u g h o ut. 
C orrecte d err or.
1. 1. S y n o psis; 1. 3. 
Sc he d ule of Acti vities; 
4. 1. O verall desi g n 
A di p ose t hic k ness will be meas ure d b y 
ultras o u n d. O pti o n t o meas ure b y 
cali per d elete d.
Clarificati o n.
1. 3. Sc he d ule of 
Act i vities ( Part A)
Ti me wi n d o ws f or V A S sc ore c ollecti o n 
u p date d.
Clarificati o n.
1. 3. Sc he d ule of 
Act i vities ( Part  A 
 
)
O n Da y -1, delete d t he d osi n g da y 
e x cl usi o n/ wit h dra wal criteria c hec k as 
c o nti n ue d eli gi bilit y will be c hec ke d
C orrecte d err or.
2. 2. Bac k gr o u n d
Delete d “ de pe n di n g o n t he t y pe of 
r eacti o n” fr o m secti o n detaili n g t he 
r ep orte d I S Rs i n t he P R O N T O-P u m p - 2 
st u d y.
Clarificati o n.
5. 2. E xcl usi o n Criteria
Criteri o n 1 3: a me n de d fr o m se vere 
ne ur o pat h y t o ha ve a pat h ol o gic t u ni n g 
f or k test.
Criteri o n 1 8: ser u m creati ni ne val ue i n 
µ m ol/ L u nit u p date d t o 1 deci mal place.
Criteri o n 2 9: a d de d ne w criteri o n t o 
e x cl u de use of L y u mje v.
Criteria 1 3 a n d 2 9: et hics 
c o m mittee re q uest.
Criteri o n 1 8: clarificati o n.
8. 2. 5. 3. L ocal I nf usi o n 
Site Reacti o ns
A me n de d t o state l ocal i nf usi o n site 
r eacti o ns will be rec or de d as A Es as 
Bf Ar M re q uest.
C CI
C CI
C CI


CONFIDENTIAL
I8B-MC-ITTC (c)
82
Section # and Name
Description of Change
Brief Rationale
clinical indicated and not only if they 
qualify as SAEs.
8.3.1. Timing and 
Mechanism for 
Collecting Events
Timing for reporting SAEs to Sponsor 
amended to “Immediately, without 
undue delay, and under no 
circumstances later than 24 hours of 
awareness”.
BfArM request.
10.2. (Appendix 2) 
Clinical Laboratory 
Tests
Ethanol testing and urine drug screen 
deleted from table of laboratory tests as 
this table refers to local and central 
testing only. These tests will be 
performed at site using a breathalyzer or 
dip stick.
Clarification.
10.3. (Appendix 3) 
Adverse Events
Deleted statement that infusion site 
reactions are not be documented as an 
AE.
BfArM request.
10.9. (Appendix 9) 
Provisions for Changes 
in Study Conduct
Appendix changed from “Provisions for 
Changes in Study Conduct During 
Exceptional Circumstances” to 
“Provisions for Changes in Study 
Conduct During COVID-19 Pandemic”.
Appendix updated to include 
procedures to manage impact of 
COVID-19.
BfArM request.


CONFIDENTIAL
I8B-MC-ITTC (c)
83
Amendment (b)
This amendment is considered to be substantial.
The amendment is considered to be substantial because it is likely to have a significant impact on 
the

safety or physical or mental integrity of the study participants,

scientific value of the trial,

conduct or management of the trial
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
8.3.1. Timing and
Mechanism for
Collecting Events
Timing for reporting SAEs to Sponsor
amended by removing “under no
circumstances later than 24 hours of
awareness”. 
BfArM request.


CONFIDENTIAL
I8B-MC-ITTC (c)
84
11.
References
Blevins T, Zhang Q, Frias JP, et al. Randomized double-blind clinical trial comparing ultra rapid 
lispro with lispro in a basal-bolus regimen in patients with type 2 diabetes: PRONTO-T2D. 
Diabetes Care. 2020;43(12):2991-2998. https://doi.org/10.2337/dc19-2550
Gan MJ, Albanese-O’Neill A, Haller MJ. Type 1 diabetes: current concepts in epidemiology, 
pathophysiology, clinical care, and research. Curr Probl Pediatr Adolesc Health Care. 
2012;42(10):269-291. https://doi.org/10.1016/j.cppeds.2012.07.002
[FDA] United States Food and Drug Administration. 2015a. SCOGS (Select Committee on 
GRAS Substances). Available at: http://www.accessdata.fda.gov/scripts/fdcc/?set=SCOGS. 
Accessed December 15, 2015.
[FDA] United States Food and Drug Administration. 2015b. Inactive Ingredient Search for 
Approved Drug Products. Available at: 
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. Accessed December 15, 2015.
Heise T, Linnebjerg H, Coutant D, et al. Ultra rapid lispro lowers postprandial glucose and more 
closely matches normal physiological glucose response compared to other rapid insulin 
analogues: A phase 1 randomized, crossover study. Diabetes Obesity Metab.
2020;22(10):1789-1798. https://doi.org/10.1111/dom.14094
Humira Prescribing Information. 2021. AbbVie Inc. North Chicago, IL 60064, USA; 2021.
https://www.rxabbvie.com/pdf/humira.pdf.
Jinnouchi H, Imori M, Nishiyama H, Imaoka T. Ultra-rapid lispro efficacy and safety compared 
to Humalog® in Japanese patients with type 2 diabetes: PRONTO-T2D subpopulation 
analysis. Diabetes Ther. 2020:11(9):2075-2088. https://doi.org/10.1007/s13300-020-00890-2
Kaiser C, Knight A, Nordström D, et al. Injection-site reactions upon Kineret (anakinra) 
administration: experiences and explanations. Rheumatol Int. 2012;32:295-299. 
https://doi.org/10.1007/s00296-011-2096-3
Klaff L, Cao D, Dellva MA, et al. Ultra rapid lispro improves postprandial glucose control 
compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-
T1D study. Diabetes Obes Metab. 2020;22(10):1799-1807. https://doi.org/10.1111/dom.14100
Krasner A, Pohl R, Simms P, et al. A review of a family of ultra-rapid-acting insulins: 
formulation development. J Diabetes Sci Technol. 2012;6(4):786-796. 
https://doi.org/10.1177/193229681200600408
Lalej-Bennis D, Selam JL, Fluteau-Nadler S, et al. Extreme insulin resistance: clinical 
management by external subcutaneous insulin infusion. Diabetes Metab. 1997;23(6):533-536. 
PMID: 9496561
Lavoisier magnesium chloride. Lavoisier magnesium chloride 10 % (1 g/10 ml), iv injectable 
solution. CDM LAVOISIER, Laboratoires Chaix et Du Marais - 7, rue Labie - 75017 PARIS –
FRANCE. 2004. 
http://www.lavoisier.com/fic_bdd/pdf_en_fichier/12133479260_Magnesium_Chlorhide_10_E
n.pdf.


CONFIDENTIAL
I8B-MC-ITTC (c)
85
Leohr J, Dellva MA, LaBell E, et al. Pharmacokinetic and glucodynamic responses of ultra rapid 
lispro vs lispro across a clinically relevant range of subcutaneous doses in healthy subjects. 
Clin Ther. 2020;42(9):1762-1777.e1764. https://doi.org/10.1016/j.clinthera.2020.07.005
Lyumjev SPC, Lyumjev Summary of Product Characteristics. Eli Lilly and Company, 
Indianapolis, IN, USA; 2020. https://www.ema.europa.eu/en/documents/product-
information/lyumjev-previously-liumjev-epar-product-information_en.pdf.
Murata T, Ushikubi F, Matsuoka T, et al. Altered pain perception and inflammatory response in 
mice lacking prostacyclin receptor. Nature. 1997;388:678-682. https://doi.org/10.1038/41780
Nash P, Vanhoof J, Hall S, et al. Randomized Crossover Comparison of Injection Site Pain with 
40 mg/0.4 or 0.8 mL Formulations of Adalimumab in Participants with Rheumatoid Arthritis. 
Rheumatol Ther. 2016;3:257-270. https://doi.org/10.1007/s40744-016-0041-3
Remodulin SPC. United Therapeutics - Remodulin Solution for Infusion: Summary of Product 
Characteristics. United Therapeutics Europe Ltd., Chertsey, KT16 9FG, UK. 2016.
https://mri.cts-mrp.eu/Human/Downloads/FR_H_0278_001_FinalSPC.pdf.
Reznik Y. Continuous subcutaneous insulin infusion (CSII) using an external insulin pump for 
the treatment of type 2 diabetes. Diabetes Metab. 2010;36(6 Pt 1):415-21. 
https://doi.org/10.1016/j.diabet.2010.08.002
Shin H-J, Na H-S, Do S-H. Magnesium and Pain. Nutrients. 2020;12(8):2184. 
https://doi.org/10.3390/nu12082184
Srebro D, Vuckovic S, Milovanovic A, et al. Magnesium in Pain Research: State of the Art. Curr 
Med Chem. 2017;24(4):424-434. https://doi.org/10.2174/0929867323666161213101744
Warren M, Bode B, Cho JI, et al. Improved postprandial glucose control with ultra rapid lispro 
versus lispro with continuous subcutaneous insulin infusion in type 1 diabetes: PRONTO-
Pump-2. [published online March 8, 2021] Diabetes Obes Metab.
https://doi.org/10.1111/dom.14368
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804. https://doi.org/10.1111/j.1365-2702.2005.01121.x


L e o  D o c u m e n t  I D  =  6 0 4 2 8 1 6 a - 8 5 5 3 - 4 4 e 0 - 8 2 5 1 - 5 8 2 b f b b b 8 0 1 9
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 4 - O c t - 2 0 2 1  1 6 : 3 6 : 1 5  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 4 - O c t - 2 0 2 1  1 7 : 3 2 : 1 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 2 I8B-MC-ITTC 
 
 
A Study to Investigate Local Infusion Site Pain after Infusion of Excipients across Infusion Sites 
and Infusion Depths 
  
  
NCT05067270 
 
Approval Date: 02-Feb-2022 
 
 


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 1 of 1 6
S T A TI S TI C A L A N A L Y SI S P L A N
A St u d y t o I n vesti g ate L oc al I nf usi o n Site P ai n after I nf usi o n of E xci pie nts acr oss I nf usi o n 
Sites a n d I nf usi o n De pt hs
Stati stical A nal ysis Pla n Stat us : Fi nal
Stati stical A nal ysis Pla n Versi o n: 2 . 0
Stati stical A nal ysis Pla n Date : 0 1- Fe br uar y -2 0 2 2
St u d y  Dr u g: L S N 3 3 2 6 7 7 7
S p o ns or Refere nce : I 8 B-M C -I T T C
C o va nce C R U St u d y : 1 0 0 1 2 1 5- 8 4 7 0 0 8 4
Cli nical P hase I
A p pr o v al D at e: 0 2- F e b- 2 0 2 2 G M T


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 2 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
1. T A B L E O F C O N T E N T S
1.
T A B L E O F C O N T E N T S ............................................................................................... 2
2.
A B B R E VI A TI O N S ........................................................................................................ 4
3.
I N T R O D U C TI O N ......................................................................................................... 5
4.
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .................................................................. 5
4. 1
Part A ...................................................................................................................... 5
4. 1. 1
Pri mar y O bject i ve a n d E n d p oi nt ..................................................................... 5
4. 1. 2
Sec o n dar y  O bjecti ve a n d E n d p oi nt ................................................................. 6
4. 1. 3
E x pl or at or y  O bjecti ve a n d E n d p oi nt............................................................... 6
5.
S T U D Y D E SI G N ........................................................................................................... 7
5. 1
P A R T A .................................................................................................................. 7
6.
I N F U SI O N SI T E L O C A TI O N S/ T R E A T M E N T S .......................................................... 9
6. 1
Part A .................................................................................................................... 1 0
7.
S A M P L E SI Z E J U S TI FI C A TI O N ............................................................................... 1 0
8.
D E FI NI TI O N O F A N A L Y S I S S E T S........................................................................... 1 0
9.
S T A TI S TI C A L M E T H O D O L O G Y ............................................................................. 1 1
9. 1
Ge neral .................................................................................................................. 1 1
9. 2
D e m o gra p hics a n d Partici pa nt Dis p osit i on ............................................................. 1 1
9. 3
S af et y a n d T olera bilit y Assess me nts ...................................................................... 1 1
9. 3. 1
Pri mar y E n d p o i nt ......................................................................................... 1 1
9. 3. 2
Sec o n dar y  E n d p oi nt...................................................................................... 1 3
9. 3. 3
E x pl or at or y  E n d p oi nt ................................................................................... 1 3
9. 3. 4
A d verse E ve nts ............................................................................................. 1 3
9. 3. 5
C o nc o mita nt Me dicati o n ............................................................................... 1 4
9. 3. 6
Cli nical La b orat or y  P ara meters ..................................................................... 1 4
9. 3. 7
Vi t al Sig ns.................................................................................................... 1 4
9. 3. 8
Electr ocar di o gra m ( E C G) ............................................................................. 1 4
9. 3. 9
He pati c M o nit orin g ...................................................................................... 1 4
9. 3. 1 0
I mm u n o ge nicit y Assess me nts ....................................................................... 1 4
9. 3. 1 1
H y perse nsi tivi t y R e a ctio ns ........................................................................... 1 4
9. 3. 1 2
Ot her Assess me nts ....................................................................................... 1 4
C CI
C CI
C CI


Final Version 2.0, 01 February 2022
             Page 3 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
10. INTERIM ANALYSES ............................................................................................... 14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 14
12. REFERENCES ............................................................................................................ 15
13. DATA PRESENTATION ............................................................................................ 15
13.1 Decimal Places...................................................................................................... 15
13.2 Missing Data ......................................................................................................... 15
13.3 Insufficient Data for Presentation .......................................................................... 15
14. APPENDICES ............................................................................................................. 16
Appendix 1: Document History...................................................................................... 16


Final Version 2.0, 01 February 2022
             Page 4 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
CI
Confidence interval
CRU
Clinical Research Unit
CSII
Continuous subcutaneous insulin infusion
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
ISR
Infusion site reaction
LSMeans
Least-squares means
MedDRA
Medical Dictionary for Regulatory Activities
SAP
Statistical Analysis Plan
SD
Standard deviation 
T1D
Type 1 diabetes mellitus
TFLs
Tables, Figures, and Listings
VAS
Visual analog scale
WHO
World Health Organization


Final Version 2.0, 01 February 2022
             Page 5 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 18 
May 2021, protocol amendment (a) dated 08 September 2021, protocol amendment (b) dated 28
September 2021 and protocol amendment (c) dated 14 October 2021).
This SAP describes the planned analysis of the safety and tolerability data from this study. A 
detailed description of the planned TFLs to be presented in the clinical study report (CSR) is 
provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical analyses of data. In general, 
the analyses are based on information from the protocol, unless they have been modified by 
agreement with Eli Lilly and Company. A limited amount of information concerning this study 
(e.g., objectives, study design) is given to help the reader’s interpretation. For open-label studies, 
this SAP must be signed off prior to first participant visit for this study. When the SAP and TFL 
shells are agreed upon and finalized, they will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES AND ENDPOINTS
4.1
Part A
4.1.1
Primary Objective and Endpoint
Primary Objective
To investigate local infusion site pain for infusions of sodium citrate and treprostinil in Humalog 
diluent with magnesium chloride (without insulin) in the abdominal, arm, thigh, and buttock 
areas in participants with type 1 diabetes mellitus (T1D) on continuous subcutaneous insulin 
infusion (CSII).
Primary Endpoint
VAS pain score.


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
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Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
4. 1. 2
Sec o n d ar y O bjecti v e a n d E n d p oi nt
Sec o n d ar y O bjecti ve
T o i n vesti gate l ocal i nf usi o n site pai n of 2 differe nt ca n n ula i nserti o n de pt hs ( 6 m m a n d 9 m m) 
i n partici pa nts wit h T 1 D o n C SII.
Sec o n d ar y E n d p oi nt
V A S pai n sc ore .
4. 1. 3
E x pl or at or y O bject i ve a n d E n d p oi nt
E x pl or at or y O bjecti ve
T o assess l ocal i nf usi o n site react i ons (I S R) usi n g t he e x pl orat or y  
 Plat f or m.
E x pl or at or y E n d p oi nt
C haracterizati o n a n d meas ure me nt of i nci de nce a n d se verit y of  lo c al  I S R data.
C CI
C CI


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 7 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
5. S T U D Y D E SI G N
St u d y  I 8 B-M C -I T T C is a 1-/ 2-ce nter, partici pa nt -( Part A  
) a n d i n vesti gat or-
bli n d, 2 -part ra n d o mize d cr oss o ver st u d y  in a d ults ( 1 8 t o 6 9 y ears of age, i ncl usi ve) wit h T 1 D o n
C SII. A p pr o xi matel y 4 6 partici pa nts will be ra n d o ml y  assi g ne d t o st u d y int er ve nt i on s uc h t hat
a p pr o xi matel y 4 0 e val ua ble partici pa nts c o m plete Part A 
Part A of t his st u d y  will be a 1-/ 2-ce nter, ra n d o mize d, 1 da y 5-p eri o d cr oss o ver base d o n t he
or der of i nf usi o n sites a n d de pt hs, bli n de d ( bet wee n i nf usi o n de pt hs), o pe n -label si n gle-treat me nt
st u d y c o n d ucte d i n a d ults wit h T 1 D.
F or  
 Part  A  
, t he partici pa nt will c o nti n ue usi n g his or her pers o nal i ns uli n p u m p
s yste m at t he c urre ntl y e mpl o y e d i nf usi on site a n d will be res p o nsi ble f or perf or mi n g t he
re q uire d actio ns t o m ai ntai n its f u ncti o nalit y. Partici pa nts will  be i nstr ucte d t o a v oid t he use of
t he ce ntral a b d omi nal area f or t heir pers o nal i nf usi o n sets d uri n g t he 
 
 a n d prior t o arri val  at t he cli nical researc h u nit ( C R U).
5. 1
P A R T A
1.
F o ll owi n g a n i nf or me d c o nse nt a n d a scree ni n g visit, partici pa nts will c o me t o t he C R U 
i n t he e ve ni n g (after di n ner) of Da y -1 f or Part A.
2.
Pri or t o t he i nserti o n of t he first i nf usi o n set, t he t hic k ness of t he S C a di p ose tiss ue la yer 
at t he a b d o me n, ar m, t hi g h, a n d b utt oc k areas will be assesse d b y ultras o u n d a n d t he 
meas ure me nt rec or de d i n m m i n t he electr o nic case re p ort f or m. T he e val uate d site 
s h o uld b e i de ntifie d wi t h a u ni q ue i d e n tifier.
3.
T he i nf usi o n sites will be assesse d, a n d a n i ma ge of eac h l ocal i nf usi o n site will be 
c ollecte d usi n g t he 
 Plat f or m prior t o i nserti o n of  t he c orres p o n di n g
i nf usi on set.
4.
Eac h Me dtr o nic ™ Mi ni Me d ™ 7 7 0 G p u m p reser v oir will be fille d b y a q ualifie d site staff
me m ber wit h 3 m L of st u d y  treat me nt (s o diu m ci trate a n d tre pr osti nil i n H u mal o g dil ue nt 
wi t h ma g nesi u m c hl ori de [ wit h o ut i ns uli n]). 
5.
Fi ve p u m ps will be use d f or eac h partici pa nt t o assess i nf usi o ns i nt o t he a b d o mi nal, ar m,
t hig h, a n d b utt oc ks areas. Partici pa nts will be ra n d o ml y assi g ne d t o 1 of 5 i nf usi o n site
se q ue nces t o i n dicate t he or der of t he i nf usi o n sites bei n g e val uate d.
6.
Si x m m ca n n ula will be i nserte d i nt o eac h of t he desi g nate d areas (a b d o me n [at least 5 c m
a wa y fr o m t he u m bilic us i n t he left or ri g ht l o wer q ua dra nts], p osteri or as pect of t he 
u p per ar m, a nterior or l at er al t hig h, a n d u p per b utt oc k), a v oi di n g areas of li p o h y pertr o p h y  
or s ur gical scars. At t he a b d o mi nal area o nl y, a 9 m m ca n n ula will als o be i nserte d i nt o 
t he o p p osit e side of t he l o wer a b d o m e n.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 8 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
7.
T he first i nf usi o n site will be i nit iate d, a n d a basal i nf usi on rate of 1 U/ h will be starte d. 
T he sa me pr oce d ure will occ ur at t he s u bse q ue nt i nf usi o n sites acc or di n g t o t he ra n d o ml y 
assi g ne d se q ue nce wit h a n a p pr o xi matel y 3 0-mi n ute i nter val bet wee n i nit iati o n of t he 
pre vi o us i nf usi o n site. I n case of i m me diate i nf usi o n set i nt olera nce, a ne w i nf usi o n set 
ca n be i nserte d wit hi n t he first 1 0 mi n utes of i nit iati on of t he i nf usi o n site.
8.
A p pr o xi matel y  3 h o urs after t he start of t he basal i nf usi o n at 1 U/ hr, a b ol us d ose of 1 5 U 
will be deli vere d at q uic k b ol us s pee d ( 1 5 U/ mi n) t o eac h i nf usi o n site acc or di n g t o t he 
treat me nt se q ue nce with a n a p pr o xi matel y 3 0 -mi n ute i nt er val bet wee n i nf usi o n sites.
9.
A sec o n d b o l us of 1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d a p pr o xi matel y  
6 h o urs after t he start of t he basal i nf usi o n t o eac h i nf usi o n site acc or di n g t o t he treat me nt
se q ue nce with a n a p pr o xi matel y 3 0 -mi n ute i nter val bet wee n i nf usi o n sites. 
1 0. A t hi r d b olus d os e of 1 5 U gi ve n at q uic k s pee d ( 1 5 U/ mi n) will be deli vere d 
a p pr o xi matel y 9 h o urs after t he start of t he basal i nf usi on t o eac h i nf usi o n site acc or di n g 
t o t he treat me nt se q ue nce with a n a p pr o xi matel y 3 0 -mi n ute i nter val bet wee n i nf usi o n 
sites.
1 1. P arti cipa nts will rate t he pai n at eac h i nf usi o n site after eac h b o l us d ose at t he f oll owi n g 
a p pr o xi mate ti me p o i nts: 5 mi n utes bef ore t he a d mi nistrati o n of a b o l us d ose a n d 1 a n d 
1 5 mi n utes after t he start of eac h b o l us d ose.
1 2. St u d y  inf usi o n sets wit h ca n n ula a n d p u m ps will  be re mo ve d.
1 3. I nf usi on sites will be e val uate d f or ac ute l ocal I S Rs a n d a n i ma ge of eac h lo c al  inf usi o n  
site will be c ollecte d usi n g t he 
Pl atfor m .
1 4. F o ll owi n g t he fi nal e val uat i on, t he partici pa nts will ha ve t he o pti o n t o s pe n d t he ni g ht or 
be disc har ge d fr o m t he C R U.
C CI
C CI


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 9 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
6. I N F U SI O N SI T E L O C A TI O N S/T R E A T M E N T S
T he f o ll owi n g i s a list of t he st u d y i nf usi on site l ocati o ns/ tr e at me nt a b bre viati o ns t hat will be 
use d i n t he T F Ls.
C CI


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 1 0 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
6. 1
P art A
I nf usi o n site l oc ati o n
I nf usi o n site l oc ati o n or der i n T F L
Ar m
1
T hi g h
2
A b d o me n 6 m m
3
A b d o me n 9 m m
4
B utt oc k
5
7. S A M P L E SI Z E J U S TI FI C A TI O N
A p pr o xi matel y  4 6 partici pa nts wit h T 1 D will be e nr olle d i n St u d y I 8 B-M C -I T T C s o t hat 
a p pr o xi matel y 4 0 particip a nts c o m plete  
 Part A  
 of t he st u d y .
 
 
 F ort y c o mplet i n g 
parti ci pa nts will pr o vi de a p pr o xi matel y 8 0 % p o wer t o de mo nstrate a p pr o xi matel y a 5 5 % 
i ncrease i n t he V A S pai n sc ore bet wee n t he i nf usi on site l ocati o ns i n Part A 
 
. Testi n g will be d o ne at al p ha-le vel of 0. 0 5 wit h a 2-side d co nfi de nce 
i nter val (CI ). T he varia bility was esti mate d b y  a nal yzi n g a Lill y i nter nal st u d y t hat s h o we d a 
l og- scale sta n dar d de viat i on of wit hi n - parti ci pa nt differe nce i n V A S pai n sc ores of 0. 9 5.
P arti cipa nts w h o di sc o nti n ue t he st u d y b efore c o m pl et i ng t he assess me nts ma y be re place d at t he
di scretio n of  t he s p o ns or a n d i n vesti gat or t o e ns ure t hat a p pr o xi matel y 4 0 partici pa nts c o mplete
t he st u d y. T he re place me nt partici pa nt will be assi g ne d t o t he sa me treat me nt se q ue nce as t he
di sc o nti n ue d partici pa nt
8. D E FI NI TI O N O F A N A L Y SI S S E T S
T he “ F ull” a nal ysis set will c o nsist of a ll ra n d omize d partici pa nts. Partici pa nts will be i ncl u de d 
i n t he a nal yses acc or di n g t o t he ra n d o ml y assig ne d se q ue nces .
T he “ Safet y” a nal ysis set will c o nsist of all ra n d o mize d partici pa nts w h o recei ve at least 
1 i nf usi on. Parti ci pa nts will be a nal yze d acc or di n g t o t he i nf usi o ns t he y  act uall y recei ve d.
C CI
C CI
C CI
C CI
C CI


Final Version 2.0, 01 February 2022
             Page 11 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
Data related to a site where an infusion set cannula is accidentally pulled out of an 
infusion site or data following a pump occlusion alarm during a bolus infusion will not 
be used in the analysis for that particular site only/part of the study.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations
before database lock.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and n; for log-normal data, the geometric mean and geometric coefficient of variation 
(CV%) will also be presented. For categorical data, frequency count and percentages will be 
presented. Data listings will be provided for all participants up to the point of withdrawal, with 
any participants excluded from the relevant population highlighted. Summary statistics and 
statistical analyses will generally only be performed for participants included in the relevant 
analysis population. For the calculation of summary statistics and statistical analysis, unrounded 
data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the timepoint. The individual participant’s change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Participant Disposition
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
site ID, body weight, height, and body mass index will be summarized by part and listed. All 
other demographic variables will be listed only.
9.3
Safety and Tolerability Assessments
9.3.1
Primary Endpoint
Descriptive statistics
Infusion site pain assessed using the VAS pain score will be listed and summarized using 
standard descriptive statistics including the geometric mean and CV% by bolus time (3, 6, and 
9 hours after initiation of basal infusion) and VAS assessment time point (5 minutes prior to 
bolus and 1 and 15 minutes after bolus). For Part A, the summary will also be by infusion site 
location. The 5 infusion site locations include the assessment of 2 cannula depths at the 


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 1 2 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
a b d o mi nal site.
 
T he rel e va nt ti me p o i nt wi n d o ws will als o be 
di s pla ye d i n t he la belli n g of t he ti me p o i nts i n t he o ut p ut.
It is p ossi ble t hat V A S sc ores will be 0; if s o, all sc ores will be a n al yze d as l og ( V A S + 1) t o all o w 
f or t he i ncl usi on of  t he 0 values i n t he ge o met ric descri pt i ve statistics. T his tra nsf or mat i on will 
be a p plie d f or t he calc ulat i on of t he ge o metric statistics o nl y a n d will n ot be a p plie d t o t he 
arit h metic statistics. T his tr a nsf or mat i on ( V A S + 1) will als o be a p plie d t o all data prior t o t he 
calc ulat i on of t he rati o of t he p ost- b ol us ti me p oi nts t o t he pre -b ol us ti me p oi nt if t here are 
occ urre nce of 0.
Fre q ue ncies a n d perce nta ges of V A S pai n sc ores i n eac h of t he cate g ories of 0, 1 t o 1 0, 1 1 t o 2 0, 
2 1 t o 4 5, a n d 4 6 t o 1 0 0 m m will be s u m marize d b y b ol us ti me, i nf usi o n site l ocat i on/st u d y
treat me nt, a n d ti me p o i nt.
Ge o m etric mea n pr ofile pl ots will be prese nte d b y b o l us ti me, i nf usi on site l ocati o n/st u d y
treat me nt, a n d ti me p o i nt.
St atistic al A n al ysis
A mi xe d effects m o d el will be use d t o a nal yze t he lo g tra nsf or m e d V A S pai n sc ore f or eac h 
b o l us ti me a n d V A S ti me p oi nt. T he statistical mo d el  for Part A will i ncl u de ter ms f or i nf usi o n 
sit e lo c ati o n, peri o d ( or der of i nf usi o ns), b o l us ti me, V A S ti me p oi nt, t he 2- a n d 3-wa y 
i nteract i ons bet wee n i nf usi o n site l ocati o n, b o l us ti me, a n d V A S ti me p oi nt as fi xe d effects a n d 
parti ci pa nt as a ra n d o m effect. C o m paris o ns will be ma de bet wee n i nf usi o n site l ocat i ons f or t he 
a b d o mi nal i nf usi o n site f or eac h b o l us ti me a n d V A S ti me p oi nt. 
 
 
 
Least -s q uares mea ns ( L S Mea ns), i nf usi o n site l ocati o n/treat me nt differe nces i n L S Mea ns, a n d 
t he c orres p o n di n g 9 5 % c o nfi de nce i nter vals ( CIs) f or t he i nf usi o n site l ocat i on/treat me nt 
differe nces will be est i mate d a n d bac k-tra nsf or me d fr o m t h e lo g scal e t o pr o vide esti mates of t he 
r atio of  ge o metric L S Mea ns a n d 9 5 % CI f or t he rati o of t hese mea ns. It is p ossi ble t hat V A S 
sc ores will be 0; if s o, all sc ores will be a nal yze d as l og ( V A S + 1) t o all o w f or t he i ncl usi o n of 
t he 0 val ues i n t he a nal ysis.
T he sa me m o del will als o be use d t o a nal yze t he c ha n ge fr o m t he pre-b ol us ti me p o i nt ( 5 mi n utes 
pri or t o t he b o l us) t o t he p ost-b ol us t i me p oi nts of ( 1 a n d 1 5 mi n utes after b ol us).
C CI
C CI


Fi nal Versi o n 2 . 0, 0 1 Fe br uar y 2 0 2 2
             Pa ge 1 3 of 1 6
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 1 2 1 5 - 8 4 7 0 0 8 4
S p o ns or Refere nce I 8 B -M C -I T T C
E xa m ple S A S c o de f or Part A is s h o w n bel o w, 
p r o c  m i x e d  d a t a = x x x ;
c l a s s  l o c a t i o n  p e r i o d  b o l u s _ t i m e  v a s _ t i m e
s u b j i d ;
m o d e l  l o g V A S
=  p e r i o d  l o c a t i o n | b o l u s _ t i m e | v a s _ t i m e  / r e s i d u a l  d d f m = k r 2 ;
r a n d o m
i n t e r c e p t
/  s u b j e c t = s u b j i d ;
l s m e a n s  l o c a t i o n * b o l u s _ t i m e * V A S _ t i m e
/  c l  p d i f f
a l p h a = 0 . 0 5 ;
o d s  o u t p u t  l s m e a n s = l s m ;
o d s  o u t p u t
d i f f s = e s t i m s ;
r u n ;
9. 3. 2
Sec o n d ar y E n d p oi nt
F or Part A , the c o m paris o n of ca n n ula de pt hs at t he a b d o mi nal i nf usi on site l ocat i on will be 
a nal yze d as part of t he sa me mi xe d effects m o del use d f or t he pri mar y e n d p o i nt.
9. 3. 3
E x pl or at or y E n d p oi nt
L ocal  I S R data (er yt he ma, i n d urati o n, cate g orical pai n, pr urit us, a n d e de ma) will be liste d a n d 
s u m marize d b y inf usi o n  sit e lo c ati o n ( Part A) 
 i n fre q ue nc y ta bles.
Data fr o m t he e x pl orat or y  
 Platf or m will n ot be i ncl u de d i n t he C S R b ut ma y 
be prese nte d i n a se parate re p ort.
9. 3. 4
A d verse E ve nts
W here c ha n ges i n se verit y are rec or de d i n t he Case Re p ort F or m, eac h se parate se verit y of  t he 
a d verse e ve nt ( A E) will be re p orte d i n t he l isti n gs, o nl y t he m ost se vere will be use d i n t he 
s u m mar y ta bles. A pre -e xist i n g c o n diti on is defi ne d as a n A E t hat starts bef ore t he partici pa nt
has pr o vi de d wri tte n i nf or me d c o nse nt a n d is o n g oi n g at c o nse nt . A n o n -treat me nt e mer ge nt A E 
is defi ne d as a n A E w hic h st arts aft er i nf or me d c o nse nt b ut pri or t o d osi n g . A treat me nt -
e mer ge nt A E is defi ne d as a n A E w hic h occ urs p ost d ose or w hic h is prese nt pri or t o d osi n g a n d 
bec o me s more se vere p ost d ose . 
All A Es will b e liste d. Treat me nt -e mer ge nt A Es will be s u m marize d b y st u d y part a n d b y  
i nf usi on site l ocati o n/st u d y treat me nt , se verity, a n d relat i ons hi p t o t he st u d y  dr u g/pr ot oc ol  
pr oce d ure . T he fre q ue nc y (t he n u m ber of A Es , t he n u m ber of parti ci pa nt s e x perie nci n g a n A E
a n d t he perce nta ge of parti ci pa nt s e x perie nci n g a n A E ) of treat me nt -e mer ge nt A Es will be 
s u m marize d b y i nf usi on site l ocat i on/st u d y treat me nt , Me dical Dicti onar y  for Re g ulat or y  
Act i vities ( Me d D R A) versi o n 2 4. 0 s yst e m or ga n class, a n d preferre d ter m. T he s u m mar y a n d 
fre q ue nc y A E ta bles will be prese nte d f or all ca usalities a n d t h ose c o nsi dere d relate d t o t he st u d y 
dr u g b y t he i n vest i gat or a n d re peate d f or t h ose c o nsi dere d relate d t o t he pr ot oc ol pr oce d ure . A n y 
serio us A Es will be listed . S u m maries b y inf usi o n  sit e lo c ati o n/st u d y treat me nt will o nl y be 
p ossi ble w here a partic ular A E is a ble t o be attri b ute d t o a partic ular i nf usi o n site l ocati o n, A E 
data will als o be s u m marize d b y  st u d y part.
Di sc o nti n uatio ns d ue t o A Es will be liste d.
C CI
C CI
C CI


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
9.3.5
Concomitant Medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2021). 
Concomitant medication will be listed.
9.3.6
Clinical Laboratory Parameters
Samples for clinical laboratory data will be performed for inclusion/exclusion criteria purposes 
only and will not be presented.
9.3.7
Vital Signs
Vital signs data including subcutaneous layer thickness data will be listed.
9.3.8
Electrocardiogram (ECG)
ECGs will be performed for inclusion/exclusion criteria purposes only and will not be presented.
9.3.9
Hepatic Monitoring
Not applicable.
9.3.10
Immunogenicity Assessments
Immunogenicity assessments are not evaluated in this study.
9.3.11
Hypersensitivity Reactions
For all hypersensitivity reactions that occur, additional follow-up data will be collected to assess 
the patient’s medical history, alternative causes, and symptoms.
These data will be listed.
9.3.12
Other Assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. If there is an impact on the study due to COVID-19, additional data 
presentations/considerations may be required. This will be assessed prior to the database lock.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


Final Version 2.0, 01 February 2022
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Decimal Places
N and percentage values should be reported as whole numbers. The geometric mean, arithmetic 
mean, median and SD will be presented to 1 decimal place more than the original data..
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”


Final Version 2.0, 01 February 2022
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8470084
Sponsor Reference I8B-MC-ITTC
14.
APPENDICES
Appendix 1: Document History
Status and Version
Date of Change
Summary/Reason for Changes
Final Version 1.0
NA
NA; the first version.
Final Version 2.0
01 February 
2022
Added reference to and updates from protocol 
amendment (c)
Added clarification for the VAS data handling
Other minor clarifications
NA = not applicable


L e o  D o c u m e n t  I D  =  e f 4 8 e 5 8 a - 0 8 9 2 - 4 7 e 0 - 8 a a 2 - 9 5 9 9 e e 2 1 2 a 0 a
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  0 1 - F e b - 2 0 2 2  1 9 : 5 8 : 2 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  0 2 - F e b - 2 0 2 2  1 1 : 1 4 : 2 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  0 2 - F e b - 2 0 2 2  1 1 : 5 7 : 3 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D
P P D