PrefHER: Participant Preference of Subcutaneous (SC) Versus Intravenous (IV) Herceptin (Trastuzumab) in Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01401166
• Collaborator: (none)
• Enrollment: 488
• Locations: 75
• Arms: 4
• Duration (Months): 50
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized, open-label, crossover study will evaluate participants' preference and healthcare professional (HCP) satisfaction with SC versus IV Herceptin administration in HER2-positive early breast cancer. Participants will be randomized to receive either SC Herceptin or IV Herceptin every 3 weeks for Cycles 1 to 4, followed by crossover to the other treatment administration for Cycles 5 to 8. For up to 10 additional cycles (for a total of 18 cycles), participants will receive IV or SC Herceptin every 3 weeks.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Herceptin; Drug: Herceptin; Device: Single-Use Injection Device; Device: Single-Use Injection Device	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 488 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: A Randomized, Multi-Center Cross-Over Study to Evaluate Patient Preference and Health Care Professional (HCP) Satisfaction With Subcutaneous (SC) Administration of Trastuzumab in HER2-Positive Early Breast Cancer (EBC)
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: SC (SID) then IV Herceptin Participants will receive Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin will be administered via single-use injection device (SID), and during Cycles 5 to 8, IV Herceptin will be given. In the continuation period, participants will receive IV Herceptin for up to 10 remaining cycles. Administration will be performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period will be offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP.	Drug: Herceptin; Herceptin will be given on Day 1 of each 3-week cycle for a total of 18 cycles. If study treatment for Cycle 1 is IV Herceptin, the initial dose will be a loading dose of 8 milligrams per kilogram (mg/kg) for de novo participants who start Herceptin treatment in the study. For all other cycles where IV Herceptin is given and for non-de novo participants, the dose will be 6 mg/kg. The SC dose will be 600 milligrams (mg) for both the SID and vial formulations for all cycles where SC Herceptin is given.; Other Names: Trastuzumab ; Device: Single-Use Injection Device; The SID will be used, containing Herceptin 600 mg per 5 milliliters (mL).
Experimental: Cohort 1: IV then SC (SID) Herceptin Participants will receive Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin will be given, and during Cycles 5 to 8, SC Herceptin will be administered via SID. In the continuation period, participants will receive IV Herceptin for up to 10 remaining cycles. Administration will be performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period will be offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP.	Drug: Herceptin; Herceptin will be given on Day 1 of each 3-week cycle for a total of 18 cycles. If study treatment for Cycle 1 is IV Herceptin, the initial dose will be a loading dose of 8 mg/kg for de novo participants who start Herceptin treatment in the study. For all other cycles where IV Herceptin is given and for non-de novo participants, the dose will be 6 mg/kg. The SC dose will be 600 mg for both the SID and vial formulations for all cycles where SC Herceptin is given.; Other Names: Trastuzumab ; Device: Single-Use Injection Device; The SID will be used, containing Herceptin 600 mg per 5 mL.
Experimental: Cohort 2: SC (Vial) then IV Herceptin Participants will receive Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin will be administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin will be given. In the continuation period, participants will receive SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration will be performed by HCP throughout the study.	Drug: Herceptin; Herceptin will be given on Day 1 of each 3-week cycle for a total of 18 cycles. If study treatment for Cycle 1 is IV Herceptin, the initial dose will be a loading dose of 8 mg/kg for de novo participants who start Herceptin treatment in the study. For all other cycles where IV Herceptin is given and for non-de novo participants, the dose will be 6 mg/kg. The SC dose will be 600 mg for both the SID and vial formulations for all cycles where SC Herceptin is given.; Other Names: Trastuzumab
Experimental: Cohort 2: IV then SC (Vial) Herceptin Participants will receive Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin will be given, and during Cycles 5 to 8, SC Herceptin will be administered via handheld syringe using the vial formulation. In the continuation period, participants will receive SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration will be performed by HCP throughout the study.	Drug: Herceptin; Herceptin will be given on Day 1 of each 3-week cycle for a total of 18 cycles. If study treatment for Cycle 1 is IV Herceptin, the initial dose will be a loading dose of 8 mg/kg for de novo participants who start Herceptin treatment in the study. For all other cycles where IV Herceptin is given and for non-de novo participants, the dose will be 6 mg/kg. The SC dose will be 600 mg for both the SID and vial formulations for all cycles where SC Herceptin is given.; Other Names: Trastuzumab

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants by Preferred Method of Drug Administration [Week 24]

   The preferred method of drug administration (IV or SC Herceptin) was assessed in trial-specific telephone interviews with each study participant. Participants were asked, "All things considered, which method of administration did you prefer?" at the end of the crossover period (Week 24). The percentage of participants who preferred each method of drug administration was reported.

Secondary Outcome Measures

1. Percentage of HCPs by Most Satisfied Method of Drug Administration [Week 24]

   The method of drug administration with which HCPs were most satisfied (IV or SC Herceptin) was assessed via questionnaire with each HCP using the question, "All things considered, with which method of administration were you most satisfied?" at the end of the crossover period (Week 24). The percentage of HCPs who were most satisfied with each method of drug administration was reported.

2. Percentage of HCPs by Time Required to Perform Each Method of Drug Administration [Week 24]

   The time required to perform each method of drug administration was assessed via questionnaire with each HCP by asking to rate the amount of time it took to administer each method of drug administration (IV or SC Herceptin) at the end of the crossover period (Week 24). Time was rated in the following time block categories: less than (<) 5 minutes, 6 to 10 minutes, 11 to 15 minutes, 16 to 20 minutes, and greater than (>) 20 minutes. Responses of "Not Sure" and "Unknown" were also allowed. The percentage of HCPs who rated the amount of time in each of the categories was reported.

3. Percentage of Participants With an Event-Free Survival (EFS) Event [From Baseline until time of event; assessed every 6 months (median follow-up of 3 years)]

   EFS events included local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The percentage of participants who had an EFS event at any time on study was reported.

4. Duration of EFS According to Kaplan-Meier Estimate [From Baseline until time of event; assessed every 6 months (median follow-up of 3 years)]

   EFS was defined as the time from randomization to a local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The median duration of EFS and corresponding 95 percent (%) CI according to Kaplan-Meier estimates were planned to be reported and expressed in months.

5. 3-Year EFS Rate [Year 3]

   EFS events included local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The proportion of participants without an EFS event (i.e., the EFS rate) and corresponding 95% CI at 3 years after randomization was reported.

6. Percentage of Participants With Responses of "Agree" or "Strongly Agree" on the SC SID Satisfaction Questionnaire [Immediately following first self-administration of SC Herceptin via SID (once during Weeks 25 to 52)]

   Participants who performed self-administration of SC Herceptin via SID were given an evaluation questionnaire during the continuation period (Weeks 25 to 52) after their first self-administration. Participants responded to 5 statements about their comfort with self-injection, the convenience of the SID, their self-confidence using the SID, their satisfaction with the SID, and whether they would consider using the SID again in the future. Each statement used a 5-item rating scale with responses from "Strongly Disagree" to "Strongly Agree". The percentage of participants with a positive response (either "Agree" or "Strongly Agree") to each questionnaire statement was reported.

7. Percentage of Participants With Anti-Trastuzumab or Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies [Baseline, pre-dose (0 hours) during Cycle 5 (cycle length of 3 weeks)]

   Participants in Cohort 1 provided blood samples for immunogenicity testing to assess for anti-drug antibodies (ADAs) to trastuzumab or rHuPH20, a component of the SC Herceptin formulation. The percentage of participants who were trastuzumab ADA-positive and the percentage of participants who were rHuPH20 ADA-positive were each reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed HER2-positive primary breast cancer

• No evidence of residual, locally recurrent, or metastatic disease after completion of surgery and chemotherapy (neo-adjuvant or adjuvant)

• Completed neo-adjuvant chemotherapy prior to entry, if received

• At least 8 remaining cycles out of the total 18 planned 3-week cycles, if received IV Herceptin

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

• History of other malignancy, except for ductal carcinoma in situ of the breast, curatively treated carcinoma in situ of the cervix, basal cell carcinoma, or other curatively treated malignancies of which the participant has been disease-free for at least 5 years

• Inadequate bone marrow function

• Impaired liver function

• Inadequate renal function

• Serious cardiovascular disease

• Human immunodeficiency virus or hepatitis B or C infection

• Prior maximum cumulative dose of doxorubicin greater than (>) 360 milligrams per meter-squared (mg/m^{2) or epirubicin >720 mg/m}2 or equivalent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Barrie	Ontario	Canada	L4M 6M2
2		Brampton	Ontario	Canada	L6R 3J7
3		Kitchener	Ontario	Canada	N2G 1G3
4		Sault Ste Marie	Ontario	Canada	P6A 2C4
5		Toronto	Ontario	Canada	M4N 3M5
6		Saskatoon	Saskatchewan	Canada	S7N 4H4
7		Herning		Denmark	7400
8		Odense		Denmark	5000
9		Vejle		Denmark	7100
10		Besancon		France	25030
11		Bobigny		France	93009
12		Bordeaux		France	33076
13		Caen		France	14076
14		La Tronche		France	38700
15		LeMans		France	72000
16		Lyon		France	69373
17		Paris		France	75970
18		Rennes		France	35042
19		St Cloud		France	92210
20		Strasbourg		France	67065
21		Berlin		Germany	10713
22		Deggendorf		Germany	94469
23		Essen		Germany	45136
24		Fuerstenwalde		Germany	15517
25		Hamburg		Germany	20246
26		Hannover		Germany	30625
27		Magedburg		Germany	39104
28		Mainz		Germany	55131
29		Meiningen		Germany	98617
30		Recklinghausen		Germany	45657
31		Ulm		Germany	89073
32		Genova	Liguria	Italy	16132
33		Milano	Lombardia	Italy	20132
34		Milano	Lombardia	Italy	20141
35		Pavia	Lombardia	Italy	27100
36		Antella (FI)	Toscana	Italy	50011
37		Terni	Umbria	Italy	05100
38		Gdansk		Poland	80-952
39		Warszawa		Poland	02-781
40		Ekaterinburg		Russian Federation	620905
41		Irkutsk		Russian Federation	664035
42		Kazan		Russian Federation	420029
43		Moscow		Russian Federation	115478
44		Orenburg		Russian Federation	460021
45		Saint-Petersburg		Russian Federation	197758
46		St Petersburg		Russian Federation
47		Oviedo	Asturias	Spain	33006
48		Barakaldo	Vizcaya	Spain	48903
49		Barcelona		Spain	08024
50		Cordoba		Spain	14004
51		Guadalajara		Spain	19002
52		Huesca		Spain	22004
53		Madrid		Spain	28046
54		Madrid		Spain	28905
55		Malaga		Spain	29010
56		Sevilla		Spain	41009
57		Sevilla		Spain	41014
58		Zamora		Spain	49021
59		Eskilstuna		Sweden	63188
60		Gävle		Sweden	80187
61		Jonkoping		Sweden	55185
62		Sundsvall		Sweden	85186
63		Baden		Switzerland	5405
64		Zürich		Switzerland	8008
65		Adana		Turkey	01120
66		Ankara		Turkey	06018
67		Bornova, ?ZM?R		Turkey	35100
68		Gaziantep		Turkey	27310
69		Brighton		United Kingdom	BN2 5BE
70		Cardiff		United Kingdom	CF14 2TL
71		Chelmsford		United Kingdom	CM1 7ET
72		Maidstone		United Kingdom	ME16 9QQ
73		Nottingham		United Kingdom	NG5 1PB
74		Peterborough		United Kingdom	PE3 6DA
75		Truro		United Kingdom	TR1 3LJ

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01401166
• Other Study ID Numbers: MO22982; 2010-024099-25
• First Posted: Jul 25, 2011
• Last Update Posted: Mar 6, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab

Study Results

Participant Flow

Pre-assignment Detail	A total of 248 participants were randomized into the study in Cohort 1 (of whom 244 were treated) and 240 participants were randomized into the study in Cohort 2 (of whom 239 were treated). Those participants who did not receive any treatment were not included in the treatment periods of the Participant Flow.

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin	Cohort 2: SC (Vial) Then IV Herceptin	Cohort 2: IV Then SC (Vial) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via single-use injection device (SID), and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by healthcare professional (HCP). Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 milligrams (mg) for all cycles where SC Herceptin was given, and the IV dose was 6 milligrams per kilogram (mg/kg) for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via handheld syringe using the vial formulation. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Period Title: Crossover Treatment 1 (Cycles 1 to 4)
STARTED	122	122	121	118
COMPLETED	119	120	119	116
NOT COMPLETED	3	2	2	2
Period Title: Crossover Treatment 1 (Cycles 1 to 4)
STARTED	119	120	119	116
COMPLETED	113	116	107	105
NOT COMPLETED	6	4	12	11
Period Title: Crossover Treatment 1 (Cycles 1 to 4)
STARTED	113	116	107	105
COMPLETED	109	109	105	102
NOT COMPLETED	4	7	2	3
Period Title: Crossover Treatment 1 (Cycles 1 to 4)
STARTED	124	124	121	119
COMPLETED	99	106	104	100
NOT COMPLETED	25	18	17	19

Baseline Characteristics

Arm/Group Title	Cohort 1 Overall: SC (SID) and IV Herceptin	Cohort 2 Overall: SC (Vial) and IV Herceptin	Total
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via SID for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via handheld syringe using the vial formulation for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received SC Herceptin for up to 10 remaining cycles. Administration was performed by HCP throughout the study. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Total of all reporting groups
Overall Participants	244	239	483
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.3 (11.40)	52.9 (10.87)	53.1 (11.13)
Sex: Female, Male (Count of Participants)
Female	244 100%	239 100%	483 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants by Preferred Method of Drug Administration
Description	The preferred method of drug administration (IV or SC Herceptin) was assessed in trial-specific telephone interviews with each study participant. Participants were asked, "All things considered, which method of administration did you prefer?" at the end of the crossover period (Week 24). The percentage of participants who preferred each method of drug administration was reported.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: All participants who received both IV and SC Herceptin and who completed the trial-specific telephone interview conducted after the end of the crossover period.

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin	Cohort 2: SC (Vial) Then IV Herceptin	Cohort 2: IV Then SC (Vial) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via handheld syringe using the vial formulation. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	117	119	118	113
SC Herceptin	95.7 39.2%	87.4 36.6%	83.9 17.4%	88.5 NaN
IV Herceptin	4.3 1.8%	9.2 3.8%	13.6 2.8%	11.5 NaN
No Preference	0.0 0%	3.4 1.4%	2.5 0.5%	0.0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: SC (SID) Then IV Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.957
	Confidence Interval	(2-Sided) 95%; 0.903 to 0.986
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding exact binomial confidence interval (CI) were determined.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: SC (SID) Then IV Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.964
	Confidence Interval	(2-Sided) 95%; 0.908 to 0.986
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding CI were determined using logistic regression with factors of previous Herceptin status and treatment.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: IV Then SC (SID) Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.874
	Confidence Interval	(2-Sided) 95%; 0.801 to 0.928
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding exact binomial CI were determined.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: IV Then SC (SID) Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.892
	Confidence Interval	(2-Sided) 95%; 0.804 to 0.943
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding CI were determined using logistic regression with factors of previous Herceptin status and treatment.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: SC (Vial) Then IV Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.839
	Confidence Interval	(2-Sided) 95%; 0.760 to 0.900
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding exact binomial CI were determined.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: SC (Vial) Then IV Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.874
	Confidence Interval	(2-Sided) 95%; 0.776 to 0.933
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding CI were determined using logistic regression with factors of previous Herceptin status and treatment.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: IV Then SC (Vial) Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.885
	Confidence Interval	(2-Sided) 95%; 0.811 to 0.937
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding exact binomial CI were determined.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: IV Then SC (Vial) Herceptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimated Proportion
	Estimated Value	0.911
	Confidence Interval	(2-Sided) 95%; 0.827 to 0.956
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated proportion of participants who preferred SC Herceptin and the corresponding CI were determined using logistic regression with factors of previous Herceptin status and treatment.

2. Secondary Outcome

Title	Percentage of HCPs by Most Satisfied Method of Drug Administration
Description	The method of drug administration with which HCPs were most satisfied (IV or SC Herceptin) was assessed via questionnaire with each HCP using the question, "All things considered, with which method of administration were you most satisfied?" at the end of the crossover period (Week 24). The percentage of HCPs who were most satisfied with each method of drug administration was reported.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

HCP Population: All HCPs who participated in the study and completed the HCP questionnaire. Results were planned to be analyzed for all HCPs combined because the objective of the study was to compare preference between SC and IV Herceptin.

Arm/Group Title	All HCPs: SC and IV Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via SID (Cohort 1) or vial (Cohort 2) for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received IV Herceptin (Cohort 1) or SC Herceptin (Cohort 2) for up to 10 remaining cycles. Participants in Cohort 1 with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered to self-administer SC Herceptin via SID under the direction of a trained HCP, whereas in Cohort 2, administration was performed by HCP throughout the study. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for both SID and vial.
Measure Participants	235
Measure HCPs	235
SC Herceptin	77.0
IV Herceptin	3.0
No Preference	20.0

3. Secondary Outcome

Title	Percentage of HCPs by Time Required to Perform Each Method of Drug Administration
Description	The time required to perform each method of drug administration was assessed via questionnaire with each HCP by asking to rate the amount of time it took to administer each method of drug administration (IV or SC Herceptin) at the end of the crossover period (Week 24). Time was rated in the following time block categories: less than (<) 5 minutes, 6 to 10 minutes, 11 to 15 minutes, 16 to 20 minutes, and greater than (>) 20 minutes. Responses of "Not Sure" and "Unknown" were also allowed. The percentage of HCPs who rated the amount of time in each of the categories was reported.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

HCP Population. Results were planned to be analyzed for all HCPs combined because the objective of the study was to compare HCP perceived time savings with use of SC over IV Herceptin.

Arm/Group Title	All HCPs: SC and IV Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via SID (Cohort 1) or vial (Cohort 2) for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received IV Herceptin (Cohort 1) or SC Herceptin (Cohort 2) for up to 10 remaining cycles. Participants in Cohort 1 with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered to self-administer SC Herceptin via SID under the direction of a trained HCP, whereas in Cohort 2, administration was performed by HCP throughout the study. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for both SID and vial.
Measure Participants	235
Measure HCPs	235
SC Herceptin, <5 minutes	44.3
SC Herceptin, 6 to 10 minutes	46.4
SC Herceptin, 11 to 15 minutes	3.4
SC Herceptin, 16 to 20 minutes	0.4
SC Herceptin, >20 minutes	0.4
SC Herceptin, Not Sure	0.0
SC Herceptin, Unknown	5.1
IV Herceptin, <5 minutes	11.1
IV Herceptin, 6 to 10 minutes	9.8
IV Herceptin, 11 to 15 minutes	3.8
IV Herceptin, 16 to 20 minutes	44.3
IV Herceptin, >20 minutes	22.1
IV Herceptin, Not Sure	5.1
IV Herceptin, Unknown	3.8

4. Secondary Outcome

Title	Percentage of Participants With an Event-Free Survival (EFS) Event
Description	EFS events included local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The percentage of participants who had an EFS event at any time on study was reported.
Time Frame	From Baseline until time of event; assessed every 6 months (median follow-up of 3 years)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin	Cohort 2: SC (Vial) Then IV Herceptin	Cohort 2: IV Then SC (Vial) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via handheld syringe using the vial formulation. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	117	119	118	113
Number [percentage of participants]	13.7 5.6%	6.7 2.8%	11.9 2.5%	7.1 NaN

5. Secondary Outcome

Title	Duration of EFS According to Kaplan-Meier Estimate
Description	EFS was defined as the time from randomization to a local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The median duration of EFS and corresponding 95 percent (%) CI according to Kaplan-Meier estimates were planned to be reported and expressed in months.
Time Frame	From Baseline until time of event; assessed every 6 months (median follow-up of 3 years)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin	Cohort 2: SC (Vial) Then IV Herceptin	Cohort 2: IV Then SC (Vial) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via handheld syringe using the vial formulation. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	117	119	118	113
Median (95% Confidence Interval) [months]	NA	NA	NA	NA

6. Secondary Outcome

Title	3-Year EFS Rate
Description	EFS events included local, regional, or distant recurrence of the original breast cancer, occurrence of contralateral breast cancer, or death due to any cause. The proportion of participants without an EFS event (i.e., the EFS rate) and corresponding 95% CI at 3 years after randomization was reported.
Time Frame	Year 3

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin	Cohort 2: SC (Vial) Then IV Herceptin	Cohort 2: IV Then SC (Vial) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via handheld syringe using the vial formulation, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via handheld syringe using the vial formulation. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP throughout the study. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	117	119	118	113
Number (95% Confidence Interval) [proportion of participants]	0.849 0.3%	0.948 0.4%	0.886 0.2%	0.937 NaN

7. Secondary Outcome

Title	Percentage of Participants With Responses of "Agree" or "Strongly Agree" on the SC SID Satisfaction Questionnaire
Description	Participants who performed self-administration of SC Herceptin via SID were given an evaluation questionnaire during the continuation period (Weeks 25 to 52) after their first self-administration. Participants responded to 5 statements about their comfort with self-injection, the convenience of the SID, their self-confidence using the SID, their satisfaction with the SID, and whether they would consider using the SID again in the future. Each statement used a 5-item rating scale with responses from "Strongly Disagree" to "Strongly Agree". The percentage of participants with a positive response (either "Agree" or "Strongly Agree") to each questionnaire statement was reported.
Time Frame	Immediately following first self-administration of SC Herceptin via SID (once during Weeks 25 to 52)

Outcome Measure Data

Analysis Population Description

Safety Population. The "Number of Participants Analyzed" reflects those who self-administered SC Herceptin using the SID and completed the SC SID questionnaire. Results were planned to be analyzed for only Cohort 1 because the objective of the study was to evaluate satisfaction among those who self-administered the SID formulation of Herceptin.

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	19	15
Comfortable	94.7 38.8%	86.7 36.3%
Convenient	100 41%	100 41.8%
Confident	100 41%	100 41.8%
Satisfied	100 41%	93.3 39%
Would Use Again	100 41%	93.3 39%

8. Secondary Outcome

Title	Percentage of Participants With Anti-Trastuzumab or Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies
Description	Participants in Cohort 1 provided blood samples for immunogenicity testing to assess for anti-drug antibodies (ADAs) to trastuzumab or rHuPH20, a component of the SC Herceptin formulation. The percentage of participants who were trastuzumab ADA-positive and the percentage of participants who were rHuPH20 ADA-positive were each reported.
Time Frame	Baseline, pre-dose (0 hours) during Cycle 5 (cycle length of 3 weeks)

Outcome Measure Data

Analysis Population Description

Safety Population. Results were planned to be analyzed for only Cohort 1 because the objective of the study was to evaluate immunogenicity within participants who received the SID formulation of Herceptin. The number of participants who provided ADA samples at each timepoint (n) is shown in the table.

Arm/Group Title	Cohort 1: SC (SID) Then IV Herceptin	Cohort 1: IV Then SC (SID) Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, SC Herceptin was administered via SID, and during Cycles 5 to 8, IV Herceptin was given. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The SC dose was 600 mg for all cycles where SC Herceptin was given, and the IV dose was 6 mg/kg for all cycles where IV Herceptin was given.	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. During Cycles 1 to 4 of the crossover period, IV Herceptin was given, and during Cycles 5 to 8, SC Herceptin was administered via SID. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. The IV dose was a loading dose of 8 mg/kg in Cycle 1 for de novo participants who started Herceptin treatment in the study, and a dose of 6 mg/kg for all subsequent cycles where IV Herceptin was given and for non-de novo participants. The SC dose was 600 mg for all cycles where SC Herceptin was given.
Measure Participants	122	122
Trastuzumab ADA-Positive, Baseline (n=120,121)	2.5 1%	4.1 1.7%
Trastuzumab ADA-Positive, Cycle 5 (n=114,119)	0 0%	3.4 1.4%
rHuPH20 ADA-Positive, Baseline (n=120,121)	5.8 2.4%	7.4 3.1%
rHuPH20 ADA-Positive, Cycle 5 (n=115,119)	2.6 1.1%	7.6 3.2%

Adverse Events

Time Frame	During treatment from Cycles 1 to 8 (crossover period) and Cycles 9 to 18 (continuation period); cycle length of 3 weeks
Adverse Event Reporting Description	Analysis Population Description: Safety Population
Arm/Group Title	Cohort 1: SC (SID) Herceptin (Crossover)		Cohort 1: IV Herceptin (Crossover)		Cohort 1: IV Herceptin (Continuation)		Cohort 1: SC (SID) Herceptin (Continuation)		Cohort 1 Overall: SC (SID) and IV Herceptin		Cohort 2: SC (Vial) Herceptin (Crossover)		Cohort 2: IV Herceptin (Crossover)		Cohort 2: IV Herceptin (Continuation)		Cohort 2: SC (Vial) Herceptin (Continuation)		Cohort 2 Overall: SC (Vial) and IV Herceptin
Arm/Group Description	Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. SC Herceptin was administered via SID as a 600-mg dose during four consecutive cycles of the crossover period. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. IV Herceptin was given as a 6-mg/kg dose during four consecutive cycles of the crossover period. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg (instead of 6 mg/kg) for de novo participants who started Herceptin treatment in the study. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. In the continuation period, participants received IV Herceptin as a 6-mg/kg dose for up to 10 remaining cycles. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID as a 600-mg dose under the direction of a trained HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via SID for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received IV Herceptin for up to 10 remaining cycles. Administration was performed by HCP. Those with at least 2 treatment cycles remaining of the 18-cycle treatment course after the crossover period were offered the opportunity to self-administer SC Herceptin via SID under the direction of a trained HCP. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for all cycles where SC Herceptin was given.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. SC Herceptin was administered via handheld syringe using the vial formulation as a 600-mg dose during four consecutive cycles of the crossover period. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. IV Herceptin was given as a 6-mg/kg dose during four consecutive cycles of the crossover period. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg (instead of 6 mg/kg) for de novo participants who started Herceptin treatment in the study. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. In the continuation period, participants were planned to receive SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. However, under protocol deviation a small number of participants received IV Herceptin as a 6-mg/kg dose for this period. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles. In the continuation period, participants received SC Herceptin via handheld syringe using the vial formulation for up to 10 remaining cycles. Administration was performed by HCP.		Participants received Herceptin on Day 1 of each 3-week cycle for 18 cycles, randomized to one of two crossover sequences: SC Herceptin via handheld syringe using the vial formulation for Cycles 1 to 4 followed by IV Herceptin for Cycles 5 to 8, or vice versa. In the continuation period, participants received SC Herceptin for up to 10 remaining cycles. Administration was performed by HCP throughout the study. If study treatment for Cycle 1 was IV Herceptin, the initial dose was a loading dose of 8 mg/kg for de novo participants who started Herceptin treatment in the study. For all other cycles where IV Herceptin was given and for non-de novo participants, the dose was 6 mg/kg. The SC dose was 600 mg for all cycles where SC Herceptin was given.
All Cause Mortality
	Cohort 1: SC (SID) Herceptin (Crossover)		Cohort 1: IV Herceptin (Crossover)		Cohort 1: IV Herceptin (Continuation)		Cohort 1: SC (SID) Herceptin (Continuation)		Cohort 1 Overall: SC (SID) and IV Herceptin		Cohort 2: SC (Vial) Herceptin (Crossover)		Cohort 2: IV Herceptin (Crossover)		Cohort 2: IV Herceptin (Continuation)		Cohort 2: SC (Vial) Herceptin (Continuation)		Cohort 2 Overall: SC (Vial) and IV Herceptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: SC (SID) Herceptin (Crossover)		Cohort 1: IV Herceptin (Crossover)		Cohort 1: IV Herceptin (Continuation)		Cohort 1: SC (SID) Herceptin (Continuation)		Cohort 1 Overall: SC (SID) and IV Herceptin		Cohort 2: SC (Vial) Herceptin (Crossover)		Cohort 2: IV Herceptin (Crossover)		Cohort 2: IV Herceptin (Continuation)		Cohort 2: SC (Vial) Herceptin (Continuation)		Cohort 2 Overall: SC (Vial) and IV Herceptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/242 (1.7%)		2/241 (0.8%)		6/226 (2.7%)		1/43 (2.3%)		12/244 (4.9%)		0/237 (0%)		2/237 (0.8%)		0/10 (0%)		5/208 (2.4%)		7/239 (2.9%)
Cardiac disorders
Left ventricular dysfunction	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		1/208 (0.5%)		1/239 (0.4%)
General disorders
Adverse drug reaction	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Chest pain	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Hepatobiliary disorders
Cholelithiasis	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		1/237 (0.4%)		0/10 (0%)		0/208 (0%)		1/239 (0.4%)
Infections and infestations
Breast abscess	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Device related infection	1/242 (0.4%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Influenza	0/242 (0%)		1/241 (0.4%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Postoperative wound infection	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Pyelonephritis	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Subcutaneous abscess	1/242 (0.4%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Wound infection	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		1/237 (0.4%)		0/10 (0%)		1/208 (0.5%)		2/239 (0.8%)
Injury, poisoning and procedural complications
Suture related complication	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		1/237 (0.4%)		0/10 (0%)		0/208 (0%)		1/239 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoma benign	1/242 (0.4%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Cerebral haemangioma	0/242 (0%)		0/241 (0%)		0/226 (0%)		1/43 (2.3%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Nervous system disorders
Dizziness	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Psychiatric disorders
Mental disorder	0/242 (0%)		1/241 (0.4%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Reproductive system and breast disorders
Endometrial hypertrophy	0/242 (0%)		0/241 (0%)		1/226 (0.4%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Surgical and medical procedures
Breast reconstruction	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		1/208 (0.5%)		1/239 (0.4%)
Knee arthroplasty	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		1/208 (0.5%)		1/239 (0.4%)
Mammoplasty	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		1/208 (0.5%)		1/239 (0.4%)
Vascular disorders
Haematoma	1/242 (0.4%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		1/244 (0.4%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: SC (SID) Herceptin (Crossover)		Cohort 1: IV Herceptin (Crossover)		Cohort 1: IV Herceptin (Continuation)		Cohort 1: SC (SID) Herceptin (Continuation)		Cohort 1 Overall: SC (SID) and IV Herceptin		Cohort 2: SC (Vial) Herceptin (Crossover)		Cohort 2: IV Herceptin (Crossover)		Cohort 2: IV Herceptin (Continuation)		Cohort 2: SC (Vial) Herceptin (Continuation)		Cohort 2 Overall: SC (Vial) and IV Herceptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/242 (33.5%)		55/241 (22.8%)		46/226 (20.4%)		7/43 (16.3%)		130/244 (53.3%)		107/237 (45.1%)		76/237 (32.1%)		6/10 (60%)		61/208 (29.3%)		154/239 (64.4%)
Cardiac disorders
Sinus bradycardia	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		1/10 (10%)		0/208 (0%)		1/239 (0.4%)
Gastrointestinal disorders
Nausea	14/242 (5.8%)		6/241 (2.5%)		6/226 (2.7%)		1/43 (2.3%)		22/244 (9%)		11/237 (4.6%)		8/237 (3.4%)		0/10 (0%)		3/208 (1.4%)		17/239 (7.1%)
Diarrhoea	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		8/237 (3.4%)		9/237 (3.8%)		0/10 (0%)		9/208 (4.3%)		23/239 (9.6%)
Dyspepsia	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		1/237 (0.4%)		2/237 (0.8%)		1/10 (10%)		0/208 (0%)		3/239 (1.3%)
General disorders
Asthenia	13/242 (5.4%)		10/241 (4.1%)		9/226 (4%)		0/43 (0%)		30/244 (12.3%)		17/237 (7.2%)		15/237 (6.3%)		0/10 (0%)		11/208 (5.3%)		36/239 (15.1%)
Fatigue	8/242 (3.3%)		10/241 (4.1%)		7/226 (3.1%)		0/43 (0%)		23/244 (9.4%)		11/237 (4.6%)		8/237 (3.4%)		1/10 (10%)		5/208 (2.4%)		21/239 (8.8%)
Injection site reaction	19/242 (7.9%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		19/244 (7.8%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Injection site erythema	13/242 (5.4%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		13/244 (5.3%)		15/237 (6.3%)		0/237 (0%)		0/10 (0%)		4/208 (1.9%)		17/239 (7.1%)
Injection site pain	12/242 (5%)		0/241 (0%)		0/226 (0%)		2/43 (4.7%)		13/244 (5.3%)		20/237 (8.4%)		0/237 (0%)		0/10 (0%)		6/208 (2.9%)		24/239 (10%)
Chest pain	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		3/237 (1.3%)		2/237 (0.8%)		1/10 (10%)		0/208 (0%)		6/239 (2.5%)
Medical device discomfort	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		1/10 (10%)		0/208 (0%)		1/239 (0.4%)
Infections and infestations
Nasopharyngitis	5/242 (2.1%)		7/241 (2.9%)		5/226 (2.2%)		1/43 (2.3%)		16/244 (6.6%)		6/237 (2.5%)		3/237 (1.3%)		1/10 (10%)		6/208 (2.9%)		13/239 (5.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/242 (4.1%)		15/241 (6.2%)		12/226 (5.3%)		1/43 (2.3%)		33/244 (13.5%)		15/237 (6.3%)		12/237 (5.1%)		0/10 (0%)		10/208 (4.8%)		33/239 (13.8%)
Pain in extremity	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		15/237 (6.3%)		5/237 (2.1%)		0/10 (0%)		2/208 (1%)		19/239 (7.9%)
Myalgia	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		2/237 (0.8%)		3/237 (1.3%)		1/10 (10%)		4/208 (1.9%)		10/239 (4.2%)
Back pain	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		3/237 (1.3%)		4/237 (1.7%)		1/10 (10%)		1/208 (0.5%)		7/239 (2.9%)
Bone pain	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		1/237 (0.4%)		1/237 (0.4%)		1/10 (10%)		4/208 (1.9%)		7/239 (2.9%)
Nervous system disorders
Headache	8/242 (3.3%)		6/241 (2.5%)		10/226 (4.4%)		0/43 (0%)		21/244 (8.6%)		12/237 (5.1%)		11/237 (4.6%)		0/10 (0%)		11/208 (5.3%)		29/239 (12.1%)
Dizziness	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		7/237 (3%)		2/237 (0.8%)		1/10 (10%)		1/208 (0.5%)		11/239 (4.6%)
Respiratory, thoracic and mediastinal disorders
Cough	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		3/237 (1.3%)		5/237 (2.1%)		0/10 (0%)		6/208 (2.9%)		13/239 (5.4%)
Skin and subcutaneous tissue disorders
Erythema	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		15/237 (6.3%)		3/237 (1.3%)		0/10 (0%)		6/208 (2.9%)		20/239 (8.4%)
Toxic skin eruption	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		0/237 (0%)		1/10 (10%)		0/208 (0%)		1/239 (0.4%)
Vascular disorders
Hot flush	8/242 (3.3%)		6/241 (2.5%)		3/226 (1.3%)		1/43 (2.3%)		18/244 (7.4%)		14/237 (5.9%)		11/237 (4.6%)		0/10 (0%)		5/208 (2.4%)		27/239 (11.3%)
Hypertension	7/242 (2.9%)		1/241 (0.4%)		5/226 (2.2%)		1/43 (2.3%)		13/244 (5.3%)		0/237 (0%)		0/237 (0%)		0/10 (0%)		0/208 (0%)		0/239 (0%)
Lymphoedema	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		5/237 (2.1%)		7/237 (3%)		0/10 (0%)		2/208 (1%)		13/239 (5.4%)
Thrombosis	0/242 (0%)		0/241 (0%)		0/226 (0%)		0/43 (0%)		0/244 (0%)		0/237 (0%)		2/237 (0.8%)		1/10 (10%)		0/208 (0%)		2/239 (0.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.