Scalp Cooling for Alopecia Prevention (SCALP)
Phase: NA
Conditions: Breast Cancer, Alopecia
Sponsor: Julie Nangia

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Scalp Cooling Alopecia Prevention Trial (SCALP) 
 
 
 
 
 
 
 
 
 
 
 
 
Julie Nangia, MD 
Assistant Professor 
 
 
 
 
Lester & Sue Smith Breast Center at 
Baylor College of Medicine 
660 MB, One Baylor Plaza 
Houston, TX 77030 
USA 

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Scalp Cooling Alopecia Prevention Trial (SCALP) 
 
 
Principal Investigator/ 
Sponsor: 
 
 
Julie Nangia, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
Lester & Sue Smith Breast Center at 
 
 
 
 
Baylor College of Medicine 
660 MB, One Baylor Plaza  
Houston, TX 77030 
USA 
 
Phone:  713-798-1311 
Fax:  713-798-8884 
Email: nangia@bcm.edu 
 
 
Co-Investigators 
Baylor College of Medicine 
Mari Rude, NP 
Susan Hilsenbeck, PhD 
Mothaffar Rimawi, MD 
 
Kent Osborne, MD 
 
Polly Niravath, MD 
 
Sao Jiralerspong, MD 
 
Matthew Ellis, MD 
 
 
 
 
US Oncology / Texas Oncology – Memorial City 
 
Houston, TX 77024 
Site PI:  Frankie Holmes, MD 
Phone: 713-467-1722 
Email:  frankie.holmes@usoncology.com 
 
Texas Oncology – Baylor Charles A. Sammons Cancer Center 
Dallas, TX 75246 
Site PI:  Cynthia Osborne, MD 
Phone:  214-370-1000 
Email: cynthia.osborne@usoncology.com 
 
Hematology & Oncology Associates of Northern New Jersey 
Morristown, NJ 07962 
Site PI:  Steven Papish, MD 
Phone:  973-538-3593 x 2338 
Email: spapish@hoannj.com 
 
Texas Oncology – Medical City Dallas 
Dallas, TX 75230 

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Site PI: Jay Courtright, MD 
Phone: 972-566-7790 
Email: jay.courtright@usoncology.com   
 
Cleveland Clinic 
Cleveland, OH 44195 
 
 
 
 
Site PI:  Jame Abraham, MD 
      
 
 
 
Phone:  216-445-0150 
     
 
 
 
Email: c/o Justina Vigluicci  vigluij@ccf.org    
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, New York, New York 10065 
Site PI:  Shari B. Goldfarb, M.D. 
 
 
 
 
Email: goldfars@mskcc.org 
 
Coordinating Center  
Baylor College of Medicine 
 
Research Coordinator 
Claudette Foreman  
Phone: 713-798-7315 
Email: caforema@bcm.edu  
 
Study Monitor 
Kristen Otte 
Phone: 713-798-8874 
Email: otte@bcm.edu  
 

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Scalp Cooling Alopecia Prevention Trial (SCALP) 
 
- Protocol Revision Record - 
 
 
Revision Number 
Details of Amendment 
Date 
0.1 
Original Protocol 
1-3-12 
0.2 
FDA recommendation changes 
5-3-13 
0.3 
Added new sponsor details 
5-29-13 
0.4 
FDA recommendation changes 
8-1-13 
0.5 
PRMC recommendation changes 
9-5-13 
0.6 
DSMB, FDA and other site recommendation changes 
11-19-13 
0.6 - Update 1 
Minor amendments associated with change to 5-year post-
study follow-up, change to use of up to 5 centers, use of 
Orbis 1 device only and correction of device software 
version 
12-22-13 
0.6 - Update 2 
Clarification of regimens allowed (allowing pertuzumab use) 
and adding baseline photographs of all subjects 
1-9-14 
0.7 
Photography guidelines, clarification of acceptable baseline 
labs windows, change to exclusion criterion re: abnormal 
TSH (option to assess T3 and free T4 levels), Taxotere 
dosing with pertuzumab 
9-19-14 
0.8 
Change in number of possible participating sites from 5 to 
10, addition of paclitaxel with carboplatin as an allowable 
chemotherapy regimen (inclusion criterion), administrative 
changes and clarifications throughout 
2-3-15 
0.9 
Addition of weekly paclitaxel with weekly carboplatin as an 
allowable chemotherapy regimen (inclusion criterion), 
clarification to definition of “blinded healthcare provider,” 
addition of interim analysis, addition of Dignity Health as 
participating site 
11-5-15 
10 
Addition of Memorial Sloan Kettering Cancer Center as a 
participating site, clarification re: allowing subjects to 
remain on study if they have an allergic reaction to taxane-
based chemotherapy and must switch to paclitaxel protein-
bound chemotherapy (Abraxane), increasing number of 
enrolled subjects due to a higher than anticipated drop out 
rate 
7-1-16 
 

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Table of Contents 
 
 
Synopsis ............................................................................................................................................................... 8 
A.1 
TITLE ....................................................................................................................................................... 8 
A.2 
DESIGN .................................................................................................................................................... 8 
A.3 
BRIEF DESCRIPTION ................................................................................................................................. 8 
A.4 
STUDY POPULATION ................................................................................................................................. 8 
A.5 
PURPOSE .................................................................................................................................................. 8 
A.6 
ENROLLMENT ........................................................................................................................................... 8 
A.7 
CLINICAL SITES ........................................................................................................................................ 8 
A.8 
PRIMARY ENDPOINTS ............................................................................................................................... 8 
A.9 
FOLLOW-UP ............................................................................................................................................. 8 
B) 
Schema ................................................................................................................................................... 9 
C) 
Background ...................................................................................................................................... 10 
C.1 
BREAST CANCER AND CHEMOTHERAPY-INDUCED ALOPECIA .................................................................. 10 
C.2 
METHODS FOR MANAGEMENT OF CHEMOTHERAPY-INDUCED ALOPECIA ................................................. 10 
C.3 
EFFECTIVENESS OF SCALP COOLING IN THE PREVENTION OF CHEMOTHERAPY-INDUCED ALOPECIA ......... 11 
C.4 
SCALP METASTASES CONCERN ............................................................................................................... 13 
C.5 
OTHER SIDE EFFECTS WITH SCALP COOLING .......................................................................................... 15 
C.6 
PSYCHOSOCIAL EFFECTS OF SCALP COOLING SYSTEM FOR ALOPECIA PREVENTION IN PATIENTS WITH 
CANCER UNDERGOING CHEMOTHERAPY ............................................................................................................. 17 
D) 
Investigational Device Information ....................................................................................... 17 
D.1 
IDENTIFICATION OF THE DEVICE ............................................................................................................. 17 
D.2 
DESCRIPTION OF THE DEVICE ................................................................................................................. 18 
D.3 
INTENDED USE OF THE DEVICE ............................................................................................................... 18 
D.4 
TRAINING AND EXPERIENCE NECESSARY FOR USE OF THE DEVICE .......................................................... 18 
D.5 
DEVICE TRACEABILITY .......................................................................................................................... 19 
E) 
Risk Benefit Analysis ..................................................................................................................... 19 
E.1 
ANTICIPATED RISKS AND ADVERSE DEVICE EFFECTS ............................................................................. 19 
E.2 
ADDITIONAL STUDY MEASURES TO MINIMIZE RISK ................................................................................ 21 
E.3 
RISK BENEFIT CONCLUSION ................................................................................................................... 21 
F) 
Purpose ............................................................................................................................................... 22 
G) 
Hypothesis ......................................................................................................................................... 22 
H) 
Endpoints ........................................................................................................................................... 22 
H.1 
PRIMARY ENDPOINTS ............................................................................................................................. 22 
H.2 
SECONDARY ENDPOINTS ........................................................................................................................ 22 
I) 
Participant Selection .................................................................................................................... 23 
I.1 
INCLUSION CRITERIA .............................................................................................................................. 23 
I.2 
EXCLUSION CRITERIA............................................................................................................................. 24 
I.3 
INCLUSION OF UNDERREPRESENTED POPULATIONS ................................................................................. 24 
J) 
Study Design ..................................................................................................................................... 24 
J.1 
GENERAL ASPECTS OF STUDY DESIGN .................................................................................................... 24 

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J.2 
CENTER SELECTION ............................................................................................................................... 25 
J.3 
LEAD CENTER ........................................................................................................................................ 25 
J.4 
OTHER PARTICIPATING CENTERS ............................................................................................................ 25 
J.5 
STUDY POPULATION ............................................................................................................................... 25 
J.6 
SUBJECT SCREENING & ENROLLMENT .................................................................................................... 26 
J.7 
SUBJECT IDENTIFICATION ....................................................................................................................... 26 
K) 
Study Procedures ............................................................................................................................ 26 
K.1 
RANDOMIZATION PROCEDURE ................................................................................................................ 26 
K.2 
BASELINE ASSESSMENT.......................................................................................................................... 27 
K.3 
PROCEDURES ......................................................................................................................................... 27 
K.4 
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES .......................................................... 31 
K.5 
DURATION OF FOLLOW-UP ..................................................................................................................... 31 
K.6 
CRITERIA FOR REMOVAL FROM STUDY ................................................................................................... 32 
K.7 
CRITERIA AND PROCEDURES FOR DISCONTINUATION OF TREATMENT ...................................................... 32 
K.8 
DELAYS ................................................................................................................................................. 33 
L) 
Study Calendar ................................................................................................................................ 34 
M) 
Adverse Events................................................................................................................................. 35 
M.1 
REPORTABLE ADVERSE EVENTS ............................................................................................................. 35 
M.2 
ADVERSE EVENT REPORTING REQUIREMENTS ........................................................................................ 35 
M.3 
ADVERSE EVENT DEFINITIONS ............................................................................................................... 35 
M.4 
ADVERSE EVENT REPORTING ................................................................................................................. 38 
N) 
Informed Consent ........................................................................................................................... 39 
O) 
Investigation Administration .................................................................................................... 40 
O.1 
ETHICAL CONDUCT ................................................................................................................................ 40 
O.2 
REGULATORY REQUIREMENTS................................................................................................................ 40 
O.3 
RESPONSIBILITIES OF THE SPONSOR ........................................................................................................ 41 
O.4 
RESPONSIBILITIES OF THE INVESTIGATOR ............................................................................................... 42 
O.5 
STUDY MONITOR ................................................................................................................................... 43 
O.6 
INVESTIGATOR SELECTION CRITERIA ...................................................................................................... 44 
O.7 
STUDY INITIATION ................................................................................................................................. 45 
O.8 
RECORDS AND REPORTS ......................................................................................................................... 45 
O.9 
DATA MONITORING AND QUALITY CONTROL ......................................................................................... 47 
O.10 
QUALITY ASSURANCE AUDITING AND INSPECTION ................................................................................. 47 
O.11 
PATIENT CONFIDENTIALITY .................................................................................................................... 48 
O.12 
INVESTIGATOR/STUDY DISCONTINUATION .............................................................................................. 48 
O.13 
PROTOCOL MODIFICATIONS.................................................................................................................... 48 
O.14 
SUPPLY AND DISPOSITION OF DEVICES ................................................................................................... 49 
O.15 
TRAINING ............................................................................................................................................... 49 
O.16 
MEETINGS .............................................................................................................................................. 49 
P) 
Statistical Considerations ........................................................................................................... 49 
P.1 
STUDY DESIGN ....................................................................................................................................... 50 
P.2 
SAMPLE SIZE/ACCRUAL RATE ................................................................................................................ 50 
P.3 
INTERIM ANALYSIS ................................................................................................................................ 50 
P.4 
STRATIFICATION FACTORS ..................................................................................................................... 51 
P.5 
ANALYSIS OF PRIMARY ENDPOINTS ........................................................................................................ 51 
P.6 
ANALYSIS OF SECONDARY ENDPOINTS ................................................................................................... 52 
P.7 
REPORTING AND EXCLUSIONS ................................................................................................................ 53 
Q) 
Publication ........................................................................................................................................ 53 

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APPENDICES .............................................................................................................................................. 56 
A) 
Orbis Paxman Hair Loss Prevention System ....................................................................... 56 
B) 
CTCAE v4.0 Grading Scale and Alopecia Pictorial Tool ................................................. 56 
C) 
Comfort Scale ................................................................................................................................... 56 
D) 
QOL Questionnaires ....................................................................................................................... 56 

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Synopsis 
A.1 Title 
Scalp Cooling Alopecia Prevention Trial (SCALP) 
A.2 Design 
Multi-center randomized non-blinded controlled prospective trial 
A.3 Brief Description  
All subjects randomized to scalp cooling will undergo scalp cooling using the Orbis 
Paxman Hair Loss Prevention System prior to, during and after administration of each 
chemotherapy infusion, for 4 complete cycles of full-dose anthracycline- or taxane-based 
chemotherapy.   
Each subject will be followed up 3 ± 1 weeks after completion of chemotherapy. 
A.4 Study Population  
Women with stage I-II breast cancer, who will undergo either neoadjuvant or adjuvant 
chemotherapy.  
A.5 Purpose 
Demonstrate that the Orbis Paxman Hair Loss Prevention System is safe and effective in 
reducing chemotherapy-induced alopecia in woman with breast cancer undergoing 
neoadjuvant or adjuvant chemotherapy.  
A.6 Enrollment 
Up to 325 subjects. 
A.7 Clinical Sites 
Up to 10 Sites in the USA. All sites will use the same protocol and undergo the same 
training on use of the Orbis Paxman Hair Loss Prevention System. 
A.8 Primary Endpoints 
Primary Efficacy Endpoint:  To compare success in hair preservation, between the Orbis 
Paxman Hair Loss Prevention System and control (no cooling) after 4 cycles of 
chemotherapy.  
Primary Safety Endpoint: To estimate the rate of significant anticipated device effects 
specified in section M.4. 
A.9 Follow-Up 
Study subjects will be followed 3 ± 1 weeks after completion of chemotherapy when the 
final alopecia assessment will occur (if grade 2 alopecia has not been reached) and the 
questionnaires will be administered.  Subjects will be followed post-study for 5 years 

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during routine clinic follow-up or via phone call for time to first recurrence, overall 
survival, site of first recurrence, and incidence of isolated scalp metastasis. 
B) Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Enrollment 
Assessment 
 Alopecia: After each cycle by a delegated 
physician/nurse practitioner, the subject and a 
delegated healthcare provider who is blinded to study 
treatment 
 Questionnaires prior to therapy, after 4 cycles, and after 
completion of chemotherapy (if subject is receiving > 4 
cycles of chemotherapy) 
Randomization 
Stratified by major chemotherapy type and center 
No Scalp Cooling 
Paxman Scalp Cooling System 

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C) Background 
C.1 Breast Cancer and Chemotherapy-Induced Alopecia  
In 2011, an estimated 230,480 new cases of invasive breast cancer will be diagnosed in 
women in the United States (American Cancer Society 2011). Chemotherapy will be part 
of the treatment planned for many of these women.  Neoadjuvant chemotherapy is given 
prior to surgery to improve surgical options and to increase the chances of cure. Post-
surgical or adjuvant chemotherapy, is given after surgery to minimize the risk of local and 
systemic tumor recurrence and therefore increase the chances of cure.    
Chemotherapy treats micro-metastatic disease and decreases the risk of recurrence. 
However, it may be associated with distressing adverse effects, including alopecia, fatigue, 
nausea, and potentially life threatening effects such as neutropenia. The most effective and 
commonly used chemotherapy regimens for breast cancer include the agents anthracyclines 
(e.g. doxorubicin and epirubicin) and taxanes (e.g. docetaxel and paclitaxel) that cause 
complete alopecia. Despite improvements in most aspects of supportive care, and newer 
chemotherapy regimens with less systemic toxicity, alopecia remains universal.     
Women with breast cancer rate chemotherapy-induced alopecia as one of the most severe, 
troublesome and distressing side effects of chemotherapy (Grevelman 2005) (Lemieux 
2009). As early as 1984, it was reported that patients who experience hair loss following 
chemotherapy reported suffering negative body image, anxiety, and depression. Auvinen et 
al noted that the hair loss acted as a constant reminder to the patient of the underlying 
cancer and it had an impact not only on the patient, but also on those individuals close to 
the patient. Among women losing their hair because of breast cancer treatment, many 
indicate that coping with hair loss is more difficult than the loss of their breast since it is 
outwardly visible to others, affects their femininity, and is a constant reminder of their 
cancer (Kaderman 1999; Benjamin 2002). In 2011, Breed et al noted that 13% of women 
cancer patients surveyed believed they would be rejected by their partner in the event they 
experienced hair loss resulting from chemotherapy. Trueb reported in 2010 that 47% of 
women cancer patients considered chemotherapy-induced hair loss the most traumatic 
aspect of cancer treatment. Furthermore, 8% of women surveyed reported that they would 
actually decline chemotherapy because of the fear of this side-effect, despite the fact that 
the hair loss is nearly always temporary. This may lead to women hesitating in taking 
chemotherapy, which may compromise their outcome. This side effect of chemotherapy is 
mostly, but not always, reversible (Massey 2004). It takes months to years after the 
completion of chemotherapy for the hair to recover, and it may be of a different quality, 
color, and thickness.   
C.2 Methods for Management of Chemotherapy-Induced Alopecia 
Chemotherapy-induced alopecia is caused by the fact that chemotherapy relies for its 
effectiveness on the ability of drugs used to inhibit and suppress growth and multiplication 
of rapidly dividing cancer cells. These drugs are not able to distinguish between cancerous 
cells & non-cancerous cells i.e. hair follicles. At any one time, approximately 85-90% of 
human hair follicles are in a state of rapid growth (Massey 2004). Numerous measures to 
prevent or reduce the effects of chemotherapy-induced alopecia, including mechanical, 

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pharmacological and physical methods, have been investigated since the 1960s with 
varying degrees of success (Massey 2004). 
Breed reports that in the late 1970s scalp tourniquets were utilized to reduce the blood flow 
to hair follicles during peak chemotherapy levels (Breed 2011). Hair loss was reduced in 
patients receiving doxorubicin. This approach was associated with side effects including 
headache and nerve compression and is no longer utilized. A number of pharmacological 
agents with different mechanisms of action have been studied over the years for their 
effects to minimize chemotherapy-induced hair loss. Of the agents that have been 
evaluated in humans, two – AS101 (an immune modulator) and minoxidil (a hair growth 
promoter) – were able to reduce the severity and shorten the duration of alopecia, but could 
not prevent it (Wang 2006). Trueb reported in 2009 that 2% topical minoxidil solution 
shortened the duration of alopecia in breast cancer patients receiving adjuvant 
chemotherapy (Trueb 2009). It was not effective in preventing chemotherapy-induced 
alopecia when doxorubicin was used as part of the treatment.   
Physical methods employed to reduce chemotherapy-induced alopecia have included 
electrotrichiogenesis and scalp cooling. The former was reported in 2002 with promising 
results in a pilot study, but no further results have been published (Christodoulou 2006). In 
an increasing number of European countries, scalp cooling has been introduced to prevent 
or reduce chemotherapy-induced alopecia. Scalp cooling cause’s cutaneous 
vasoconstriction, which reduces the blood flow to the hair follicles during peak plasma 
concentrations of the chemotherapeutic agents and therefore reduces cellular uptake of 
these agents. It also results in reduced biochemical activity, which makes hair follicles less 
susceptible to the damage of the chemotherapy agents (Grevelman 2005).   
Scalp cooling was at first performed using crushed ice packs that were placed on the 
patient’s head, but with unsatisfactory results. The ice packs were subsequently replaced 
with cryogel ice caps (ChemoCap, Elasto-Gel, Hypothermia Cap and Penguin Cold Cap).   
Since the caps are put on freezing cold, and thaw over time, they are uncomfortable for the 
patient and also very labor-intensive for the nurse. The fluctuation in temperature affects 
the results of the scalp cooling treatment. This led to the development of cooling systems 
that could provide a continuous cooling of the scalp. 
Continuous scalp cooling relies on circulation of a liquid coolant. Available options 
include the Orbis and Paxman Scalp Cooling models of scalp cooler manufactured by 
Paxman Coolers and the DigniCap system manufactured by Digitana.    
C.3 Effectiveness of Scalp Cooling in the Prevention of Chemotherapy-Induced 
Alopecia 
The efficacy of scalp cooling depends on several factors: chemotherapy regimen and dose, 
dose interval, performance status of the patient, scalp cooling temperature, post cooling 
time, and scalp cooling system (Lemieux 2008). Comfort and ease of use are also factors in 
success, as discomfort or difficulties with cooling or changing the cap can result in poor 
compliance. Most studies looking at scalp cooling utilize the WHO Criteria for hair loss to 
grade alopecia or a variation of this. Hair loss is rated grade 0 (no significant hair loss) 
through grade 4 (non-reversible alopecia). Success is commonly defined as the patient not 
requiring a wig (grades 0, 1, and 2).   

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There are several review articles looking at scalp cooling. One of the first is the review by 
Grevelman and Breed looking at the efficacy of scalp cooling.  Included were 53 studies 
and 3 personal communications in which over 2,610 patients were treated with scalp 
cooling. The efficacy in terms of good hair preservation was 56% for studies before 1995 
and 73% for studies carried out from 1995 to 2005. The improvement of results is likely 
due to improved scalp cooling systems and techniques (Grevelman 2005).  
In 2011, Breed, et al reported on a review of 60 scalp cooling studies, which used the 
various techniques described above and were published between 1977 and 2010 (Breed 
2011). Included in the review were 7 randomized, controlled studies, 7 non-randomized, 
controlled studies with statistical analysis, 11 non-randomized, controlled studies without 
statistical analysis, and 36 non-controlled studies.  In six of the seven randomized, 
controlled studies, which included 111 scalp-cooled patients, scalp cooling resulted in 
significantly better hair preservation than controls. The proportion of treated patients 
having good hair preservation (WHO grade 0-2) ranged from 25% to100%. The non-
randomized, controlled studies with statistical analysis resulted in significantly better hair 
preservation following scalp-cooling in all seven studies. This dataset included a total of 
1207 scalp-cooled patients, including 770 from a single study. The proportion of treated 
patients classified as having good hair preservation ranged from 41 to 97% (compared to 
0-38% for controls).  In the 11 non-randomized, controlled studies without statistical 
analysis, an average of 67% of patients had good hair preservation. In the 36 non-
controlled studies, positive effects of scalp cooling on hair preservation were seen in all but 
one study. The median value of good hair preservation in this latter serious was 
approximately 80%. Together, these studies are considered to constitute reasonable clinical 
evidence that scalp cooling is effective in reducing chemotherapy-induced alopecia.    
Many of the studies provide additional detail about the various chemotherapy regimens 
and include outcome measures other than the severity of hair loss. In a Danish study of 62 
evaluable women, several outcomes were considered including: severity of hair loss, 
burden of hair loss, burden of scalp cooling, wig use, hair regrowth, and body image.    
Drug regimens included Adriamycin/Cytoxan (AC), 5-FU/Epirubicin/Cytoxan (FEC), 5-
FU/Adriamycin/Cytoxan (FAC) and Taxotere/Adriamycin/Cytoxan (TAC). Scalp cooling 
was effective in preventing chemotherapy-induced hair loss in 32 of 62 evaluable patients 
(Mols 2009). In this study, patients did not perceive scalp cooling as burdensome. In this 
study and others, the TAC regimen is associated with poor hair preservation even with the 
use of scalp cooling (likely related to concurrent taxane & anthracycline use).   
The effect of alopecia and the effects of scalp cooling on well-being were looked at in a 
study by van den Hurk (Van den Hurk 2010). This was a prospective multi-center study 
performed in 13 hospitals. The Paxman system for scalp cooling was utilized. Breast 
cancer patients receiving chemotherapy combinations including anthracyclines and taxanes 
were included. This study looked at both the severity of alopecia and at several quality of 
life measures to assess well-being of patients. Scalp cooling was effective in 52% of the 
cases. There was a trend toward higher well-being and a better body image in the scalp-
cooled patients 
Several additional studies have looked specifically at the Orbis Paxman Hair Loss 
Prevention System. One of the first was the study by Massey that looked at scalp cooling at 
8 centers in United Kingdom with data collection from 1997 to 2000 (Massey 2004). All 

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patients were women with breast cancer being treated in the adjuvant or palliative setting.  
Twelve different chemotherapy regimens were utilized. The procedure included 
application of small amount of conditioner to dampened hair, to allow for closer contact of 
the PSC with the scalp. A pre-cooling time of 15-20 minutes was recommended, with a 
post infusion cooling time of 2 hours for most regimens. A variation of the WHO criteria 
for alopecia was utilized. Nurses graded the alopecia and patients were asked to complete 
report forms on attitude toward the process and side effects. A total of 94 patients were 
included in the study, with 66% of patients receiving FEC. Of these patients, 89% had 
grade 0 alopecia and did not require a wig.   
In summary, there are many studies and reviews that have looked at scalp cooling.  Many 
of these studies were small and not well designed.  It is also difficult to compare these 
studies because of differences in patient characteristics, chemotherapy agents, length of 
cooling, and hair loss assessments.  Most of these studies have been done in Europe and 
more recently Asia.  Success rates are variable, but scalp cooling appears to be effective in 
preventing chemotherapy-induce alopecia especially in more recent studies.  The Orbis 
Paxman Hair Loss Prevention System is widely used to prevent chemotherapy-induced 
alopecia in Europe, Australia, and Asia. In the United States scalp cooling is rarely used as 
it is not approved by the Food and Drug Administration. 
C.4 Scalp Metastases Concern 
As scalp cooling acts by reducing the effect of chemotherapy in the scalp, a theoretical 
increased risk of scalp metastases is often discussed. Since breast cancers may metastasize 
to the scalp, the discussion most often concerns these patients. Published data demonstrate 
that the incidence of scalp metastasis following adjuvant therapy in breast cancer is 
inherently low and it is exceedingly rare to have scalp metastases as the first site of 
metastases as they nearly always occur late in the course of the disease when other 
metastases are already present. Thus, increasing a woman’s chance of dying of breast 
cancer because she underwent scalp cooling at the time of adjuvant chemotherapy seems 
remote if possible at all.    
Rugo and Melin analyzed all the literature to date in a correspondence (Rugo 2010).  This 
included a study by Browstein and Helwig where metastatic sites were identified in a 1972 
study of 167 women with breast cancer and cutaneous metastasis who did not receive 
chemotherapy. The incidence of scalp involvement in these women with cutaneous 
metastasis was only 3%. The authors emphasized that the scalp metastasis in women with 
breast cancer usually occurred late in the disease. Furthermore Rugo and Melin, looked at 
three studies from 1976 to 2009, involving a total of 2,697 breast cancer patients who 
received chemotherapy without scalp cooling and who were followed up for around 5 
years; the incidence of scalp metastases ranged from 1.2% to 2.5% (while the incidence of 
all skin metastases ranged from 24% to 30%). When breast cancer is metastatic and 
involves the skin or scalp, the breast cancer is usually widespread and it would be 
exceedingly rare to have breast cancer recur with the scalp as the only site of metastatic 
disease. It is also exceedingly rare for scalp metastases to be the first site of recurrence in 
breast cancer patients.   
In consideration of scalp metastases as the first site of recurrence of cancer, Rugo and 
Melin looked at reference data from the National Surgical Adjuvant Breast and Bowel 

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Project (NSABP), involving 7,800 women with breast cancer treated with surgery alone or 
combined with chemotherapy (Rugo 2010). Of these 7,800 women, only 2 (0.025%) 
experienced scalp metastasis as their first site of recurrence. Both of these patients had 
positive lymph nodes and one of them had received adjuvant chemotherapy. It is not 
mentioned in the correspondence how many of these women had skin metastases or scalp 
metastases. Rugo & Melin’s expert opinion was “that scalp cooling can and should be 
offered to breast cancer patients who will be treated with adjuvant chemotherapy, and also 
those who are offered palliative chemotherapy associated with a significant risk of 
alopecia. The risks involved appear to be extremely small and the potential gain for the 
large number of women receiving adjuvant chemotherapy for breast cancer in the United 
States is substantial.” 
A number of other studies investigating the incidence of scalp skin metastases, and its 
relationship to scalp cooling, have been published in the literature. In a review of scalp 
cooling by Grevelman and Breed that included 56 studies and approximately 2,500 
patients, scalp metastasis were reported in 9 patients (0.36%) (Grevelman 2005). In a total 
of 24 of the 56 studies reviewed, specific attention was paid to the risk of scalp skin 
metastases following the use of scalp cooling. It was reported that no scalp skin metastases 
were found in 16 of these studies. The follow-up time of the studies included in the review 
varied from 2 months to 63 months.   
In addition to the review by Grevelman and Breed, a number of more recent studies have 
investigated the incidence of scalp metastases following scalp cooling of women with 
breast cancer receiving chemotherapy.  In 2006, Christodoulu et al reported on a series of 
227 breast cancer patients who underwent scalp cooling with a cold cap while receiving 
chemotherapy (Christodoulou 2006). Two of the breast cancer patients (0.88%) developed 
scalp metastases.  Both patients had advanced cancer with multiple sites of metastases.  
The follow-up period for this study was not specified. The authors concluded that “the 
incidence of scalp metastases in patients using scalp cooling methods during chemotherapy 
is low and it does not seem to influence the clinical outcome.” 
In a prospective multicenter study by Spaeth and colleagues, 911 cancer patients were 
included from 2002 to 2006 (Spaeth 2008). 876 of these patients were women, most with 
localized or advanced breast cancer, whom were treated with adjuvant chemotherapy or 
palliative chemotherapy. There were 770 cancer patients who chose chemotherapy with 
scalp cooling and 141 who chose to have chemotherapy without scalp cooling. During the 
follow-up, a minimum time of at least 2 years, there was one cutaneous scalp metastasis 
and two subcutaneous scalp metastases occurring among the patients who had scalp 
cooling, and no scalp metastases among the patients who abstained from scalp cooling. 
The brief report does not give any indication of what kind of primaries the three patients 
with scalp metastases had, or if the chemotherapy was given as adjuvant treatment or as 
palliative treatment for advanced disease.   
In 2009, Lemieux et al reported on a retrospective cohort study of women diagnosed with 
invasive breast cancer between June 1998 and June 2002 at a single institution in Quebec 
(Lemieux 2009). Scalp cooling was routinely offered to women with breast cancer. Of a 
total of 640 patients included, 86.4% received scalp cooling during neoadjuvant or 
adjuvant chemotherapy. Six patients (1.1%) in the scalp cooling group developed scalp 
metastases (with or after the diagnosis of metastases to multiple other sites), along with 

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one patient in the control group (1.2%). The rate of scalp metastases in the scalp cooling 
group and the control group was not statistically different. In this cohort, scalp metastases 
never presented as the sole metastatic site and these patients with scalp metastasis had 
widely metastatic disease. See Table 1 below for details of the 7 patients with scalp 
metastasis.   
 
 Table 1 
 
 
Recently at the San Antonio Breast Cancer Symposium held in December 2011, there were 
two posters presented related to the issues of chemotherapy-induced alopecia and scalp 
cooling devices. The first was from the Netherlands and included 1,696 scalp cooled breast 
cancer patients from 43 hospitals from 2006-2011. 1,057 of these patients were included in 
the analysis; 48% of them had hair preservation defined as not needing a head cover. As of 
November 2011 no scalp metastasis had been reported. This study also standardized the 
cooling times with a 30 minute pre-cooling time and a 90 minute post-cooling time (C. van 
den Hurk 2011). The second poster was from Canada and looked at survival in women 
with breast cancer who used or did not use a scalp cooling device in the neoadjuvant 
/adjuvant setting. This was a retrospective study of 1,370 women with breast cancer 
diagnosed between June 1998 and June 2002. There was no difference in survival between 
these 2 groups of women (J Lemieux 2011). 
In the past there has been a theoretical concern for scalp metastases. The literature and 
studies to date clearly show that there is not an increased rate of scalp metastases or a 
difference in survival compared to women who did not receive scalp cooling. The known 
rate of scalp metastases in breast cancer patients is <2.5%. The rate of scalp metastases in 
review of the NSABP data by Rugo and Melin as a single site is 0.025% (Rugo 2010).  
The rate of scalp metastasis in women with breast cancer is very small, and as a single site 
of recurrence is exceedingly rare. If a patient has scalp metastases, there are usually 
multiple other sites of metastatic disease and there are usually other sites cutaneous 
metastases. Studies done to date do not show an increase in scalp metastasis in breast 
cancer patients receiving scalp cooling to prevent alopecia. 
C.5 Other Side Effects with Scalp Cooling 
The effect of scalp cooling on patient comfort, possible side effects, and well-being has 
been evaluated. Based on published accounts of more than 2,000 patients, it is concluded 
that the majority of patients tolerate scalp cooling very well (Breed 2004). The side effects 

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of scalp cooling are not frequent and are not serious. Side effects are rarely a reason for 
stopping the cooling.  
Common side effects reported with scalp cooling include headache, complaints of 
coldness, and/or uncomfortable sensations, heavy feeling of the head, transient 
lightheadedness, and neck pain (Massey 2004). Uncomfortable cold sensations and 
headaches were more frequently reported in studies when pre-cooled caps (which are 
chilled to -15°C to -25°C) were used. Patients also complain about a heavy feeling of the 
head and transient light-headedness following cap removal. In addition, patients 
experienced neck pain due to heavy weight of some cooling caps. Cold injuries have never 
been reported. A potential disadvantage of scalp cooling is the additional pre-cooling and 
post-cooling time required which would have patients remain in the oncology clinic for a 
longer duration. 
Known short-term adverse effects anticipated to occur during or following scalp cooling 
with the Orbis Paxman Hair Loss Prevention System (based on clinical experience with 
scalp cooling, including that obtained from use of the previous PSC model of scalp cooling 
system manufactured by Paxman Coolers) are as follows: 
 complaints of coldness/cold-related discomfort (during scalp cooling) 
 headache, ranging from mild to severe (during and following scalp cooling) 
 forehead pain (during scalp cooling) resulting from pressure and tightness from the 
cooling cap 
 light-headedness or dizziness (during scalp cooling and/or following removal of the 
cooling cap at the end of scalp cooling) 
 complaints of uncomfortable sensations 
 heavy feeling of the head 
 transient lightheadedness 
 transient neck pain   
 cold injuries 
 nausea 
All of these adverse effects are transient in duration and of relatively low clinical 
significance. As such, the potential clinical benefits to the patient associated hair 
preservation through scalp cooling using the Orbis Paxman Hair Loss Prevention System 
(i.e. improved quality of life through avoidance of negative body image and depression 
resulting from alopecia) outweigh the risks associated with the known short-term adverse 
effects of scalp cooling. 
The only known potential long-term adverse effect associated with scalp cooling (and 
which could thus occur following use of the Orbis Paxman Hair Loss Prevention System) 
is an increased incidence of scalp metastases. At the time this concern was initially raised 
during the late 1980s, there was little long-term data available to address this risk.  
However, since that time, a number of published studies extending out to more than 5 
years (described in section C.4) have identified that: 

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 the rate of incidence of scalp metastases as the first site of recurrence in breast 
cancer patients is extremely low (2 out of 7,800 subjects, or 0.025%) 
 the rate of incidence of scalp metastases in breast cancer patients is generally low 
(up to 2.5%) and is always greatest in patients with multiple metastatic sites 
 the rate of incidence of scalp metastases in patients who have undergone scalp 
cooling during chemotherapy is low (1.1%) and is not significantly different from 
the incidence of scalp metastases in patients who did not receive scalp cooling 
(1.2%) 
 there is not an increased rate of scalp metastases or a difference in survival compared 
to women who did not receive scalp cooling 
Given that the this study is specifically designed to investigate scalp cooling in breast 
cancer patients who are newly diagnosed with stage I – II breast cancer, and that patients 
with a history of scalp metastases, or with any other metastatic site are specifically 
excluded from enrollment, then it is considered that the risk relating to increased incidence 
of scalp metastases is low. In particular, this risk is outweighed by the potential clinical 
benefits to the patient associated with hair preservation through scalp cooling, given that 
up to 8% of women surveyed have reported that they would decline chemotherapy (and 
thus risk compromising their clinical outcome) because of the fear of chemotherapy-
induced hair loss. The above points notwithstanding, the sponsor has additionally 
committed to a program of ongoing, post-study 5 year follow-up of all participating 
subjects to check for the incidence of scalp metastases, with annual reports to the FDA. 
C.6 Psychosocial Effects of Scalp Cooling System for Alopecia Prevention in 
Patients with Cancer Undergoing Chemotherapy 
There is considerable evidence that the wide range of surgical, chemotherapeutic, and 
radiations therapies can leave permanent damage to organs and physiological functioning 
and disfigurement, across the different cancer diagnoses (Llescher LJ 1989).  
Consequently, body image has frequently been included in many studies of survivors in 
order to assess the long-term psychological impact of these injuries to the body (Sneeuw 
KCA 1992). The findings from several studies underscore the fundamental point that body 
image often reflects one’s physical ability to function as well as appearance. Further, 
poorer body image appears to be broadly related to ‘survivors’ coping with chronic 
uncertainty and frequent reminders of their past treatment ordeal (Sugarbaker PH 1982) 
(Kornblith 1998).  
D) Investigational Device Information 
D.1 Identification of the Device 
The investigational device which will be used in this study is the Orbis Paxman Hair Loss 
Prevention System.  This device is manufactured by: 
Paxman Coolers Limited 
International House 
Penistone Road 
Fenay Bridge 

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Huddersfield 
HD8 0LE 
United Kingdom 
There are two models of the Orbis Paxman Hair Loss Prevention System:   
 Orbis I 
 Orbis 2  
Only the Orbis 1 model will be used to provide the scalp cooling intervention in this study: 
Both models have the same performance characteristics – the only difference between 
them is that the Orbis I can be used with one patient at a time, whereas the Orbis 2 can be 
used with either one or two patients at a time. 
D.2 Description of the Device 
The Orbis Paxman Hair Loss Prevention System is a free-standing, electrically-powered, 
mobile refrigeration unit which circulates a refrigerated liquid coolant, at a pre-set 
temperature and flow rate, through a cooling cap which is attached to, and covers, the top 
of the patient’s head.  
A detailed description of the Orbis Paxman Hair Loss Prevention System, including the 
cooling caps and cap covers necessary for scalp cooling, is provided in Appendix A. 
The Orbis I device used in this study will use software version V 1.1.3 
D.3 Intended Use of the Device 
The Orbis Paxman Hair Loss Prevention System is intended by the manufacturer to be 
used for scalp cooling of patients who are receiving anthracycline- or taxane-based 
chemotherapy for the treatment of solid tumors, in order to reduce the risk of 
chemotherapy-induced alopecia.  
The use of the Orbis Paxman Hair Loss Prevention System is contraindicated in the 
following situations: 
 patients with hematological malignancies (leukemia and lymphomas) 
 patients with cold urticaria 
 patients with cold agglutinin disease 
 patients with manifest scalp metastases 
 patients who are scheduled for bone marrow ablation chemotherapy 
 patients who are scheduled to undergo skull irradiation 
D.4 Training and Experience Necessary for Use of the Device 
The Orbis Paxman Hair Loss Prevention System is a professional use device, intended for 
use by qualified oncology nursing staff.   
Successful results from scalp cooling are dependent on the correct fitting of the cooling cap 
to the patient’s head and on correct operation of the scalp cooling system. As such, all 
potential users of the Orbis Paxman Hair Loss Prevention System in this study will receive 
formal training in the setting up, use and post-scalp cooling procedures to be followed.  

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This training will take the form of Paxman Coolers’ standard device familiarity training 
which is provided to all new users. This training will be provided by Paxman Coolers 
qualified training personnel. A record will be maintained in the clinical study file of staff at 
each participating center who has received this training.   
Fitting of cooling caps, cooling cap covers and operation of the Orbis Paxman Hair Loss 
Prevention System for scalp cooling in this study will only be performed by staff who have 
received this formal training. All sites will receive the same training on use of the Orbis 
Paxman Hair Loss Prevention System.   
D.5 Device Traceability  
The Orbis Paxman Hair Loss Prevention Systems used in the study shall be traceable by 
the unique serial number printed on the manufacturer’s identification plate, which is 
affixed to the back of each unit. 
Cooling caps and cap covers shall both be traceable by the unique serial number affixed to 
each cap and cover. 
The Sponsor/Principal Investigator shall maintain a record of the serial numbers of every 
Orbis Paxman Hair Loss Prevention System, cooling cap and cap cover used in this study, 
stratified by participating center. Following completion of the last scalp cooling procedure 
in the study, every Orbis Paxman Hair Loss Prevention System, cooling cap and cap cover 
released for use in the study shall be recovered and returned to the device manufacturer’s 
manufacturing facility in the UK.  
E) Risk Benefit Analysis 
E.1 Anticipated Risks and Adverse Device Effects 
E.1.1 Efficacy Risks and Evaluation of Risk Benefit 
The only known efficacy risk is that scalp cooling with the Orbis Paxman Hair Loss 
Prevention System will not result in a reduced risk of chemotherapy-induced alopecia. 
Existing published clinical data for scalp cooling has demonstrated a variable success rate 
for hair preservation, which depends on a number of factors, including: 
 the type of scalp cooling device used 
 the chemotherapy regimen being used 
 the scalp cooling procedure used 
 patient compliance with the scalp cooling procedure 
The risk of failure to reduce chemotherapy-induced alopecia has been minimized in this 
study through the careful selection of a patient population (i.e. stage I – II breast cancer 
patients), chemotherapy regimens (anthracycline or taxane based) and scalp cooling 
procedure, for which there is evidence of acceptable levels of clinical effectiveness from 
published clinical studies which used equivalent continuous-cooling systems (i.e. the 
Paxman Scalp Cooling system). Moreover, the published clinical data demonstrate that 
scalp cooling using the Orbis Paxman Hair Loss Prevention System is generally well-
tolerated by patients, with only a few percent choosing to discontinue the treatment. 

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As such, the potential clinical benefits to the patient associated with hair preservation 
through scalp cooling using the Orbis Paxman Hair Loss Prevention System (i.e. 
improved quality of life through avoidance of negative body image and depression 
resulting from alopecia) outweigh the risk of failure to reduce chemotherapy-induced hair 
loss.  
E.1.2 Adverse Device Effects and Evaluation of Risk Benefit 
Common side effects reported with scalp cooling include headache, complaints of 
coldness, and/or uncomfortable sensations, heavy feeling of the head, transient 
lightheadedness, and neck pain (Massey 2004). Uncomfortable cold sensations and 
headaches were more frequently reported in studies when pre-cooled caps (which are 
chilled to -15 to -25°C) were used. Patients also complain about a heavy feeling of the 
head and transient light-headedness following cap removal.  In addition, patients 
experienced neck pain due to heavy weight of some cooling caps. Cold injuries have 
never been reported. A potential disadvantage of scalp cooling is the additional pre-
cooling and post-cooling time required which would have patients remain in the oncology 
clinic for a longer duration. 
Known short-term adverse effects anticipated to occur during or following scalp cooling 
with the Orbis Paxman Hair Loss Prevention System (based on clinical experience with 
scalp cooling, including that obtained from use of the previous PSC model of scalp 
cooling system manufactured by Paxman Coolers) are as follows: 
 complaints of coldness/cold-related discomfort (during scalp cooling) 
 headache, ranging from mild to severe (during and following scalp cooling) 
 forehead pain (during scalp cooling) resulting from pressure and tightness from the 
cooling cap 
 light-headedness or dizziness (during scalp cooling and/or following removal of the 
cooling cap at the end of scalp cooling) 
 complaints of uncomfortable sensations 
 heavy feeling of the head 
 transient lightheadedness 
 transient neck pain 
 cold injuries 
 nausea 
All of these adverse effects are transient in duration and of relatively low clinical 
significance. As such, the potential clinical benefits to the patient associated hair 
preservation through scalp cooling using the Orbis Paxman Hair Loss Prevention System 
(i.e. improved quality of life through avoidance of negative body image and depression 
resulting from alopecia) outweigh the risks associated with the known short-term adverse 
effects of scalp cooling. 
The only known potential long-term adverse effect associated with scalp cooling (and 
which could thus occur following use of the Orbis Paxman Hair Loss Prevention System) 
is an increased incidence of scalp metastases. At the time this concern was initially raised 

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during the late 1980s, there was little long-term data available to address this risk.  
However, since that time, a number of published studies extending out to more than 5 
years (described in section C.4) have identified that: 
 the rate of incidence of scalp metastases as the first site of recurrence in breast 
cancer patients is extremely low (2 out of 7,800 subjects, or 0.025%); 
 the rate of incidence of scalp metastases in breast cancer patients is generally low 
(up to 2.5%) and is always greatest in patients with multiple metastatic sites; 
 the rate of incidence of scalp metastases in patients who have undergone scalp 
cooling during chemotherapy is low (1.1%) and is not significantly different from 
the incidence of scalp metastases in patients who did not receive scalp cooling 
(1.2%); 
 there is not an increased rate of scalp metastases or a difference in survival compared 
to women who did not receive scalp cooling. 
Given that this study is specifically designed to investigate scalp cooling in breast cancer 
patients who are newly diagnosed with stage I – II breast cancer, and that patients with a 
history of scalp metastases or with any other metastatic site are specifically excluded 
from enrollment, then it is considered that the risk relating to increased incidence of scalp 
metastases is low. In particular, this risk is outweighed by the potential clinical benefits to 
the patient associated with hair preservation through scalp cooling, given that up to 8% of 
women surveyed have reported that they would decline chemotherapy (and thus risk 
compromising their clinical outcome) because of the fear of chemotherapy-induced hair 
loss. The above points notwithstanding, the sponsor has additionally committed to a 
program of ongoing, post-study 5 year follow-up of all participating subjects to check for 
the incidence of scalp metastases, with annual reports to the FDA. 
E.2 Additional Study Measures to Minimize Risk 
Every precaution will be taken pre-, during and post- procedure in order to minimize the 
risk of technical and procedural complications to patients.   
Examples of control measures implemented within the study design to achieve this aim 
include: 
 Selection of suitably qualified investigators and center personnel, who have suitable 
experience of the administration of the specified chemotherapy regimens to breast 
cancer patients 
 Investigators and center personnel to be trained by the device manufacturer, prior to 
the commencement of the study, in the safe and effective use of the Orbis Paxman 
Hair Loss Prevention System for its intended purpose, and in particular in the 
Instructions For Use supplied with the device. 
E.3 Risk Benefit Conclusion 
Taking into account all of the known risks related to the use of the Orbis Paxman Hair Loss 
Prevention System in this study for the reduction of chemotherapy-induced alopecia in 
breast cancer patients, together with the published clinical evidence concerning the safety 

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and effectiveness of scalp cooling, it is considered that the potential clinical benefits of 
successful hair preservation outweigh the clinical risks.   
F) Purpose 
Demonstrate that the Orbis Paxman Hair Loss Prevention System is safe and effective in 
reducing chemotherapy-induced alopecia in woman with breast cancer undergoing 
neoadjuvant or adjuvant chemotherapy.  
G) Hypothesis 
a)   The Orbis Paxman Hair Loss Prevention System will significantly reduce 
chemotherapy-induced alopecia in woman with breast cancer undergoing neoadjuvant 
or adjuvant chemotherapy; 
b)   Women who do not have clinically significant alopecia will have a better quality of life 
compared to those with alopecia and that the reduction of alopecia in breast cancer 
patients undergoing chemotherapy is associated with a lower risk of depression; 
c)   Scalp cooling using the Orbis Paxman Hair Loss Prevention System is not associated 
with any unanticipated, clinically significant short-term safety effects, and the scalp 
cooling procedure is well-tolerated by patients undergoing chemotherapy; 
d)   Scalp cooling using the Orbis Paxman Hair Loss Prevention System  does not present an 
increased risk of scalp metastases for patients newly diagnosed with stage I – II breast 
cancer 
Data collected in this clinical investigation will be used to support a premarket approval 
(PMA) application to the US FDA for approval to market the Orbis Paxman Hair Loss 
Prevention System in U.S.A., for the intended use of reduction of chemotherapy-induced 
alopecia in stage I – II breast cancer patients who are receiving neoadjuvant or adjuvant 
chemotherapy with anthracycline or taxane based drug regimens. 
H) Endpoints  
H.1 Primary Endpoints 
Efficacy: To compare success in hair preservation, between the Orbis Paxman Hair Loss 
Prevention System and control (no cooling) after 4 cycles of chemotherapy. Hair 
preservation is defined as CTCAE v4.0 grade 0 or 1 alopecia determined by the 
independent, blinded healthcare professional. All eligible study subjects who receive at 
least one cycle of chemotherapy will be evaluable for hair preservation response.    
Safety: To estimate the rate of significant cold-related anticipated adverse device effects 
(AADEs) specified in section M.3.5.  
H.2 Secondary Endpoints 
Efficacy: To compare the two groups on the basis of subject-perceived hair preservation 
(assessed by the CTCAE v4.0 and the alopecia pictorial tool), medical oncologist 
perceived hair preservation (assessed by the CTCAE v4.0), rate of use of wigs and/or head 

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wraps, and change in quality of life as assessed by the EORTC QLQ-30, Hospital Anxiety 
& Depression Scale (HADS), and Body Image Scale (BIS).  
Safety:  To compare the two groups on the basis of subject reported comfort, rate of early 
scalp metastases and survival.  
I) 
Participant Selection 
I.1 
Inclusion Criteria 
 New diagnosis of breast cancer stage I-II 
 Planning to undergo neoadjuvant or adjuvant chemotherapy with curative intent   
 Chemotherapy must be planned for at least 4 cycles of full-dose anthracycline or 
taxane based chemotherapy regimen,    
o Defined as one of the following regimens: 
 Adriamycin 60 mg/m2 with cyclophosphamide 600 mg/m2 
 Epirubicin 90-100 mg/m2 with cyclophosphamide 600 mg/m2 
 Doxorubicin 50 mg/m2 with 5-Fluroruacil 500 mg/m2 and 
cyclophosphamide 500 mg/m2 
 Paclitaxel 80-90 mg/m2 weekly (every 3 weeks constitutes a cycle), or 175 
mg/m2 every 2-3 weeks as a single agent 
 Paclitaxel 80-90 mg/m2 weekly with carboplatin AUC of 6 every 3 weeks 
 Paclitaxel 80-90 mg/m2 weekly with carboplatin AUC of 2 weekly 
 Docetaxel 100 mg/m2 as a single agent 
 Docetaxel 75-100 mg/m2 with pertuzumab and trastuzumab at standard 
doses 
 Docetaxel 75 mg/m2 with cyclophosphamide 600 mg/m2  
 Docetaxel 75 mg/m2 with carboplatin AUC of 6  
o Concurrent trastuzumab and/or pertuzumab at standard doses is allowed.  
o Administration of chemotherapy on a dose dense schedule is allowed as 
clinically indicated. 
o Subjects who have an allergic reaction to taxane-based chemotherapy are 
allowed to continue on trial with paclitaxel protein-bound (Abraxane) 80 mg/m2 
– 100 mg/m2 weekly (every 3 weeks constitutes a cycle), or 200 mg/m2 – 260 
mg/m2 every 3 weeks as a single agent or in combination with 
cyclophosphamide 600 mg/m2 to complete the course of chemotherapy that was 
originally planned. 
 Subjects must have TSH collected within 1 year prior to treatment and found within 
acceptable limits (defined under exclusion criteria). 
 If subject has a history of diabetes, hemoglobin A1c  must be drawn within 3 months 
prior to treatment and found to be within acceptable limits (defined under exclusion 
criteria). 
 CBC and CMP should be done within 4 weeks prior to treatment and found to be 
within acceptable limits (defined under exclusion criteria). 

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I.2 Exclusion Criteria 
 Stage III-IV breast cancer or any other concurrent malignancy including 
hematological malignancies (i.e. leukemia or lymphoma) 
 Baseline alopecia (defined CTCAE v4.0 grade > 0, see Appendix B) 
 Subjects with cold agglutinin disease or cold urticaria 
 Subjects who are scheduled for bone marrow ablation chemotherapy  
 Subjects receiving chemotherapy with concurrent anthracycline and taxane (AT or 
TAC)  
 Male gender 
 Age ≥ 70 years 
 Personal history of migraines, cluster or tension headaches as defined as actual 
medical diagnosis by a physician and/ or prescribed medications.  If personal history 
of migraines was related to a past medical problem that is now resolved, subject may 
go on study at the discretion of the Principal Investigator.  
 Elevated liver enzymes or bilirubin defined as 3 times the upper limits of normal 
 Serum Albumin < 3.0 
 Subjects with anemia (defined as a hemoglobin < 10) 
 Abnormal TSH, AND: 
o If high, abnormal free T4 defined as out of normal limits 
o If low, abnormal free T4 or T3 defined as out of normal limits 
 Subjects who have diabetes with a Hgb A1c > 7 
 Subjects who have lichen planus or lupus 
 Subjects who are underweight (defined as a BMI < 17.5) 
 Subjects who have had previous chemotherapy exposure 
I.3 Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards 
age or race in the clinical trial outlined. 
J) Study Design 
J.1 General Aspects of Study Design 
This is a prospective, randomized, controlled, multi-center, pivotal clinical investigation to 
be conducted in up to 10 centers within the USA which are routinely engaged in the 
administration of adjuvant or neoadjuvant chemotherapy to women with stage I – II breast 
cancer. 
This is a non-blinded, parallel group (no intervention control), clinical outcome study. 

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The study will require 213 response evaluable subjects and ~325 consented patients  (see 
section P.2 for sample size justification).  Subjects will be randomized to either scalp 
cooling or non-scalp cooling (control) on a 2:1 basis. 
All subjects randomized to scalp cooling will undergo scalp cooling using the Orbis 
Paxman Hair Loss Prevention System prior to, during and after administration of each 
chemotherapy session, for 4 complete cycles of full-dose anthracycline or taxane based 
chemotherapy.   
In each case the scalp cooling protocol followed will comprise: 
 Minimum 30 minutes pre-infusion cooling 
 Cooling for the duration of chemotherapy infusion 
 Minimum 90 minutes post-infusion cooling 
Each subject will be followed up 2-3 weeks after completion of each chemotherapy cycle, 
and 2-4 weeks after completion of the final chemotherapy cycle. Each subject will also be 
followed for 5 years after chemotherapy for evaluation of secondary safety endpoints.   
J.2 Center Selection 
Participating centers will be chosen based on their experience in conducting clinical 
studies, their experience in administering neoadjuvant or adjuvant chemotherapy to breast 
cancer patients, excellent academic and medical reputation as well as their ability to recruit 
a robust study population. 
Each participating center is required to have a study coordinator to assist the Principal 
Investigator. In addition, each center must have the time and resources available to 
participate in the study and fulfill their obligations under this protocol. 
J.3 Lead Center 
Baylor College of Medicine will be designated the Lead Center for this multi-center study 
and is the place of work of the Sponsor/Principal Investigator. 
The Lead Center will be responsible for the acquisition of all regulatory documentation 
prior to the activation of all other participating centers and will be responsible for assuring 
the quality and accuracy of data provided by the other participating centers.   
J.4 Other Participating Centers 
All participating centers are responsible for providing all required documentation to the 
Lead Center. 
J.5 Study Population 
Women with stage I-II breast cancer who will undergo either neoadjuvant or adjuvant 
chemotherapy. 

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J.6 Subject Screening & Enrollment 
Screening and enrollment of each individual subject will be performed prior to the subject 
receiving her first chemotherapy infusion under this protocol. 
J.6.1 Screening Procedure 
The screening procedure is intended to determine whether or not a patient meets the 
eligibility criteria for inclusion in the study. All screened patients will be asked to sign the 
informed consent form.  
 
J.6.2 Enrollment 
A subject will be considered enrolled in the study when all of the following three steps are 
completed: 
 Signed informed consent is obtained. 
 Based on the screening assessment, it is determined that the subject meets all of the 
specified inclusion criteria and none of the specified exclusion criteria. 
 Subject is randomized. 
Eligible subjects will be randomized and entered on study centrally at the Lead Center by 
the Study Monitor or designee. All sites will send the applicable eligibility source 
documents to the Study Monitor via email (otte@bcm.edu) or fax (713-798-8884) to verify 
eligibility.  
Following randomization, subjects should begin protocol treatment within 4 weeks.  
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a subject does not receive protocol therapy following registration within 
the allowed time period, the subject will become ineligible and will be withdrawn from the 
study, and will be inevaluable for efficacy and safety. 
J.7 Subject Identification 
Subjects will be identified using unique subject identification numbers. Subject 
identification numbers will be assigned centrally by the Study Monitor after a subject signs 
the informed consent form and will be assigned consecutively, starting at 1. All sites must 
contact the Study Monitor to receive a subject identification number for all subjects who 
sign consent. 
K) Study Procedures 
K.1 Randomization Procedure 
To avoid bias, subjects included in the study will be randomly assigned to either the 
intervention (scalp cooling) group or to the control (no scalp cooling). 
Randomization will be performed prior to performing any procedures and will use the 
permuted block method. Randomization will be stratified by major chemotherapy type and 
center. 

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K.2 Baseline Assessment 
All subjects who have satisfied the enrollment criteria will be subjected to baseline 
assessment prior to performing any study procedures. All information collected will be 
recorded for each subject. 
The following baseline data will be collected for all subjects prior to performing any study 
procedures: 
 Subject demographics (date of birth, weight, height, race, ethnicity) 
 Clinical information (stage of breast cancer, scheduled chemotherapy regimen) 
 History & Physical including menopausal status, and history of hormone 
replacement therapy and oral contraceptive use 
 ECOG Performance Status 
 Current medication(s) 
 Baseline EORTC QLQ-C30, HADS, and BIS Questionnaires  
 Baseline Alopecia Score assessed by the subject’s oncologist/nurse practitioner and 
the blinded healthcare provider 
 Baseline photographs to include the following views of the subject’s head: front 
hairline, back, top, left and right 
K.3 Procedures 
Subjects randomized to the scalp cooling group will undergo the procedures described in 
sections K.3.1 through K.3.3. 
Subjects randomized to the control (no scalp cooling) group will not use the device and 
will undergo the procedures described in section K.3.4. 
K.3.1 Preparation for Scalp Cooling 
Effective scalp cooling relies on good contact between the inner surfaces of the cooling 
cap and the patient’s scalp. As such, prior to the first scalp cooling procedure, each 
subject must undergo a cooling cap fitting with a healthcare professional trained in use of 
the Orbis Scalp Cooler. This fitting process is necessary to ensure that the most 
appropriate size of cooling cap is selected. For optimum cooling, the cap must both fit 
snugly onto the head at the crown and also cover the entire scalp area down to the 
hairline. Effective scalp cooling over the entire scalp is only achieved with the 
combination of correct size of cooling cap and correct size of cooling cap cover; the 
cover – with its adjustable straps – is necessary to ensure that the cooling cap is 
maintained securely and comfortably in the correct position on the subject’s head for the 
duration of the scalp cooling process. For some subjects, the cap fitting process will 
simply involve the selection of the most appropriate size cooling cap and corresponding 
cap cover. For subjects whose head size does not correspond to one of the five available 
cooling cap sizes, a combination of the larger size cooling cap and smaller size cover is 
used to obtain the required cooling cap contact with the scalp. 

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Selection and fitting of the optimum size of cooling cap and cooling cap cover for each 
subject will be performed in accordance with the instructions provided in the user manual 
supplied with the Orbis Paxman Hair Loss Prevention System. The user manual describes 
the use of both pre-cooled and warm caps.  Either option can be chosen for patient 
tolerance.   
A record will be maintained in the study file at each center of the size of cooling cap and 
cap cover selected for each subject at that center as well as if the cap was pre-cooled or 
warm, based on the above process. The Principal Investigator will retain a copy of this 
record from each participating center. 
K.3.2 Scalp Cooling 
Scalp cooling will occur with each dose of chemotherapy. Prior to scalp cooling, the 
cooling cap is always attached to the subject’s head with the cap disconnected from the 
coolant lines. Before placing the cooling cap on the subject’s head, it is placed inside the 
appropriate size of cap cover and manually pressed into position against the inner surface 
of the cover, such that the entire cooling cap is within the cover. The cooling cap and 
cover are then placed onto the study participant’s head such that the cap is on straight and 
covers the subject’s entire scalp to the hairline. The cover chin-strap and circumferential 
straps are then adjusted to achieve a snug fit of the cooling cap to the scalp, which is also 
comfortable for the subject. The healthcare professional then checks the fit of the cooling 
cap to ensure good contact all over the scalp – particularly at the crown and hairline.  
Once this is done, the subject is ready to begin scalp cooling and the cooling cap outward 
and return tube quick release connectors are connected to the corresponding connectors 
on the distal end of the coolant lines. 
Powering on the system using the power switch on the back of the main unit activates the 
refrigeration unit, which then reduces the temperature of the coolant in the coolant tank to 
between -4.0°C and -5.0°C through standard refrigeration technology. Once this 
temperature is attained, the coolant temperature in the coolant tank is maintained within 
this temperature range by the system software, which monitors the coolant temperature 
from an electronic sensor in the reservoir and electronically switches off the refrigeration 
compressor when the temperature reads -4.0°C and switches on the compressor when the 
sensor temperature reads -3.0°C. 
Once the pre-set coolant temperature is reached, the pump is activated using a separate 
switch on the rear of the main unit. This causes the refrigerated coolant to be pumped 
from the reservoir at a pre-set constant flow rate via the outward coolant line through the 
cooling cap and back to the reservoir via the return coolant line. Coolant flow rate is 
monitored via flow turbines located in the return tube. In the event of a low coolant flow 
rate (< 0.6 L/min) being detected (which may indicate coolant loss, or kinking of one of 
the coolant lines), the software displays a warning message on the touch screen and 
sounds a buzzer to alert the user. 
The touch screen controller provides feedback to the user concerning the status of the 
Orbis Scalp Cooler as it relates to achievement of the pre-set temperature of the coolant, 
operation of the recirculation pump and connection of a cooling cap to the system. The 
software also provides a countdown timer function which allows the user to set a post 

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infusion cooling time. At the end of the pre-set time, a message is displayed on the touch 
screen and a buzzer sounds to alert the user to the fact that the scalp cooling time is 
complete. 
Following completion of scalp cooling, the recirculation pump is switched off and the 
cooling cap and cover are then removed from the subject’s head. The device will be worn 
for a standardized pre-cooling time of at least 30 minutes, during chemotherapy, and a 
standardized post-cooling time of at least 90 minutes. After the post-cooling time, the cap 
will be loosened and left in place for at least 5 minutes to allow the cap to warm up 
before removal. In addition, the subject will be given at least 5 additional minutes to 
acclimatize before being asked to stand up.   
Administration of the chemotherapy agent will be performed according to the standard 
procedure at each center for the intravenous infusion of the chemotherapy regimen 
concerned, using the recommended volume and infusion rate for the specific 
chemotherapy regimen. 
If the subject is being treated with a regimen that includes trastuzumab and/or 
pertuzumab, these can be administered during the 90 minute post-cooling phase, as they 
are not chemotherapy drugs. 
For each subject who undergoes scalp cooling, a record will be maintained at each 
participating center of the details of each scalp cooling procedure. This record will 
include the following details: 
 subject ID 
 date of treatment 
 serial number of the Orbis Paxman Hair Loss Prevention System used for scalp 
cooling 
 size and serial number of the cooling cap and cooling cap cover used for scalp 
cooling 
 the name of the healthcare professional who fitted the cap and cap cover, who 
operated the scalp cooling device and who removed the cap and cap cover at the end 
of the scalp cooling process 
 start and finish time of the pre-infusion scalp cooling, of the infusion scalp cooling 
and of the post-infusion scalp cooling for each use 
 side effects reported by the subject during scalp cooling 
 the time and duration of, and the reason for, any temporary, or permanent 
interruption to the scalp cooling process 
 the time of occurrence of any alarms or warning messages from the Orbis Paxman 
Hair Loss Prevention System used for scalp cooling 
 the time and duration of, and the reason for, any temporary, or permanent 
interruption to the chemotherapy infusion process 
 if a subject withdraws from the study, the reason for withdrawal 

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K.3.3 Visit Assessments 
At baseline and after each cycle, subjects will have an alopecia assessment by a delegated 
physician or nurse practitioner and a second independent healthcare provider who is 
blinded to study treatment. The independent healthcare provider is a healthcare 
professional (physician, nurse, medical assistant, or research coordinator) who is trained 
in alopecia assessment, who is fully independent from the study, and who is completely 
blinded to the subject’s treatment. This alopecia assessment will be made using the 
CTCAE v4.0 grading system. The independent observer will assess the subject either 
before or after the subject sees the clinician. By signing the consent, the clinician and the 
subject agree not to tell the independent observer the subject’s randomization assignment. 
The alopecia assessment will always be performed prior to subjects receiving their next 
cycle of chemotherapy. Subjects will also perform their own alopecia assessment and be 
asked about wig and scarf use after each cycle using the CTCAE v4.0 and the alopecia 
pictorial tool (see Appendix B). 
Photographs of the heads of the first 25 subjects’ enrolled from each site who complete at 
least 1 cycle of chemotherapy will be taken at each alopecia assessment (until the subject 
develops grade 2 alopecia), and these photographs will be included in the final study 
report. For subjects enrolled after these 25 subjects, photographs will only be taken at 
baseline, after 4 cycles, and after completion of chemotherapy (if receiving more than 4 
cycles). If a subject develops grade 2 alopecia at a visit prior to the post-Cycle 4 or post-
completion visit, photographs should be taken at the visit and do not need to be taken 
from that point forward. 
These photographs will be taken with a digital camera or camera phone in a well-lit exam 
room with the subject sitting and the photographer standing. There will be 5 photographs 
taken which will include the following views: front hairline taken 8-12” from the subject, 
right side & left side taken 15-25” from the subject, back of the head taken 15-25” from 
the subject, and top of the head taken 8-12” from the subject. 
The EORTC QLQ-C30, HADS, and BIS questionnaires will be administered at baseline, 
after 4 cycles of chemotherapy and after completion of chemotherapy (if subject is 
receiving more than 4 cycles). Immediately after each cycle, subjects will be 
administered a comfort scale after the scalp cooling device has been removed.   
Duration of device use will depend on the type of chemotherapy the subject is 
receiving, if the subject is assessed as having grade 2 alopecia during the study, and 
will occur with each cycle of chemotherapy (maximum of 8 cycles). 
Subjects who develop grade 2 alopecia (determined by the blinded independent 
provider, the delegated physician/nurse practitioner and the subject) will discontinue 
alopecia assessments at subsequent visits. Photographs will only continue if the subject 
elects to continue to wear the device after development of grade 2 alopecia.   
K.3.4 Control Group Procedures 
Administration of the chemotherapy agent will be performed according to the standard 
procedure at each center for the intravenous infusion of the chemotherapy regimen 
concerned, using the recommended volume and infusion rate for the specific chemotherapy 
regimen. 

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At baseline and after each cycle, subjects will have an alopecia assessment by a physician 
or nurse practitioner and a second healthcare provider who is blinded to study treatment.  
The independent healthcare provider is a healthcare professional (physician, nurse, medical 
assistant or research coordinator) who is trained in alopecia assessment, who is fully 
independent from the study, and who is completely blinded to the subject’s treatment. This 
alopecia assessment will be made using the CTCAE v4.0 grading system.  The independent 
observer will assess the subject either before or after the subject sees the clinician. By 
signing the consent, the clinician and the subject agree not to tell the independent observer 
the subject’s randomization assignment. The alopecia assessment will always be performed 
prior to subjects receiving their next cycle of chemotherapy. Subjects will also perform 
their own alopecia assessment and be asked about wig and scarf use after each cycle using 
the CTCAE v4.0 and the alopecia pictorial tool (see Appendix B). 
Photographs of the heads of the first 25 subjects’ enrolled from each site who complete at 
least 1 cycle of chemotherapy will be taken at each alopecia assessment (until the subject 
develops grade 2 alopecia), and these photographs will be included in the final study report. 
For subjects enrolled after these 25 subjects, photographs will only be taken at baseline, 
after 4 cycles, and after completion of chemotherapy (if receiving more than 4 cycles). If a 
subject develops grade 2 alopecia at a visit prior to the post-Cycle 4 or post-completion 
visit, photographs should be taken at the visit and do not need to be taken from that point 
forward. 
These photographs will be taken with a digital camera or camera phone in a well-lit exam 
room with the subject sitting and the photographer standing. There will be 5 photographs 
taken which will include the following views: front hairline taken 8-12” from the subject, 
right side and left side taken 15-25” from the subject, back of the head taken 15-25” from 
the subject, and top of the head taken 8-12” from the subject. 
The EORTC QLQ-C30, HADS, and BIS questionnaires will be administered at baseline, 
after 4 cycles of chemotherapy and after completion of chemotherapy (if receiving more 
than 4 cycles). 
Subjects who develop grade 2 alopecia (determined by the blinded independent provider, 
the delegated physician/nurse practitioner and the subject) will discontinue alopecia 
assessments and photographs at subsequent visits.   
K.4 Concomitant Treatment and Supportive Care Guidelines 
Subjects are allowed to be on other research studies that do not have additional 
chemotherapeutic agents that are associated with alopecia. 
K.5 Duration of Follow-Up  
Subjects will be followed 2-4 weeks after completion of chemotherapy when the final 
alopecia assessment will occur (if grade 2 alopecia has not been reached) and the 
questionnaires will be administered. Subjects will be followed post-study for 5 years 
during routine clinic follow-up for survival, recurrence and site of recurrence. 

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K.6 Criteria for Removal from Study  
The reasons for removal from the study include: 
 
Subject withdraws consent for follow-up 
 
Subject is lost to follow-up 
 
Study is terminated for any reason 
 
The subject’s best interest as determined by the treating investigator with approval 
from the Principal Investigator 
Subjects who complete at least one cycle of chemotherapy will be included in the overall 
evaluation of response (intent-to-treat analysis). All reasons for removal from the study 
should be documented clearly in the medical record.  
K.7 Criteria and Procedures for Discontinuation of Treatment 
The reasons for discontinuation of protocol treatment include: 
 
Non-compliance with the study protocol, including, but not limited to: not attending 
the majority of scheduled visits, and not using the device for at least 80% of the 
prescribed time on the cooling device (defined as time device worn divided by the 
sum of 30 minute pre-cooling time + duration of chemotherapy + 90 minute post-
cooling time) without medical reason. The Protocol Chair will determine when non-
compliance should lead to removal from study. 
 
Unacceptable major adverse events. 
 
At subject’s own request. 
 
Study is closed for any reason.  
 
Development of CTCAE v4.0 grade 2 alopecia, as assessed by the delegated 
physician/nurse practitioner, the blinded healthcare provider, and the subject. 
 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the opinion of the treating 
investigator. 
If a subject is assessed as having grade 2 alopecia (by the physician/nurse 
practitioner, blinded provider and the subject), or if the subject decides she no 
longer wants to participate in treatment with the device, the device will be 
discontinued. The required alopecia assessments and photographs will be 
performed on the day of determining grade 2 alopecia, but should not be 
performed at subsequent visits. All subjects (both cooling and non-cooling), 
regardless of whether or not treatment was discontinued early, must complete the 
QOL questionnaires after Cycle 4 and after completion of chemotherapy (if 
receiving more than 4 cycles). 
Subjects who discontinue treatment will still be included in the overall evaluation 
of response (intent-to-treat analysis) if they have completed at least one cycle of 
chemotherapy prior to withdrawal/discontinuation. 

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K.8 Delays 
If a subject’s chemotherapy is delayed because of toxicities from chemotherapy (i.e. 
neutropenic fever or infection) she will be allowed to continue on study. Chemotherapy 
delays do routinely occur because of chemotherapy toxicities. When the subject requires a 
delay in chemotherapy due to toxicities and when chemotherapy is safe to resume will be 
left to the discretion of the subject’s physician. Delays > 2 weeks will have to be approved 
by the Sponsor/Principal Investigator. 

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L) Study Calendar 
Parameter 
Pre-
Study1 
Day 1 of each chemotherapy cycle 
2-3 weeks AFTER each chemotherapy 
cycle2, 9 
Year  
1, 2, 3, 
4, 5 
1 
2 
3 
4 
5-83 
1 
2 
3 
410 
5-83, 10 
History & Physical and Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physician/nurse practitioner and blinded provider: 
Alopecia Assessment8 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Patient: Alopecia Assessment and Wig/Scarf Use 
Questions8 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Photographs7, 8 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Laboratory Assessments (TSH1*, Hgb A1c1*, CBC, CMP) 
X 
 
 
 
 
 
 
 
 
 
 
 
Questionnaires: EORTC QLQ-C30, HADS, BIS 
X 
 
 
 
 
 
 
 
 
X 
X6 
 
Subjects 
Randomized to 
Cooling Arm 
Only 
 
Cooling Cap Fitting  
X 
 
 
 
 
 
 
 
 
 
 
 
Paxman Cooling System Administration4 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Comfort Scale5 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Long Term Follow-Up: Survival, Recurrence, Site of First 
Recurrence (if applicable) 
 
 
 
 
 
 
 
 
 
 
 
X 
1. Within 4 weeks prior to starting treatment, unless otherwise specified: *TSH within 1 year prior to treatment, Hgb A1c within 3 months prior to treatment (if history of diabetes). 
2. If chemotherapy is delayed due to toxicities from chemotherapy, this will be done with the next cycle once chemotherapy is resumed. 
3. If the subject is receiving more than 4 cycles.  
4. The Orbis Paxman Hair Loss Prevention System will be used with each dose of chemotherapy. The pre-cooling time is at least 30 minutes and the post-cooling time is at least 90 minutes.   
5. A comfort scale will be administered after the device is removed with each cycle (see Appendix C). 
6. Only after last cycle of chemotherapy if receiving more than 4 cycles. 
7. Photographs will be taken of ALL subjects at baseline, after 4 cycles, and after completion of chemotherapy (if receiving more than 4 cycles).  Additionally, photographs of the first 25 subjects enrolled from each site who 
complete at least 1 cycle will be taken at each Alopecia Assessment. 
8. Alopecia Assessments and photographs should be discontinued after a subject is determined to have Grade 2 alopecia by the clinician, the blinded provider AND the subject. All assessments and photographs will be done on 
the day of determining Grade 2 alopecia, but should not be done at subsequent visits. 
9. This visit typically occurs on Day 1 of each cycle (e.g. Post-Cycle 2 visit = Cycle 3 visit). 
10. If subject is only receiving 4 cycles, Post-Cycle 4 visit should occur 2-4 weeks after Cycle 4. If subject is receiving more than 4 cycles, the End of Treatment visit should occur 2-4 weeks after the final cycle of chemotherapy.     
 

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M) Adverse Events 
M.1 Reportable Adverse Events 
Any adverse events that are possibly, probably or definitely related to the Orbis Paxman 
Hair Loss Prevention System will be reported to the Sponsor/Principal Investigator via the 
Adverse Event case report form. If the related event is serious, the study will be put on 
hold while the toxicity is investigated and until the safety of the device is ensured.   
Any adverse events or toxicities that are determined to be related to the chemotherapy 
should NOT be reported unless they are unusual (i.e. not listed in the chemotherapy 
package insert).   
M.2 Adverse Event Reporting Requirements 
M.2.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) that is available at 
http://ctep.cancer.gov/reporting//ctc.html for the grading of safety with the exception of 
the comfort scale (see Appendix C).  
Information on all adverse events, whether reported by the subject, directly observed, or 
detected by physical examination or other means, will be collected, recorded, followed 
and reported as described in the following sections.  
Adverse events experienced by subjects will be collected and reported from initiation of 
study device, throughout the study, and within 30 days of the last use of study device. 
Subjects who experience an ongoing adverse event related to a study procedure and/or 
study medication beyond 30 days will continue to be contacted by a member of the study 
team until the event is resolved, stabilized, or determined to be irreversible by the 
participating investigator.  
Subjects should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The Investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a subject has discontinued or terminated study participation that may 
reasonably be related to the study.  
M.3 Adverse Event Definitions 
M.3.1 Adverse Event (AE) 
An adverse event is any undesirable sign, symptom, medical condition or experience that 
develops or worsens in severity after starting the first device treatment, even if the event 
is not considered to be related to the device. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  

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All reportable adverse events which occur during this clinical study will be graded as 
shown in table 2. Grades refer to the severity of the AE. The CTCAE displays grades 1 
through 5 with unique clinical descriptions of severity for each AE based on this general 
guideline.   
 
Table 2: Grading of Severity of Adverse Events  
 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental 
Activities of Daily Living (ADLs)* 
Grade 3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care 
ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated 
Grade 5 
Death related to AE 
 
 *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
  
 
The relationship of the adverse event to the device which is the subject of this clinical 
investigation will be graded as shown in Table 3. 
 
Table 3: Expectedness & Attribution 
Expectedness 
Expected 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 
Unexpected 
An adverse event is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. 
 
 
 
Attribution 
Attribution is the relationship between an adverse event and the study treatment. 
Attribution will be assigned as follows: 
 
Definite 
The AE is clearly related to the study device 
Probable 
The AE is likely related to the study device 

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Possible 
The AE may be related to the study device 
Unlikely 
The AE is doubtfully related to the study device 
Unrelated 
The AE is clearly NOT related to the study device 
M.3.2 Serious Adverse Event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition which:  
 is fatal or life-threatening; 
 requires or prolongs inpatient hospitalization; 
 results in persistent or significant disability/incapacity; 
 constitutes a congenital anomaly or birth defect; or 
 jeopardizes the subject and requires medical or surgical intervention to prevent one 
of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 respite care 
M.3.3 Adverse Device Effect (ADE) 
This is an adverse event which is possibly, probably, or definitely related to the study 
device.  This includes any event which occurred due to: 
 insufficiency or inadequacy in the instructions for use provided with the device; 
 installation and/or use of the device; 
 malfunction of the device; or, 
 user error. 
M.3.4 Serious Adverse Device Effect (SADE) 
This is an adverse event related to the study device which: 
 has led to the death a patient, user, or other person 
 has led to a serious deterioration in the health of a patient, user, or other person 
 could have led to the death, or serious deterioration in the health, of a patient, user, 
or other person, if fortunate circumstances or the intervention of healthcare 
personnel had not prevented it, and might lead to this if the same event occurred 
again 

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M.3.5 Anticipated Adverse Device Effects (AADE) 
The following complications are known to be associated with use of the Orbis Paxman 
Hair Loss Prevention System for the management of chemotherapy-induced alopecia: 
 cold discomfort (during scalp cooling) described in Appendix C 
 headache (during and after scalp cooling) described in CTCAE v4.0 
 forehead pain (during scalp cooling) caused by pressure and tightness of the cooling 
cap described in CTCAE v4.0 
 dizziness or light-headedness (during scalp cooling) described in CTCAE v4.0 
 nausea described in CTCAE v4.0 
M.3.6 Unanticipated Adverse Device Effect (UADE) 
This is any adverse device effect which was not previously identified in the device 
manufacturer’s risk management documentation for the design and use of the Orbis 
Paxman Hair Loss Prevention System for the management of chemotherapy-induced 
alopecia, and was not identified in the informed consent form for this study. 
M.4 Adverse Event Reporting 
Information on all reportable adverse events (AEs, SAEs, ADEs, SADEs and UADEs) 
experienced by subjects during the course of the study, from initiation of study treatment 
up until final follow-up assessment at 3 weeks ± 1 week after the last cycle of 
chemotherapy, will be collected, recorded and reported. It is the responsibility of the 
Investigator at the center where the event occurred to ensure that all event information is 
recorded on the relevant case report form (CRF) and entered accurately into the electronic 
database. 
Details recorded should include the following information: 
 study center identifier 
 description of the event 
 the dates of the onset and resolution of the event 
 any action taken and the outcome of this action 
 the relationship of the event to the device 
 whether or not the adverse event meets the criteria for designation as ‘serious’ 
 whether the adverse events arises from insufficiencies in the IFU 
 whether the adverse event arises from user error 
Subjects who experience an ongoing AE, SAE, ADE, SADE or UADE related to the study 
device will continue to be contacted by a member of the study team until the event is 
resolved, stabilized, or determined to be irreversible by the participating Investigator.  
Additionally, subjects will be instructed to report all serious post-study AEs, SAEs, ADEs, 
SADEs and UADEs that might reasonably be related to participation in this study, 
specifically to the device use.  

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An adverse event may be detected by a physical examination or may be volunteered by 
subjects, elicited from questioning by an Investigator or designee, or collected via 
observation by an Investigator. The Investigator will determine whether or not the event is 
related to the device and/or procedure, and whether or not the event meets the criteria for 
designation as ‘serious.’    
In the event of an adverse event, the Investigator and/or other professional personnel in 
attendance will undertake whatever therapy is indicated by established standards of care 
that will protect the life and health of the subject. 
All reportable serious adverse events, serious adverse device effects and unanticipated 
adverse device effects must be fully recorded and notified to the Sponsor/Principal 
Investigator within one (1) working day after the Investigator at any other participating 
center becomes aware of the event. The nature and causes of the problem and any 
treatment that is administered will be reported on the relevant form.  
The Sponsor/Principal Investigator will be responsible for immediate reporting of SAEs, 
SADEs and UADEs to the DSMB, IRBs of the participating centers, to the US FDA and to 
the device manufacturer, within one (1) working day of becoming aware of the event.  
SAEs, SADEs and UADEs should be reported to the US FDA, either using a MedWatch 
form (ref. 3500) available on the FDA website at 
https://www.accessdata.fda.gov/scripts/medwatch/, or by telephone (1-800-FDA-1088), or 
by fax (1-800-FDA-0178) using the form available at 
http://www.fda.gov/medwatch/report/hcp.htm).  The Lead Center will be responsible for 
correspondence with the FDA regarding adverse events for all participating centers. 
It is the responsibility of the Sponsor/Principal Investigator, in conjunction with the device 
manufacturer’s appointed clinical and regulatory advisors, to conduct an evaluation of each 
reportable adverse event which occurs. If the event is determined to be an SAE, SADE or 
UADE, the Sponsor/Principal Investigator will notify all participating Investigators within 
five (5) working days of becoming aware of the event. 
If it is determined through the evaluation process that an ADE presents an unreasonable 
risk to the subject population, study enrollment will be terminated. Termination will occur 
no later than five (5) working days after the determination is made, and no later than 
fifteen (15) working days after initial notification of the ADE. A terminated investigation 
will not resume at any participating center without approval from the relevant IRB and 
from the US FDA. 
The Sponsor/Principal Investigator, will ensure that all AEs and ADEs are reported and 
reviewed with the clinical investigator(s) and, where appropriate, that all SAEs and all 
SADEs are reported to the relevant IRBs and to the US FDA, in accordance with relevant 
national reporting requirements. 
N) Informed Consent 
Written informed consent will be obtained for all patients who are potential study candidates 
before any study-specific tests or procedures are performed. The subject will be given 
adequate time to consider to the risks associated with participation in any study procedures 
and to ask any questions the subject may have.  The subject (or the subject’s legal 

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40 
 
representative) must sign the IRB-approved informed consent form prior to participation in 
the study. Failure to provide informed consent renders the subject ineligible for the study. 
For each subject consented to the study, the original signed informed consent form will be 
retained on file at the center where the subject was consented; a copy of this form will also 
be given to the subject. Case histories (subject charts) will also document that informed 
consent was obtained prior to the subject’s participation in the study. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction with 
the consent document) will include a subject’s authorization to release medical information 
to the study sponsor or allow the sponsor, and/or the US FDA and/or the IRB of any of the 
participating centers to access study subjects’ medical information that includes all hospital 
records relevant to the study, including study subjects’ medical history. 
O) Investigation Administration 
O.1 Ethical Conduct 
The study will be conducted in accordance with Good Clinical Practice, as defined in ISO 
14155:2011 and in the US Code of Federal Regulations (21 CFR §50) governing the 
protection of human subjects and the obligations of clinical investigators, and in 
accordance with the requirements of the Declaration of Helsinki concerning the protection 
of human subjects. 
The Sponsor/Principal Investigator is responsible for the ongoing safety of the device and 
will promptly notify all participating investigators, the DSMB, the IRBs and the US FDA 
of all findings that could adversely affect the safety of subjects, affect the conduct of the 
study, or alter the IRB’s and US FDA’s approval for the study. 
O.2 Regulatory Requirements 
This study will be conducted in compliance with the Code of Federal Regulations 
concerning clinical investigation in USA with non-approved medical devices (ref. 21 CFR 
§812), as well as Good Clinical Practice (GCP) for the clinical investigation of medical 
devices, as defined in ISO 14155:2011.   
All participating centers are required to maintain at the site the appropriate regulatory and 
study documentation, which documentation should be made available for inspection by the 
Lead Center and /or the US regulatory authorities, on request. 
O.2.1 Study Approvals Prior to Study Initiation 
The protocol and supporting documents for this study will be reviewed and approved by 
the appropriately constituted IRB of each participating center and by the US FDA, prior 
to study initiation. 
All reviews and approvals will be in accordance with Good Clinical Practice (GCP) as 
contained in ISO 14155:2011, and the Declaration of Helsinki. 
Prior to study initiation, the Sponsor must have received: 

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 a letter from the IRB documenting approval of: the investigator(s) (who must be 
identified by name), the study protocol, (must be identified by title and revision 
number), and the patient information brochure and Subject Informed Consent Form 
 a letter from the US FDA, documenting approval of the study protocol and 
supporting documentation.  
O.2.2 Study Reporting 
A progress report will be submitted by the Sponsor/Principal Investigator to the study’s 
DSMB at intervals specified by the DSMB. 
If required, a progress report will be submitted by the Sponsor/Principal Investigator to 
the IRB and to US FDA at intervals specified by the IRB or by the US FDA. A copy of 
the progress report will be sent to the device manufacturer.  
After completion of the study, the Sponsor/Principal Investigator will submit a signed 
clinical safety summary of the study to the IRB and to the US FDA. 
O.3 Responsibilities of the Sponsor 
The Sponsor has the overall responsibility for the management and monitoring of 
this study. The sponsor may delegate some aspects of conducting and monitoring the study 
to other qualified individuals (such as the Principal Investigator).  
The Sponsor and/or the Sponsor’s designee will oversee the progress of this clinical study 
and ensure it is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, FDA requirements, GCP, on-site monitoring and regular 
communication with each participating center by telephone or correspondence and 
applicable country specific regulatory requirements. 
The Sponsor’s contact details are listed below: 
Julie Nangia, MD 
 
Assistant Professor 
 
Lester & Sue Smith Breast Center at 
 
Baylor College of Medicine 
 
660 MB, One Baylor Plaza,  
 
Houston, TX 77030 
 
USA 
 
Phone:  713-798-1311 
Fax:  713-798-8884 
Email: nangia@bcm.edu 
The Sponsor is responsible for: 
 selecting suitably qualified investigators and providing them with the information 
they need to conduct the study properly 
 ensuring proper monitoring of the investigation 
 ensuring that prior IRB and US FDA approval for the study are obtained 
Additionally, the Sponsor is responsible in ensuring that the IRBs and the US FDA  

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are promptly informed of significant new information about the investigation. The Sponsor 
is responsible for compliance with applicable governmental regulations in the USA 
concerning the conduct of the study. 
O.4 Responsibilities of the Investigator 
O.4.1 Definitions 
According to 21 CFR 56.102 (h) the Investigator is defined as an individual who actually 
conducts a clinical investigation (i.e., under whose immediate direction the test article is 
administered or dispensed  to, or used involving, a subject) or, in the event of an 
investigation conducted by a team of individuals, is the responsible leader of that team.  
According to ISO 14155:2011, 9.2 (a), the Investigator is an individual who is qualified 
by education, training and experience to assume responsibility for the proper conduct of 
the clinical investigation in accordance with the aforementioned International Standard. 
O.4.2 Investigator Responsibilities 
The Investigator(s) shall be responsible for the day-to-day conduct of the clinical 
investigation as well as for the safety and well-being of the human subjects involved in 
the clinical investigation. The Investigator(s) shall thus take responsibility for the 
following: 
 having the resources to conduct the clinical investigation properly 
 ensuring that conducting the clinical investigation will not give rise to a conflict of 
interest 
 obtaining from the sponsor the information which the clinical investigator judges 
essential about the device, being familiar with this information and being well 
acquainted with the clinical investigation plan before signing it 
 supporting the monitor and auditor, if applicable, in their activities to verify 
compliance with the clinical investigation plan, to perform source data verification 
and  to correct the case report form where inconsistencies or missing values are 
identified 
 discussing with the sponsor and the monitor any question of modification of the 
clinical investigation plan, and obtaining the written approval of the sponsor 
 making sure that the clinical investigation plan is followed by all responsible for the 
conduct of the clinical investigation at his institution. Any deviation shall be 
documented and reported to the sponsor. 
 making the necessary arrangements to ensure the proper conduct and completion of 
the clinical investigation 
 making the necessary arrangements for emergency treatment, as needed, to protect 
the health and welfare of the subject 
 ensuring that appropriate IRB approval has been received to start the clinical 
investigation at his center providing the results from the IRB to the sponsor 

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 informing the IRB and asking for its opinion and/or approval regarding any 
significant change in the clinical investigation plan that has been approved by the 
sponsor and the reasons for the change 
 informing the IRB and, if applicable, the US FDA about any serious adverse device 
effects 
 informing the sponsor about all adverse events and adverse device effects in a timely 
manner 
 endeavoring to ensure an adequate recruitment of subjects 
 ensuring that the subject has adequate information to give informed consent 
 ensuring that informed consent is obtained and documented 
 ensuring that clinical records shall be clearly marked to indicate that the subject is 
enrolled in a particular clinical investigation 
Sub-Investigator 
A Sub-Investigator participates in the study (e.g., obtains subject informed consent, 
performs clinical procedures using the investigational device, conducts subject follow-up 
examinations) under the direction of the Principal Investigator. 
Research Coordinator  
The research coordinator assists with clinical study activities as assigned under the direct 
supervision of the Principal Investigator. The duties of the research coordinator may 
include ensuring that the required test and evaluations are done for each subject at the 
required intervals, completing the data entry based on the medical records, assisting with 
administrative activities, and scheduling subject follow-up appointments. 
Each Investigator agrees to comply with all applicable governmental regulations and the 
requirements of this study. Investigators who do not comply with the protocol, or 
conditions included in approvals granted by the reviewing committee, will have their 
participation in the study terminated. 
O.5 Study Monitor 
O.5.1 General 
The Lead Center will conduct investigational site monitoring of all participating centers 
to ensure that all investigators are in compliance with the protocol, regulatory 
requirements and the Investigator's agreement. The Study Monitor will ensure that the 
completed CRFs and data entered into the electronic database match the Sponsor records 
and resolve differences. The Sponsor will evaluate circumstances where an investigator 
deviates from the clinical protocol and will retain the right to remove either the 
investigator or the investigational center from the study. 
The Sponsor will review significant new information, including unanticipated adverse 
events and ensure that such information is provided to the study investigators and all 
reviewing IRBs and the US FDA as required. 

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O.5.2 Study Monitor Responsibilities 
Monitoring functions shall be performed in compliance with Good Clinical Practices, ISO 
14155-2011, and as outlined in 21CFR§821.43(d) and 21CFR§812.46. 
The major function of the Study Monitor is to observe and assess the quality of the 
clinical study. For this study, qualified personnel appointed by the Sponsor will serve as 
clinical monitors and will operate under written procedures to assure a high quality study. 
Thus, periodic visits are intended to assess investigators’ adherence to the protocol, 
maintenance of records and reports, and review of source documents for accuracy, 
completeness, and legibility. At the close of the study, the Study Monitor may be required 
to make a final on-site visit to assure that all study data has been properly completed and 
that the investigational product has been returned to the manufacturer. 
Reports of on-site visits shall be made by the Study Monitor and should include, as 
applicable, resolution of concerns, completion of appropriate follow-up activities, 
completion of assigned tasks, and corrective actions. 
O.5.3 Monitoring Visits 
Site monitoring visits will follow a documented monitoring plan in order to: 
 
ensure Investigator adherence to the study protocol; 
 
ensure correct maintenance of study records;  
 
verify the accuracy and integrity of recorded study data. 
During these visits, the Study Monitor will review the collected data against the subject 
charts and any additional source data, to verify its accuracy and completeness. When 
discrepancies are identified, only the site personnel will correct the data. 
The Study Monitor will discuss any findings or concerns with the Principal Investigator 
and/or appropriate site study staff and make suggestions for corrective action. All 
discussions, suggestions, and corrective actions will be documented in the visit follow-up 
letter. These and other observations regarding the conduct of the study at the site will be 
documented in a site monitoring report that is maintained on file with the Sponsor. 
O.6 Investigator Selection Criteria 
The Sponsor/Principal Investigator is responsible for the overall conduct of the study at all 
participating centers. The Sponsor/Principal Investigator must be qualified by education, 
training, and experience in oncology and in the administration of chemotherapy to breast 
cancer patients.  
The following criteria will be used to select the Investigators for participation in the 
clinical investigation: 
 
Ensure a Confidentiality Disclosure Agreement is in place and filed with the 
Sponsor. 
 
The Sponsor/Principal Investigator and all participating center Investigators agree to 
follow the study protocol and to ensure the compliance of all Investigators, Sub-
investigators and other study personnel. 

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 
The Sponsor/Principal Investigator and all participating center Investigators have 
appropriate experience of chemotherapy to breast cancer patients and also clinical 
investigation experience. 
 
Each investigational center has a sufficient subject population to support the implant 
requirements for the study. 
 
The Sponsor/Principal Investigator and all participating center Investigators agree to 
perform all procedures and report results according to the study protocol. 
 
Each participating center has a designated and easily accessible Research 
Coordinator. 
 
The Sponsor/Principal Investigator will obtain IRB approval for the investigation 
and will obtain renewal of this approval as per local requirements. 
 
All investigators participating in this study will provide the Sponsor/Principal 
Investigator with curriculum vitae (CV) to be maintained in the Sponsor/Principal 
Investigator’s files as documentation of appropriate previous medical experience and 
training for the procedures covered by the study protocol. 
Additional specific training, as needed, for use of the investigational device and 
compliance with the study protocol will be provided by the device manufacturer. 
Each Investigator agrees to comply with all applicable governmental regulations and the 
requirements of this study. Investigators who do not comply with the protocol, or 
conditions included in approvals granted by the reviewing IRB, will have their 
participation in the study terminated. 
O.7 Study Initiation 
Prior to study initiation, the Sponsor/Principal Investigator must confirm the following 
documents are on file: 
 
a signed contract/clinical study agreement to include the budget 
 
a signed protocol signature page 
 
a signed original FDA Form 1572 
 
copies of the US FDA and IRB approval letters 
 
a financial disclosure form for all personnel listed on the FDA Form 1572 
 
a copy of the US FDA / IRB-approved Informed Consent Form 
 
signed and dated CVs (including current professional licenses) from all site 
personnel listed on the FDA Form 1572 
O.8 Records and Reports 
O.8.1 General 
All records and reports related to this investigation are subject to inspection. The records 
from this study will be retained together in an organized, retrievable manner for a 
minimum of two (2) years after either the date the clinical study is terminated or the date 
that the records are no longer required to support regulatory approval of the device as 
determined by the sponsor, whichever is longer. 

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O.8.2 Review of Data Collection 
The Sponsor, or the Sponsor’s designee, will review all data collection for errors, 
omission, and discrepancies 
All morbid events and related documentation will be reviewed.  
O.8.3 Investigator Records and Reports 
The Investigator is responsible for the retention, and in some cases, preparation of the 
records and reports cited below: 
 all correspondence that pertains to the investigation; 
 subject records, including but not limited to: 
o screening forms of all subjects screened for the study, whether included or 
excluded 
o each enrolled subject’s signed Informed Consent Form 
o all relevant source documents including preoperative medical history 
o information on the condition of the subject during the investigation, the results 
of all diagnostic tests, a record of the exposure of each subject to the device, and 
records of any other therapy initiated 
o observation of adverse device effects, whether anticipated or unanticipated 
o signed copy of the study protocol 
 copy of all signed Investigator agreements and the CV of each investigator at the 
participating centers; 
 IRB approval documentation and correspondence; the Sponsor/Principal Investigator 
will obtain IRB approval for the investigation and will obtain renewal of this 
approval per local requirements. 
The Investigator will arrange for the retention of the subject identification log for at least 
three (3) years after the final report has been signed. All other documentation related to 
this trial (source documents, informed consent forms, approvals) will be kept at the Lead 
Center no less than two (2) years after the later of the date of which the study is 
terminated or completed, or the date that the records are no longer required to support 
marketing applications.  
The Investigator will not relocate or dispose of any study documents before obtaining 
written permission from the Sponsor/Principal Investigator. 
O.8.4 Sponsor Records and Reports 
The Sponsor/Principal Investigator will maintain the following records and reports: 
 All correspondence and reports pertaining to the investigation 
 Records of shipment and disposition of devices, including records of devices 
returned to the device manufacturer 
 Signed Investigator agreements and the CV of each participating Investigator 
 Records concerning adverse device effects (whether anticipated or unanticipated) 
and complaints 

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 The IRB- and FDA-approved study protocol, including all amendments or 
modification, and reports of prior investigations 
 Pre-study visit reports 
 Monitoring reports 
 Copies of IRB and US FDA approvals for the study and all correspondence relating 
to these approvals 
 Final report of the study. A preliminary report will be prepared upon obtaining 
adequate data to evaluate the primary efficacy endpoint. A final report will be 
prepared after adequate data have been collected to evaluate all secondary endpoints. 
When adequate data have been collected, or when the clinical study is terminated for 
any reason, each Investigator will be notified in writing. This letter will briefly 
describe the status of the study and will inform the Investigator of any remaining 
responsibilities he/she may have to the study. A study close-out visit may also be 
conducted. 
O.9 Data Monitoring and Quality Control 
Case report forms (CRFs) will be used to collect all subject data during the study and must 
be fully completed for each subject and signed by the site Principal Investigator. CRFs 
should be completed at the first earliest opportunity after the data are obtained. 
An electronic database for capture of clinical data will reside on a central server via the 
internet. Data entry is performed by a study coordinator on a dedicated website. All data 
entered is subjected to data type verification and range checking. The operator is notified 
of errors that may occur, and depending on the data verification sub-routines, the operator 
might need to resolve that error before moving to the next entry field. 
The database hosting facility is a multi-level protected environment. Access is severely 
restricted with high-end user recognition technology. Multi-point backup of critical data is 
standard.  Firewalls and other undisclosed technologies provide strong data security. 
The database is available year-round, 24 hours a day. 
O.10   Quality Assurance Auditing and Inspection 
During the course of this clinical study, the Sponsor will appoint Quality Assurance 
personnel to provide audit of the administration and conduct of the study, both at the 
participating study centers and at the Sponsor’s coordination center. These procedures are 
in accordance with Good Clinical Practice (GCP) to ensure that: 
 complete, accurate and timely data are collected 
 the study protocol requirements are followed and that all complications and adverse 
events are reported in a timely manner 
The US FDA may also conduct audits/inspections of participating study centers and of the 
Sponsor. The Investigator and the relevant center personnel must set aside a reasonable 
amount of his/her time for study-related monitors, audits and inspection by the Sponsor, 
IRB, US FDA, and institution compliance and quality assurance groups, and provide 
adequate access to all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). 

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O.11  Patient Confidentiality 
All information and data sent to the data management center concerning subjects of their 
participation in this study will be considered confidential according to local data protection 
laws. Only authorized data management center personnel from the regulatory authorities 
have the right to inspect and copy all records pertinent to this study. All data used in the 
analysis and reporting of this evaluation will be without identifiable reference to the 
patient. The Sponsor will keep all data related to subject identification in strict confidence. 
Subject identity will not be revealed in any of the reports or publication resulting from this 
study. 
O.12   Investigator/Study Discontinuation 
O.12.1 Investigator Discontinuation 
Any investigator will be subject to removal from the study if he/she demonstrates a 
pattern of non-adherence to the study protocol and/or unethical behavior. 
O.12.2 Study Discontinuation 
The study may be discontinued if: 
 At any time, in the opinion of the hospital ethics committee and the Principle 
Investigator, the study represents an unreasonable medical risk to patients 
 The device manufacturer decides to terminate the study due to company 
considerations 
O.13   Protocol Modifications 
O.13.1 Protocol Deviations 
The instructions and procedures specified in this protocol require diligent attention to 
their execution. The Investigator will not deviate from the protocol without the prior 
written approval of the Sponsor except in medical emergencies in which proper care for 
the protection, safety and well-being of the study subject requires alternative treatment, or 
in unforeseen, isolated instances where minor changes are made that will not increase the 
subject’s risk or affect the validity of the study. The Sponsor must be notified of all such 
deviations within two (2) working days of each occurrence. 
Periodic monitoring of protocol compliance will be performed for each participating 
center. The Sponsor holds the right to halt enrollment in centers deemed to have 
excessive protocol compliance issues. 
O.13.2 Protocol Amendments 
The approved study protocol cannot be amended by the investigators, or study personnel, 
without first obtaining review and documented written approval of the Sponsor. The 
Sponsor will hold the responsibility of notifying all Investigators of all proposed changes 
to the protocol. The Sponsor will be responsible for forwarding any changes to the IRBs 
and for notifying all involved study personnel of approved changes to the protocol. 

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Medically significant amendments to the protocol (i.e. those which affect the rights, 
safety, or welfare of the human subjects involved in the investigation, the scientific 
soundness of the investigational plan, the validity of data or information resulting from 
the completion of an approved protocol, or the relationship of likely patient risk to benefit 
relied upon to approve a protocol or if they are otherwise significant inclusion of new 
categories of patients, etc.) may not be instituted prior to regulatory approval by the IRBs 
and the US FDA.  
O.14    Supply and Disposition of Devices 
Orbis Paxman Hair Loss Prevention Systems and associated accessories (including cooling 
caps and cap covers) will be supplied to the investigational site, free of charge and prior to 
investigation initiation.   
These devices are authorized for use only in subjects enrolled under this protocol and under 
the supervision of the investigator. Furthermore, the scalp cooling devices and accessories 
will be clearly marked as investigational products to prevent unauthorized use. Upon study 
completion all devices will be returned to the device manufacturer. 
O.15 
Training 
The training of appropriate participating center personnel will be the responsibility of the 
Sponsor. To ensure proper device usage, uniform data collection and protocol compliance, 
the Sponsor, in conjunction with the device manufacturer, will present a formal training 
session to study site personnel which will review: 
 The instructions for use of the Orbis Paxman Hair Loss Prevention System 
 The study protocol 
 Techniques for the identification of the eligible patient; 
 Instructions on in-hospital data collection 
 Methods for soliciting data from patients 
 Regulatory requirements 
O.16 
   Meetings 
At least annually, the study’s Data Safety Monitoring Board (coordinated by the Dan L. 
Duncan Cancer Center office) will review and monitor study progress, adverse events, 
safety and other data from this trial. Information that raises any questions about participant 
safety or protocol performance will be addressed with the Principal Investigator, statistician 
and study team members. Should any major concerns arise, the DSMB will offer 
recommendations regarding whether or not to suspend the trial. Any events that are 
reportable to the IRB should be simultaneously reported to the DSMB Chair.   
After study completion, annually for 5 years, a report will be sent to the FDA with 
information on breast cancer recurrence, site of first recurrence, and survival.   
P) Statistical Considerations 

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P.1 Study Design 
We propose to conduct a multi-center parallel group, randomized clinical trial to compare 
success in hair preservation, between the Orbits Paxman Hair Loss Prevention System and 
control (no cooling) after 4 cycles of chemotherapy.  
Data collected in this clinical investigation will be used to support a premarket approval 
(PMA) application to the US FDA for approval to market the Orbis Paxman Hair Loss 
Prevention System in USA, for the intended use of reduction of chemotherapy-induced 
alopecia in stage I-II breast cancer patients who are receiving neoadjuvant or adjuvant 
chemotherapy with anthracycline- or taxane-based drug regimens. 
P.2 Sample Size/Accrual Rate 
The trial will require 213 response evaluable subjects and we expect to consent at most 325 
subjects. 
Our primary endpoint is hair preservation. We expect to see very low rates (< 10-15%) of 
hair preservation in the control group, and propose to use a 2 to 1 randomization in order to 
gain additional experience with the experimental arm, and to make participation more 
attractive. An absolute difference of 20% (i.e. 15% vs. 35%) will be deemed a clinically 
meaningful difference. A total sample size of 213 response evaluable study participants 
will provide 85% power to detect a difference in preservation of 20% between control 
(15%) and Paxman (35%) at the 5% level of significance. If, as we expect, the rate of 
preservation will be lower than 15% in the control group, then the power to detect a 20% 
improvement will be higher (Table 2).  
 
Table 2 – Power to detect differences under difference scenarios 
 
Scenario 1 Scenario 2 
Level of Significance 
5% 
5% 
Proportion Alopecia Grade <2 
 
 
Control 
0.15 
0.10 
Paxman Scalp Cooling 
0.35 
0.30 
Odds Ratio 
3.05 
3.86 
Power 
0.85 
0.90 
N control 
71 
71 
N Paxman 
142 
142 
Total N 
213 
213 
 
The study will require 213 response evaluable subjects and ~325 consented patients.  
Considering a 22% drop-out rate, we expect to accrue 273 subjects so that we will have 213 
evaluable subjects at the final analysis. If we also consider a 16% screen failure, we will 
need to consent 325 subjects for this study. 
P.3 
 Interim Analysis 
One interim analysis will take place about two-thirds of the way through the study after 95 
patients are enrolled to the cooling group and 47 patients are enrolled to the no cooling 
group and have been evaluated for the primary endpoint. The purpose of the interim 

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analysis is to allow the study to stop early for efficacy (superiority). To maintain the 
overall type 1 error rate, an O’Brien-Fleming spending function has been used to calculate 
the superiority boundary. Calculations were performed using nQuery Advisor + nTerim 3.0 
(Statistical Solutions. Boston, MA).  
The following table summarizes the superiority boundary at each of 2 looks when 66% and 
100% patients are enrolled and evaluated, respectively. The superiority boundary on the p-
value scale at the interim analysis is calculated as p=0.0061 (or Z=2.509). If the one-tailed 
p-value from a Fisher’s exact test is less than or equal to 0.0061, it will be recommended 
that the trial stop for efficacy. 
 
Looks  
Accumulated 
‘Information’  
Evaluable N 
(cooling 
group) 
Evaluable N 
 (no cooling 
group) 
Superiority 
Boundary  
(Z value)1 
Superiority 
Boundary   
(One-tailed 
p-value) 
1 
66% 
95 
47 
2.509 
0.0061 
2 
100% 
142 
71 
1.993 
0.0231 
1. For the software, Z-value boundaries are specified assuming that a Z test for proportions (unpooled variance) will be 
used, however the corresponding p-values apply equally well to Fisher’s exact test, which was used in the original 
sample size calculations, and is still proposed for the analysis. 
P.4 
Stratification Factors 
Randomization will be stratified by two major chemotherapy types (anthracycline or 
taxane) and up to 10 centers with total of up to 20 strata, and employ permuted blocks with 
block size of 6: 4 in the experimental arm and 2 in the control arm. 
P.5 
Analysis of Primary Endpoints 
Descriptive and summary statistics will be computed for demographic and clinical data of 
all subjects enrolled in each treatment group at each center. A table of baseline subjects’ 
demographic and clinical data, grouped by major chemotherapy type and center will be 
reported. Since randomization will be stratified by major chemotherapy type and center, 
each center will contribute the same number of subjects to each treatment group. A non-
significant test for interaction between the treatment effect and center will be performed to 
confirm the consistency of the treatment effect. Summary table will also be provided for 
the status of the protocol treatment such as the number of subjects who stop the scalp 
cooling earlier and the reason of stopping.  
The primary efficacy analysis will be based on the intent to treat (ITT) population, defined 
as eligible and randomized subjects who undergo at least one cycle of chemotherapy. The 
primary efficacy endpoint will be success in hair preservation, defined as CTCAE v4.0 
alopecia grade < 2, and will be assessed by a healthcare professional who is blinded to 
study treatment. The rates of hair preservation in the scalp cooling group and the control 
group will be calculated and summarized. The hypothesis testing for the primary 
effectiveness endpoint is H0: pt = pc [i.e., proportion of women in the treated group who 
have CTCAE v4.0 grade 0 or 1, equals to the proportion of women in control group who 
have CTCAE v4.0 grade 0 or 1], versus Ha: pt ≠ pc testing for 2-sided alpha of 5% level of 
significance. Fisher’s exact test will be used to test whether there is a difference in the rates 

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of hair preservation. The study will be deemed as success if there is a significant difference 
in rates of hair preservation between the scalp cooling group and the control group. P-
value, the difference in rates and its 95% confidence interval will be reported.   
The primary safety endpoint is anticipated adverse device effects specified in section M.4. 
All study subjects who begin the first cycle of chemotherapy will be evaluable for adverse 
events. All adverse device effects, including serious adverse device effect and 
unanticipated adverse device effect, will be described and summarized. The primary safety 
analysis will be based on incidence rates of adverse device effects and their exact 95% 
confidence intervals.  
The primary efficacy and safety endpoints will be used to obtain marketing approval for 
the Orbis Paxman Hair Loss Prevention System.   
P.6 
Analysis of Secondary Endpoints 
The secondary effectiveness and safety endpoints analysis will be based on the intent to 
treat (ITT) population, defined as eligible and randomized subjects who undergo at least 
one cycle of chemotherapy.  
Data of hair preservation assessed by subject self and oncologist, and the use of wig or 
head wrap will be analyzed using descriptive statistics with rates and their 95% confidence 
intervals. Comparison of secondary effectiveness endpoints between the scalp cooling 
group to the control group will not be performed. 
Lack of compliance is also seen as a threat to evaluation of the efficacy of the device, and 
high rates of non-compliance will reduce clinical utility. Compliance will be assessed by 
proportion of prescribed time (defined as 30 minutes pre-chemotherapy + duration of 
chemotherapy + 90 minutes post-chemotherapy) to the time that the device is worn.  In the 
event of high rates of noncompliance, exploratory analyses will attempt to discern 
potentially modifiable factors associated with noncompliance. 
Improved quality of life as a result of reduced hair loss is a primary motivator for 
developing the Paxman Scalp Cooling device. Quality of life will be assessed at baseline, 
after 4 cycles of chemotherapy, and after completion of chemotherapy (if receiving more 
than 4 cycles). Three widely used and validated scales will be used: the EORTC QLQ C-
30, HADS and BIS. Subjects will be evaluated at multiple time points and data will be 
analyzed using descriptive methods with median and inter quartile range to assess the 
effect of treatment group and alopecia status on functioning, quality of life and depression. 
Subject-reported comfort is categorized into 5 levels from very comfortable to very 
uncomfortable. The comfort data will be summarized using median and range.  
A post-market approval follow-up for safety data will be done yearly for 5 years looking at 
time to first recurrence, overall survival, site of first recurrence, and incidence of isolated 
scalp metastasis. This will be collected during routine clinical observation. A report of this 
will be sent to the FDA annually for 5 years. Time to first recurrence and overall survival 
will be estimate using the Kaplan-Meier survival curve median and 95% confidence 
interval. Site of first progression will be tabulated. Incidence rate of isolated scalp 
metastasis and its 95% confidence interval will be estimated and will be compared to the 
scalp metastasis rate reported in NSABP (see Background B.4). 

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P.7 Reporting and Exclusions 
Evaluable for response. All eligible study subjects who receive at least one cycle of 
chemotherapy will be evaluable for hair-preservation response. Participants who stop 
wearing the scalp cooling system during the study will continue to be evaluated after every 
chemotherapy cycle. For purposes of estimating treatment success rates, study subjects 
who cannot be evaluated at the post-Cycle 4 time point will be deemed treatment failures. 
Missing or lost hair preservation evaluations will be deemed treatment failures. Any 
missing questionnaire assessment will be handled as last observation carried forward.   
Evaluable for adverse events. All study subjects who begin the first cycle of 
chemotherapy will be evaluable for adverse events.   
Q) Publication 
Publication or public presentation of the overall clinical study results from this study 
requires the prior written approval of the device manufacturer. 
It is understood that any manuscript or releases resulting from the collaborative research 
will be circulated to all participating sites prior to submission for publication or 
presentation. 

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 REFERENCES 
 
Aaronson, N. K., S. Ahmedzai, et al. (1993). "The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology." Journal of the National Cancer Institute 85(5): 365-376. 
American Cancer Society, e. a. (2011). "What are the key statistics about breast cancer?"   
Retrieved 9/22/11from 
http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-key-
statistics. 
Benjamin, B., Ziginskas, D., Harman, J. & Meakin.T (2002). "Pulsed electrostatic field 
(ETG) to reduce hair loss in women undergoing chemotherapy for breast cancer: A 
pilot study." Psycho-Oncology 11: 244-248. 
Breed, W. (2004). "What is wrong with the 30-year-old practice of scalp cooling for the 
prevention of chemotherapy-induced hair loss?  ." Suppor Care Cancer 12: 3-5. 
Breed, W., van due Hurk, CJ, Peerbooms, M (2011). "Presentation, impact and prevention 
of chemotherapy-induced hair loss, scalp cooling potentials and limitations." Expert 
Rev Dermatol 6(1): 109-125. 
C. van den Hurk, e. a. (2011). Multicenter results of scalp cooling to prevent 
chemotherapy-induced alopecia in 1500 breast cancer patients. . San Antonio Breast 
Cancer Conference. San Antonio, TX, AACR. Poster P5-20-08. 
Christodoulou, C. T., G, Galani, E, Skarlos, DV (2006). "Scalp metastases and scalp 
cooling for chemotherapy-induced alopecia prevention." Ann Oncol 17(2): 350. 
Fayers, P., N. Aaronson, et al. (2001). The EORTC QLQ-C30 Scoring Manual (3rd 
Edition). Brussels, European Organisation for Research and Treatment of Cancer. 
Grevelman, E. B., WP (2005). "Prevention of chemotherapy –induced hair loss by scalp 
cooling." Ann.Oncol 17(2): 352-358. 
J Lemieux, e. a. (2011). Survival in women with breast cancer who used or did not use scalp 
cooling in the neoadjuvant/adjuvant setting. San Antonio Breast Cancer Symposium 
San Antonio, TX, AACR. Poster P5-20-06. 
Kaderman, C., Kaderman, R., & Toonkei, R (1999). "The psycho-social aspects of breast 
cancer." Nurse Practitioner Forum 10(3): 165-174. 
Kornblith, A. (1998). "Psychosocial adaptation of cancer survivors. 
." Holland JC ed. Psycho-Oncology.  Holland JC ed. : 223-241. 
Kroenke, K., R. L. Spitzer, et al. (2001). "The PHQ-9: validity of a brief depression severity 
measure." Journal of general internal medicine 16(9): 606-613. 
Lemieux, J., Amireault, C, Provencher, L, Maunsell, E (2009). "Incidence of scalp 
metastases in breast cancer: A retrospective cohort study in women who were 
offered scalp cooling." Breast Cancer Res Treat 118: 547-552. 
Lemieux, J., Maunsell, E., & Provencher, L (2008). "Chemotherapy-induced alopecia and 
effects on quality of life among woman with breast cancer: A literature review." 
Psycho-Oncology 17: 317-328. 
Llescher LJ, W.-M. D., Laigh SA, et al (1989). "Surviving adult cancers.  Part 1:  
Physiologic effects." Ann Intern Med 111(411-432). 
Massey, C. (2004). "A multicentre study to determine the efficacy and patient acceptability 
of the Paxman Scalp Cooler to prevent hair loss in patients receiving 
chemotherapy." European Journal of Onc Nursing 8: 121-130. 

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Mols, F., van den Hurk, CJ, Vingerhoets, AJJM, & Breed, W (2009). "Scalp cooling to 
prevent chemotherapy-induced hair loss: Practical and clinical considerations." 
Suppport Care Cancer 17(181-189). 
Rugo, H. M., SA (2010). Expert statement on scalp cooling with adjuvant/neoadjuvant 
chemotherapy for breast cancer and the risk of scalp metastases. 
Sneeuw KCA, A. N., Yarnold JR, et al (1992). "Cosmetic and functional outcomes of breast 
conserving treatment for early stage breast cancer.  2: Relationship with 
psychosocial functioning." Radiother Oncol 25: 160-166. 
Spaeth, D., Luporsi, E, Weber, S, et al (2008). "Efficacy and safety of cooling helmets for 
the prevention of chemotherapy-induced alopecia: A prospective study of 911 
patients." J Clin Oncol 26 (May Suppl)(abstract 9564). 
Sugarbaker PH, B. I., Rosenberg SA, Gianola FJ (1982). "Quality of life assessment of 
patients in extremity sacoma clinical trials." Surgery 91: 17-23. 
Trueb, R. (2009). "Chemotherapy-induced alopecia." Semin Cutan Med Surg 28(1): 11-14. 
Van den Hurk, C., Mols, F, Vingerhoes, AJ, Breed, WP (2010). "Impact of alopecia and 
scalp cooling on the well-being of breast cancer patients." Psycho-Oncology 19: 701-
709. 
Wang, J., Ku, Z, Au, JL (2006). "Protection against chemotherapy-induced alopecia." 
Pharm Res 23(11): 2505-2514. 
 

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APPENDICES 
A) Orbis Paxman Hair Loss Prevention System 
B) CTCAE v4.0 Grading Scale and Alopecia Pictorial Tool 
C) Comfort Scale 
D) QOL Questionnaires 

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Appendix A: Orbis Paxman Hair Loss Prevention System  
 
. 
 DEVICE DESCRIPTION 
 
The Orbis Scalp Cooler (newer generation of Paxman Scalp Cooling System) is a free-
standing, electrically-powered, mobile refrigeration unit which circulates a refrigerated 
liquid coolant, at a pre-set temperature and flow rate, through a cooling cap which is 
attached to, and covers, the top of the patient’s head.  
Two models of the Paxman Cooling System also known as the Orbis Scalp Cooler are 
available: 
1) Orbis 1 - designed for scalp cooling of one patient at a time; and,  
2) Orbis 2 - designed for scalp cooling of up to 2 patients at a time. 
Photographs of the front and rear aspects of the Orbis 2 model are provided in figures 
1 and 2 (on pages 4 and 5). The Orbis 1 model differs from the Orbis 2 model only in 
that the former features one pair of coolant lines for attaching and treating one patient 
at a time, instead of two pairs of coolant lines. Only the Orbis 1 device will be used in 
this study. 
 
 
Technological Characteristics 
 
  
Hardware Configuration 
 
 
The Orbis Scalp Cooler is composed of the following components: 
 
 Main unit 
 Touch screen controller 
 Software 
 Coolant lines 
 Cooling caps and covers 
 Coolant 
 
 
 
Main Unit  
This comprises a plastic-fronted, coated steel cabinet which contains the refrigeration 
unit, coolant tank, recirculation pump, mains power and fuse block, microprocessor 
control unit; a touch-screen user interface is built in to the plastic front cover of the 
unit. The back of the unit features the mains power inlet, mains power and 
recirculation on/off switches, a sight glass for visualizing the level of liquid coolant in 
the coolant tank and a capped top-up port for addition of liquid coolant. The unit is 
fitted with 4 swivel castors – one on each corner of its base – to provide for unit 
mobility; it also has a lifting handle on each side to enable the unit to be lifted over 
obstacles (should this be required). The two castors at the front of the unit feature a 
foot-operated brake mechanism to allow the unit to be secured in position prior to its 
use. The unit also features a height-adjustable, stainless steel support arm for the 
coolant lines. 

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Figure 1: Photograph of front aspect of Orbis Scalp Cooler model Orbis 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height-adjustable support 
arm for coolant lines 
Silicone cooling cap, 
covered with neoprene cap 
Touch screen controller 
Neoprene-covered coolant 
line. 

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Figure 2: Photograph of rear aspect of Orbis Scalp Cooler model Orbis 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mains power 
on/off switch  
Height adjustment 
handle for support 
arm 
Recirculation pump 
on/off switch 
Coolant level sight 
glass and top-up 
port 
Mains electrical 
power inlet 
Rear vent for 
refrigeration unit 
fan 

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Physical characteristics: 
 
Height: 25.2 inches  
Extended height (i.e. with support arm fully extended): 64.7 inches 
Width: 12.6 inches 
Depth: 16.5 inches  
Weight: 64.9 lbs. 
 
 
Electrical characteristics: 
 
Power requirements: 110 - 120v 60Hz single phase 
Input rating: 432W 
Current: 8.0A (start) / 3.6A (running) 
Classification (under IEC 60601-1 ed.3.0 b: 2005): Class I 
 
  
Description of components 
 
Refrigeration unit 
This is composed of standard refrigeration components – i.e. a compressor, condenser, 
evaporator and cooling. The refrigerant used is R-134a (1,1,1,2-tetrafluoroethane) – a 
chlorofluorocarbon-free, inert gas, which has been used for domestic refrigeration and 
automobile air-conditioners since the 1990s.   
 
Coolant tank 
This is a sealed tank of 2.5 liter capacity, manufactured from AISI grade 304 stainless 
steel, in a fully welded construction. Tank inlets and outlets are located in the top of 
the reservoir. The coolant tank is not pressurized and is insulated. 
 
 
 
 
Recirculation pump  
A centrifugal mechanically coupled pump is mounted in the top plate of the coolant 
tank. The pump helps achieve an even temperature throughout and also pumps the 
coolant, via the coolant lines, to the cooling cap and back to the coolant tank. 
The Orbis 1 is fitted with a 30W pump (Totton Pumps, model SPC-51); the Orbis 2 is 
fitted with a 60W pump (Totton Pumps, model SPC-42). Both are semi-submersible 
column pumps with the column and pump body constructed in glass-filled acrylonitrile 
butadiene styrene (ABS), with an IPX4 motor housing, polypropylene impellers, and a 
stainless steel shaft and nylon agitator. Both pumps operate at a flow rate of 1.5 
liters/minute. 
 
 
 
Touch screen controller unit 
This comprises 3 printed circuit boards mounted beneath, and connected to, a touch 
screen. The primary function of the control unit is to monitor and control the 
temperature of the coolant, monitor the coolant flow rate and provide for user 
initiation and time monitoring of the scalp cooling process. 
 

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Touch screen   
 
This is a 5.7-inch, transmissive, color, TFT-LCD, with a display resolution of 320 x 
240 pixels (4:3 aspect ratio). The touch screen is a resistance type with an antiglare 
surface.  
 
Microprocessor unit 
The printed circuit boards are a bespoke design, manufactured specifically for Paxman 
Coolers. The main board incorporates a Microchip Technology Inc. Peripheral 
Interface Controller (PIC) and is programmed in C general purpose computer 
programming language.  
 
 
Coolant lines  
Refrigerated coolant is circulated through the cooling cap and back to the coolant tank 
in the main unit via a pair of 2-metre long coolant lines – one line to transport the 
coolant from the unit to the cap and one line to return coolant from the cap to the main 
unit. Each coolant line is composed of silicone tubing (the silicone used is medical 
grade, USP Class VI, Shore A 60) with an outer diameter of 0.315 inches and an inner 
diameter of 0.197 inches. The tube is encased in closed cell, elastomeric, nitrile rubber 
insulation material (Armaflex®). Each end of the coolant line terminates in a push-fit 
quick release coupling composed of polypropylene (John Guest Speedfit®). A male 
connector is used on one line and a female connector on the other. The couplings are 
fitted with rapid action non-return valves, which are designed to prevent leakage of 
residual coolant from the tubes following disconnection from the unit.  
Each pair of coolant lines is covered with a neoprene shroud, the purpose of which is 
to absorb any condensation which forms on the outer surfaces of the coolant lines.   
 
 
Cooling cap  
The cooling cap is manufactured from extruded, clear silicone tubing (the silicone 
used is medical grade, USP Class VI, Shore A 40) with an outer diameter of 0.315 
inches and an inner diameter of 0.236 inches. The tubing is formed into a cap shape by 
gluing the spiral-wound tubing together using a one-part, solvent-free, USP Class VI 
silicone adhesive (MED-1000, Nusil Technology LLC).  
Caps are available in 5 different sizes (extra small, small, medium, large and extra-
large) to account for variation in patient head size. Each cap has a color-coded apex 
for ease of size identification: 
 
extra small = yellow 
 
small = red 
 
medium = purple 
 
large = blue 
 
extra-large = green  
 
A photograph of the cooling caps is shown in Figure 3. 
The cooling caps are supplied with integral outward and return cooling lines composed 
of the same silicone material as the caps. These two cooling lines terminate in one 

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male and one female quick release coupling, for connection to the corresponding 
connectors on the outward and return coolant lines. 
The silicone cap is supplied non-sterile and is reusable. 
 
Figure 3: Photograph of Orbis Scalp Cooler Cooling Caps 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cap cover 
Each silicone cooling cap comes supplied with a neoprene cap cover which is designed 
to be worn over the cap and is required to secure the cap in the correct position on top 
of the patient’s head.  The cap cover incorporates an adjustable chin strap and 
adjustable circumferential strap to enable the cover to be securely fastened onto the 
patient’s head so that the cooling cap maintains optimum coverage of, and contact 
with the scalp, for the duration of the scalp cooling procedure. The neoprene cap cover 
also absorbs any condensation which may form on the exterior surface of the cap. 
Cap covers are available in 5 sizes, corresponding to the available cap sizes.  The cap 
cover is supplied non-sterile and is reusable.   
 
 
Coolant 
The coolant used in the Orbis Scalp Cooler is a specially designed solution designated 
OrbisC – it is an aqueous solution of potassium formate and corrosion inhibitors (30% 
– 70% w/v), colored with a purple food-grade, vegetable dye for ease of visualization.  
The coolant has a density of 1.17 – 1.34 g/cm3, a pH between 10.6 and 11.4 and 
freezes solid at - 15°C.  
The coolant is designed to remain within the circulation system and does not come 
into direct contact with the patient or user during normal operation. 
Silicone cooling 
cap 
Neoprene-covered 
integral silicone 
coolant lines 
Speedfit quick 
release 
couplings 

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Software Configuration 
The software within the touch screen controller unit is written in C Programming 
language and serves three functions: 
a) the touch screen displays a menu-driven, graphical user interface (GUI) which 
provides information to the user concerning the operational status of the scalp 
cooling unit; it also prompts the user to initiate certain actions relating to the scalp 
cooling procedure and provides a timer count-down function (for scalp cooling 
sessions). The software GUI does not, however, directly control the scalp cooling 
process. An example of the GUI home screen (system powered on and at 
operating temperature but recirculation pump not yet switched on) is shown in 
figure 4. 
 
Figure 4: Photograph of Orbis Scalp Cooler Touch Screen Displaying GUI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
b) the software monitors the temperature of the coolant in the coolant reservoir, 
interpreting an incoming resistance signal from the temperature probe in the 
coolant tank using a standard mathematical algorithm which accounts for non-
linearity of the probe over a known temperature range. The software also 
electronically switches the compressor on or off in response to the measured 
temperature, when pre-set upper and lower temperature limits (-5°C and -4°C) are 
recorded. The software also monitors the flow rate of the liquid coolant returning 
to the coolant tank via signals received from turbines placed in the coolant return 
tube; 
c) in the event of pre-set limits for coolant temperature and flow rate being 
exceeded, the software displays an appropriate visual cue on the GUI and sounds 
an audible buzzer to alert the user to the situation, and - under certain conditions - 
the software will shut down the unit. 
 
 
Principle of Operation 

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The Orbis Scalp Cooler is designed to reduce the epicutaneous temperature of a 
patient’s scalp to between 16°C and 19°C. This is achieved by circulation of a 
refrigerated coolant through a silicone cap attached to the patient’s head, covering and 
in contact with the entire scalp area. The reduction in temperature is designed to effect 
both vasoconstriction of the blood vessels in the scalp which supply the hair follicles 
and also a reduction in the metabolic rate of the hair follicle cells, both of which 
mechanisms are intended to reduce the damage caused to the scalp hair follicle cells 
by cytostatic chemotherapy agents in the blood.   
Scalp cooling is initiated at least 30 minutes prior to chemotherapy administration and 
is maintained continuously thereafter during administration of the chemotherapy agent 
and also for a period of time after the agent has been administered. The duration of 
post-infusion scalp cooling varies from 45 minutes to 2 hours and is based on the 
known pharmacokinetics of the chemotherapy treatment administered. Recommended 
post-infusion cooling times for a variety of commonly used chemotherapy treatments, 
but for the purposes of this study have been standardized at 90 minutes. These 
regimens are designed to ensure that adequate cooling of the scalp occurs during the 
time when the concentration in the blood of the cytostatic agent is at its peak. 
As indicated above, effective scalp cooling relies on good contact between the inner 
surfaces of the cooling cap and the patient’s scalp. As such, prior to the first scalp 
cooling procedure, each patient undergoes a cooling cap fitting with a healthcare 
professional trained in use of the Orbis Scalp Cooler – this fitting process is necessary 
to ensure that the most appropriate size of cooling cap is selected. For optimum 
cooling, the cap must both fit snugly onto the head at the crown and also cover the 
entire scalp area down to the hairline. Effective scalp cooling over the entire scalp is 
only achieved with the combination of correct size of cooling cap and correct size of 
cooling cap cover; the cover – with its adjustable straps – is necessary to ensure that 
the cooling cap is maintained securely and comfortably in the correct position on the 
patient’s head for the duration of the scalp cooling process. For some patients, the cap 
fitting process will simply involve the selection of the most appropriate size cooling 
cap and corresponding cap cover. For patients whose head size does not correspond to 
one of the five available cooling cap sizes, a combination of the larger size cooling cap 
and smaller size cover is used to obtain the required cooling cap contact with the scalp. 
Prior to scalp cooling, the cooling cap is always attached to the patient’s head with the 
cap disconnected from the coolant lines. Before placing the cooling cap on the 
patient’s head, it is placed inside the appropriate size of cap cover and manually 
pressed into position against the inner surface of the cover, such that the entire cooling 
cap is within the cover. The cooling cap and cover are then placed onto the patient’s 
head such that the cap is on straight and covers the patient’s entire scalp to the hairline.  
The cover chin-strap and circumferential straps are then adjusted to achieve a snug fit 
of the cooling cap to the scalp, which is also comfortable for the patient. The 
healthcare professional then checks the fit of the cooling cap to ensure good contact all 
over the scalp – particularly at the crown and hairline. Once this is done, the patient is 
ready to begin scalp cooling and the cooling cap outward and return tube quick release 
connectors are connected to the corresponding connectors on the distal end of the 
coolant lines. 

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Powering on the system using the power switch on the back of the main unit activates 
the refrigeration unit, which then reduces the temperature of the coolant in the coolant 
tank to between -5°C and -4.0°C through standard refrigeration technology. Once this 
temperature is attained, the coolant temperature in the coolant tank is maintained 
within this temperature range by the system software, which monitors the coolant 
temperature from an electronic sensor in the reservoir and electronically switches off 
the refrigeration compressor when the temperature reads -4.0°C and switches on the 
compressor when the sensor temperature reads -3.0°C. 
Once the pre-set coolant temperature is reached, the pump is activated using a separate 
switch on the rear of the main unit. This causes the refrigerated coolant to be pumped 
from the reservoir at a pre-set constant flow rate via the outward coolant line through 
the cooling cap and back to the reservoir via the return coolant line. Coolant flow rate 
is monitored via flow turbines located in the return tube. In the event of a low coolant 
flow rate (< 0.6 L/min) being detected (which may indicate coolant loss, or kinking of 
one of the coolant lines), the software displays a warning message on the touch screen 
and sounds a buzzer to alert the user. 
The touch screen controller provides feedback to the user concerning the status of the 
Orbis Scalp Cooler as it relates to achievement of the pre-set temperature of the 
coolant, operation of the recirculation pump and connection of a cooling cap to the 
system. The software also prompts the user to initiate scalp cooling for at least 30 
minutes prior to administration of the chemotherapy agent and allows the user to select 
a pre-set post-administration scalp cooling time, which should be appropriate to the 
type of chemotherapy agent used. The software also provides a timer count-down 
function for the initiated pre- and post-infusion cooling procedure. At the end of the 
pre-set time, a message is displayed on the touch screen and a buzzer sounds to alert 
the user to the fact that the scalp cooling time is complete. 
Following completion of scalp cooling, the recirculation pump is switched off and the 
cooling cap and cover are then removed from the patient’s head. 
 
2.1 
Development and Marketing History 
The Orbis Scalp Cooler range (incorporating models Orbis 1 and models Orbis 2) was 
launched commercially in Europe in 2010; it represents the latest design iteration of 
liquid coolant-based, continuous scalp cooling devices manufactured by Paxman 
Coolers, which are indicated for use to reduce of chemotherapy-induced alopecia in 
patients who are undergoing chemotherapy for the treatment of solid tumors, such as 
breast cancer.  To date, 150 units of the Orbis Scalp Cooler have been sold.  
The design of the Orbis Scalp Cooler is based heavily on the previous PSC range 
(comprising models PSC1 and PSC2) of Paxman Cooler scalp cooling devices, which 
have been marketed commercially since 1997, with a total of 928 units sold to date. 
The Orbis Scalp Cooler models use the same principle of operation as the PSC 
devices, and – in many cases – the same components as are used in the PSC devices.  
As such, the Orbis Scalp Cooler is essentially a design modification of the PSC device, 
featuring cosmetic and functional design changes which are intended to further 
improve both the user’s and the patient’s experience of scalp cooling.    

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Appendix B 
 
 
 
 
 
 
 
 
 
 
 
CTCAE v4.0 Alopecia  (Hair Loss) 
Grade 0 
No hair loss 
Grade 1 
Hair loss of up to 50% of normal for that individual that is 
not obvious from a distance but only on close inspection; a 
different hair style may be required to cover the hair loss but 
it does not require a wig or hair piece to camouflage 
Grade 2 
Hair loss of > 50% normal for that individual that is readily 
apparent to others; a wig or hair piece is necessary if the 
patient desires to completely camouflage the hair loss; 
associated with psychosocial impact. 

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Appendix C 
 
 
Comfort Scale used in the Massey study (Massey 2004).  Patients will also be asked if 
they find the procedure to be acceptable or unacceptable as was done in the Massey 
study. 
 
 
How comfortable were you in general throughout 
 the scalp-cooling period? 
Very Comfortable 
Reasonably Comfortable 
Comfortable 
Uncomfortable 
Very uncomfortable 
 
 
 
 
 

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Appendix D: QOL Questionnaires 
 
1. EORTC QLQ-30 
2. HADS 
3. BIS 

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Body Image Scale (BIS) 
 
 
  
  
Not at 
all 
A little 
 Quite 
a bit 
Very 
Much 
1 
Have you been feeling self-conscious about your 
appearance? 
  
  
  
  
2 
Have you felt less physically attractive as a result of 
your disease or treatment? 
  
  
  
  
3 
Have you been dissatisfied with your appearance when 
dressed? 
  
  
  
  
4 
Have you been feeling less feminine/masculine as a 
result of your disease or treatment 
  
  
  
  
5 
Did you find it difficult to look at yourself naked? 
  
  
  
  
6 
Have you been feeling less sexually attractive as a 
result of your disease or treatment? 
  
  
  
  
7 
Did you avoid people because of the way you felt about 
your appearance? 
  
  
  
  
8 
Have you been feeling the treatment has left your body 
less whole? 
  
  
  
  
9 
Have you felt dissatisfied with your body? 
  
  
  
  
10 
Have you been dissatisfied with the appearance of your 
scar(s)?