A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer

• ClinicalTrials.gov Identifier: NCT00950300
• Recruitment Status: Completed
• First Posted: July 31, 2009
• Results First Posted: January 23, 2017
• Last Update Posted: January 23, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: 5-Fluorouracil; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Epirubicin; Drug: Herceptin IV [trastuzumab]; Drug: Herceptin SC [trastuzumab]
• Enrollment: 596

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 833 participants were screened, out of which, 596 participants were enrolled into the study.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m^2, epirubicin 75 mg/m^2, and cyclophosphamide 500 mg/m^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Period Title: Neoadjuvant/Adjuvant Treatment Periods
Started	299	297
Received Neoadjuvant Treatment	298	297
Underwent Surgery	277	273
Entered Adjuvant Treatment	277	274
Completed	257	255
Not Completed	42	42
Reason Not Completed
Adverse Event or Intercurrent Illness	6	15
Death	1	3
Insufficient Therapeutic Response	3	0
Violation of Selection Criteria	2	1
Protocol Violation	1	0
Participant Refusal/Withdrawal	4	5
Lost to Follow-up	2	1
Progression of Disease	12	11
Recurrence of Disease	10	5
Other	1	1
Period Title: TFFU Period
Started	265 [1]	268 [1]
Completed	165 [2]	161 [2]
Not Completed	100	107
Reason Not Completed
Adverse Event or Intercurrent Illness	3	4
Death	4	1
Refused Treatment	10	11
Failure to Return	16	16
Recurrence of Disease	63	72
Other	4	3
[1] Participants could withdraw from the study entirely or advance directly to the TFFU or SFU Period.; [2] Includes participants who completed either 2 years of follow-up or 5 years of follow-up.
Period Title: SFU Period
Started	118 [1]	123 [1]
Completed	40 [2]	45 [2]
Not Completed	78	78
Reason Not Completed
Death	44	42
Lost to Follow-up	30	28
Withdrawal by Subject	4	8
[1] Participants could withdraw from the study entirely or advance directly to the SFU Period.; [2] Includes participants who completed either 2 years of follow-up or 5 years of follow-up.

Baseline Characteristics

Arm/Group Title		Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy	Total
Arm/Group Description		Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Total of all reporting groups
Overall Number of Baseline Participants		297	294	591
Baseline Analysis Population Description		Intent-to-Treat (ITT) Population: All participants with at least one efficacy assessment after administration of the first treatment cycle.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	297 participants	294 participants	591 participants
		49.5 (10.83)	50.3 (11.08)	49.9 (10.95)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	297 participants	294 participants	591 participants
	Female	297 100.0%	294 100.0%	591 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery
Description	Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL).
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Primary Pharmacokinetic (PK) Per Protocol (PP) Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the primary endpoint.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	235	234
Mean (Standard Deviation); Unit of Measure: μg/mL
	57.8 (30.3)	78.7 (43.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	PK sample size calculations based on percentage of coefficient of variation (CV%) for Ctrough of trastuzumab from previous metastatic breast cancer (MBC) and early breast cancer (EBC) studies. Because pre-surgery situation was comparable to MBC setting, interpatient CV% of 60 percent (%) was assumed and 130 participants per arm (260 participants total) were needed to demonstrate Ctrough comparability with 80% power if the true means of the two formulations did not differ by greater than (>) 5%.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was concluded if the lower limit of the 90% confidence interval (CI) was greater than or equal to (≥) 0.8 for the geometric mean ratio.
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 90%; 1.24 to 1.44
	Estimation Comments	Ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

2. Primary Outcome

Title	Percentage of Participants With Pathological Complete Response (pCR)
Description	Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time Frame	After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

Outcome Measure Data

Analysis Population Description

Efficacy (E) PP Population: All participants with at least one on-treatment efficacy assessment who received a full eight cycles of study treatment according to randomization and who met additional protocol-specified criteria.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	263	260
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	40.7; (34.7 to 46.9)	45.4; (39.2 to 51.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	Assuming pCR rates of at least 40% in both arms, 552 participants were necessary to conclude non-inferiority in pCR rate with a power of 80% using a one-sided 97.5% CI for the difference of the response rates and a non-inferiority margin of 12.5%.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was concluded if the lower limit of the one-sided 97.5% CI was above -12.5% for the difference in response (pCR) rates.
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	4.70
	Confidence Interval	(1-Sided) 97.5%; -4.0
	Estimation Comments	The one-sided 97.5% CI for the difference in response (pCR) rates was calculated using the Anderson-Hauck continuity correction.

3. Secondary Outcome

Title	Observed Ctrough of Trastuzumab After Surgery
Description	Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL.
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Secondary PKPP Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the secondary endpoint.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	223	227
Mean (Standard Deviation); Unit of Measure: μg/mL
	62.1 (37.1)	90.4 (41.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	Additional supportive analysis.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 90%; 1.40 to 1.63
	Estimation Comments	Ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

4. Secondary Outcome

Title	Predicted Ctrough of Trastuzumab Prior to Surgery
Description	Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

PKPP Population: All participants with at least one measurable trastuzumab serum concentration.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	276	278
Mean (Standard Deviation); Unit of Measure: μg/mL
	51.4 (19.4)	80.3 (33.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	Additional supportive analysis.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 90%; 1.46 to 1.64
	Estimation Comments	Ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

5. Secondary Outcome

Title	Predicted Ctrough of Trastuzumab After Surgery
Description	Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

PKPP Population; only participants with a Cycle 13 pre-dose PK measurement were included in the analysis.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	236	236
Mean (Standard Deviation); Unit of Measure: μg/mL
	51.7 (20.0)	80.6 (33.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	Additional supportive analysis.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 90%; 1.45 to 1.64
	Estimation Comments	Ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

6. Secondary Outcome

Title	Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery
Description	Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough >20 μg/mL was reported.
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Primary PKPP Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	235	234
Measure Type: Number; Unit of Measure: participants
	232	227

7. Secondary Outcome

Title	Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery
Description	Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough >20 μg/mL was reported.
Time Frame	Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Secondary PKPP Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	223	227
Measure Type: Number; Unit of Measure: participants
	216	227

8. Secondary Outcome

Title	Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery
Description	PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in μg/mL.
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Primary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	235	233
Mean (Standard Deviation); Unit of Measure: μg/mL
	221 (118)	149 (64.8)

9. Secondary Outcome

Title	Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery
Description	PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Primary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	235	233
Mean (Standard Deviation); Unit of Measure: days
	0.05 (0.04)	4.12 (2.91)

10. Secondary Outcome

Title	Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery
Description	PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d*μg/mL).
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Primary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	235	233
Mean (Standard Deviation); Unit of Measure: d*μg/mL
	2056 (598)	2268 (875)

11. Secondary Outcome

Title	Cmax of Trastuzumab After Surgery
Description	PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL.
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Secondary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	223	223
Mean (Standard Deviation); Unit of Measure: μg/mL
	230 (118)	166 (58.8)

12. Secondary Outcome

Title	Tmax of Trastuzumab After Surgery
Description	PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Secondary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	223	222
Mean (Standard Deviation); Unit of Measure: days
	0.06 (0.13)	4.08 (2.87)

13. Secondary Outcome

Title	AUC21d of Trastuzumab After Surgery
Description	PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d*μg/mL.
Time Frame	Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Outcome Measure Data

Analysis Population Description

Secondary PKPP Population; only those participants who provided evaluable data were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	223	223
Mean (Standard Deviation); Unit of Measure: d*μg/mL
	2179 (725)	2610 (945)

14. Secondary Outcome

Title	Percentage of Participants With Total Pathological Complete Response (tpCR)
Description	Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time Frame	After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

Outcome Measure Data

Analysis Population Description

EPP Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	263	260
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	34.2; (28.5 to 40.3)	39.2; (33.3 to 45.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	5.01
	Confidence Interval	(2-Sided) 95%; -3.5 to 13.5
	Estimation Comments	The 95% CI for the difference in response (tpCR) rates was calculated using the Anderson-Hauck continuity correction.

15. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline
Description	Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (≥) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.
Time Frame	Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall)

Outcome Measure Data

Analysis Population Description

EPP Population; only participants with measurable disease at Baseline were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	260	258
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	88.8; (84.4 to 92.4)	87.2; (82.5 to 91.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-1.64
	Confidence Interval	(2-Sided) 95%; -7.4 to 4.2
	Estimation Comments	The 95% CI for the difference in response (CR+PR) rates was calculated using the Anderson-Hauck continuity correction.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.46
	Estimation Comments	OR of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

16. Secondary Outcome

Title	Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline
Description	Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm with no prior assessment of PD. PR was defined as ≥30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR.
Time Frame	Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall)

Outcome Measure Data

Analysis Population Description

EPP Population; only participants with measurable disease at Baseline and a response of CR or PR were included.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	231	225
Median (Full Range); Unit of Measure: weeks
	6.14; (3 to 25)	6.14; (3 to 28)

17. Secondary Outcome

Title	Percentage of Participants Who Experienced a Protocol-Defined Event
Description	Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.
Time Frame	Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	297	294
Measure Type: Number; Unit of Measure: percentage of participants
	33.3	32.7

18. Secondary Outcome

Title	Event-Free Survival (EFS)
Description	Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event.
Time Frame	Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	297	294
Median (Full Range); Unit of Measure: months
	NA [1]; (1 to 82)	NA [1]; (1 to 76)

[1]

The median time to event could not be determined because of a high number (>50%) of censored observations. Full range includes censored observations.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8651
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.29
	Estimation Comments	HR of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

19. Secondary Outcome

Title	Percentage of Participants Who Died
Description	The percentage of participants who died at any time during the study was reported.
Time Frame	Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	297	294
Measure Type: Number; Unit of Measure: percentage of participants
	14.5	13.6

20. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.
Time Frame	Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	297	294
Median (Full Range); Unit of Measure: months
	NA [1]; (2 to 82)	NA [1]; (3 to 79)

[1]

The median time to event could not be determined because of a high number (>50%) of censored observations. Full range includes censored observations.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin IV + Chemotherapy, Herceptin SC + Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7767
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.45
	Estimation Comments	HR of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

21. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab
Description	Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
Time Frame	Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of study medication. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.

Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	296	295
Measure Type: Number; Unit of Measure: participants
Treatment-induced ADAs	28	46
Treatment-enhanced ADA	2	1

22. Secondary Outcome

Title	Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20)
Description	Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).
Time Frame	Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18

Outcome Measure Data

Analysis Population Description

Safety Population; as rHuPH20 is unique to SC formulation, this outcome measure was applicable for "Herceptin SC + Chemotherapy" arm only. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.

Arm/Group Title	Herceptin SC + Chemotherapy
Arm/Group Description:	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Number of Participants Analyzed	295
Measure Type: Number; Unit of Measure: participants
Treatment-induced ADA	49
Treatment-enhanced ADA	13

Adverse Events

Time Frame	Approximately 87 months overall
Adverse Event Reporting Description	Analysis was performed on Safety Population.
Arm/Group Title	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
Arm/Group Description	Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
All-Cause Mortality
	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	45/298 (15.10%)	65/297 (21.89%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	10/298 (3.36%)	13/297 (4.38%)
Neutropenia * 1	9/298 (3.02%)	7/297 (2.36%)
Leukopenia * 1	0/298 (0.00%)	1/297 (0.34%)
Thrombocytopenia * 1	0/298 (0.00%)	1/297 (0.34%)
Lymphadenopathy * 1	1/298 (0.34%)	0/297 (0.00%)
Cardiac disorders
Cardiac failure congestive * 1	0/298 (0.00%)	2/297 (0.67%)
Arrhythmia * 1	0/298 (0.00%)	1/297 (0.34%)
Myocardial infarction * 1	1/298 (0.34%)	1/297 (0.34%)
Angina pectoris * 1	1/298 (0.34%)	0/297 (0.00%)
Atrial fibrillation * 1	0/298 (0.00%)	1/297 (0.34%)
Coronary artery disease * 1	1/298 (0.34%)	0/297 (0.00%)
Myocardial ischaemia * 1	0/298 (0.00%)	1/297 (0.34%)
Endocrine disorders
Goitre * 1	1/298 (0.34%)	0/297 (0.00%)
Gastrointestinal disorders
Haemorrhoids * 1	1/298 (0.34%)	1/297 (0.34%)
Nausea * 1	1/298 (0.34%)	1/297 (0.34%)
Diarrhoea * 1	1/298 (0.34%)	0/297 (0.00%)
Vomiting * 1	1/298 (0.34%)	0/297 (0.00%)
General disorders
Pyrexia * 1	0/298 (0.00%)	2/297 (0.67%)
General physical health deterioration * 1	0/298 (0.00%)	1/297 (0.34%)
Sudden death * 1	0/298 (0.00%)	1/297 (0.34%)
Death * 1	1/298 (0.34%)	0/297 (0.00%)
Immune system disorders
Hypersensitivity * 1	2/298 (0.67%)	0/297 (0.00%)
Infections and infestations
Respiratory tract infection viral * 1	0/298 (0.00%)	1/297 (0.34%)
Tonsillitis * 1	0/298 (0.00%)	2/297 (0.67%)
Pneumonia * 1	4/298 (1.34%)	2/297 (0.67%)
Atypical pneumonia * 1	0/298 (0.00%)	1/297 (0.34%)
Cellulitis * 1	0/298 (0.00%)	2/297 (0.67%)
Febrile infection * 1	1/298 (0.34%)	0/297 (0.00%)
Gastroenteritis * 1	1/298 (0.34%)	0/297 (0.00%)
H1N1 influenza * 1	1/298 (0.34%)	0/297 (0.00%)
Hepatitis B * 1	1/298 (0.34%)	0/297 (0.00%)
Lower respiratory tract infection * 1	0/298 (0.00%)	2/297 (0.67%)
Periorbital cellulitis * 1	0/298 (0.00%)	1/297 (0.34%)
Postoperative wound infection * 1	0/298 (0.00%)	2/297 (0.67%)
Respiratory tract infection * 1	0/298 (0.00%)	1/297 (0.34%)
Septic shock * 1	0/298 (0.00%)	1/297 (0.34%)
Urinary tract infection * 1	1/298 (0.34%)	0/297 (0.00%)
Cystitis * 1	0/298 (0.00%)	1/297 (0.34%)
Abscess * 1	0/298 (0.00%)	1/297 (0.34%)
Encephalitis viral * 1	0/298 (0.00%)	1/297 (0.34%)
Herpes zoster * 1	0/298 (0.00%)	1/297 (0.34%)
Infected lymphocele * 1	1/298 (0.34%)	0/297 (0.00%)
Infection * 1	1/298 (0.34%)	0/297 (0.00%)
Post procedural infection * 1	0/298 (0.00%)	1/297 (0.34%)
Pyelonephritis acute * 1	0/298 (0.00%)	1/297 (0.34%)
Sepsis * 1	0/298 (0.00%)	1/297 (0.34%)
Wound infection * 1	0/298 (0.00%)	1/297 (0.34%)
Mastitis * 1	1/298 (0.34%)	1/297 (0.34%)
Tonsillitis bacterial * 1	0/298 (0.00%)	1/297 (0.34%)
Breast abscess * 1	1/298 (0.34%)	1/297 (0.34%)
Injury, poisoning and procedural complications
Post procedural haematoma * 1	1/298 (0.34%)	0/297 (0.00%)
Radius fracture * 1	1/298 (0.34%)	1/297 (0.34%)
Humerus fracture * 1	1/298 (0.34%)	0/297 (0.00%)
Incision site haematoma * 1	1/298 (0.34%)	0/297 (0.00%)
Lumbar vertebral fracture * 1	0/298 (0.00%)	1/297 (0.34%)
Pulmonary radiation injury * 1	0/298 (0.00%)	1/297 (0.34%)
Radiation pneumonitis * 1	1/298 (0.34%)	0/297 (0.00%)
Investigations
Tumour marker increased * 1	0/298 (0.00%)	1/297 (0.34%)
Ejection fraction * 1	0/298 (0.00%)	1/297 (0.34%)
Musculoskeletal and connective tissue disorders
Back pain * 1	0/298 (0.00%)	1/297 (0.34%)
Spinal pain * 1	0/298 (0.00%)	1/297 (0.34%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer * 1	0/298 (0.00%)	2/297 (0.67%)
Myeloid leukaemia * 1	1/298 (0.34%)	0/297 (0.00%)
Thyroid cancer * 1	0/298 (0.00%)	1/297 (0.34%)
Nervous system disorders
Dizziness * 1	0/298 (0.00%)	1/297 (0.34%)
Cerebrovascular accident * 1	0/298 (0.00%)	1/297 (0.34%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous * 1	0/298 (0.00%)	1/297 (0.34%)
Pregnancy * 1	0/298 (0.00%)	1/297 (0.34%)
Psychiatric disorders
Anxiety * 1	1/298 (0.34%)	0/297 (0.00%)
Depression * 1	0/298 (0.00%)	1/297 (0.34%)
Schizophrenia * 1	0/298 (0.00%)	1/297 (0.34%)
Renal and urinary disorders
Renal colic * 1	0/298 (0.00%)	1/297 (0.34%)
Reproductive system and breast disorders
Menorrhagia * 1	0/298 (0.00%)	1/297 (0.34%)
Ovarian haemorrhage * 1	0/298 (0.00%)	1/297 (0.34%)
Ovarian mass * 1	1/298 (0.34%)	0/297 (0.00%)
Vaginal prolapse * 1	0/298 (0.00%)	1/297 (0.34%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax * 1	1/298 (0.34%)	0/297 (0.00%)
Emphysema * 1	1/298 (0.34%)	0/297 (0.00%)
Pleural effusion * 1	0/298 (0.00%)	2/297 (0.67%)
Pulmonary embolism * 1	0/298 (0.00%)	2/297 (0.67%)
Skin and subcutaneous tissue disorders
Erythema multiforme * 1	0/298 (0.00%)	1/297 (0.34%)
Vascular disorders
Lymphorrhoea * 1	0/298 (0.00%)	1/297 (0.34%)
Haematoma * 1	1/298 (0.34%)	1/297 (0.34%)
Thrombophlebitis * 1	0/298 (0.00%)	1/297 (0.34%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (19.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Herceptin IV + Chemotherapy	Herceptin SC + Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)
Total	277/298 (92.95%)	283/297 (95.29%)
Blood and lymphatic system disorders
Neutropenia * 1	135/298 (45.30%)	128/297 (43.10%)
Leukopenia * 1	46/298 (15.44%)	30/297 (10.10%)
Anaemia * 1	41/298 (13.76%)	34/297 (11.45%)
Gastrointestinal disorders
Nausea * 1	147/298 (49.33%)	145/297 (48.82%)
Diarrhoea * 1	109/298 (36.58%)	101/297 (34.01%)
Vomiting * 1	69/298 (23.15%)	69/297 (23.23%)
Stomatitis * 1	51/298 (17.11%)	57/297 (19.19%)
Constipation * 1	45/298 (15.10%)	43/297 (14.48%)
Dyspepsia * 1	30/298 (10.07%)	33/297 (11.11%)
Abdominal pain upper * 1	27/298 (9.06%)	21/297 (7.07%)
Abdominal pain * 1	16/298 (5.37%)	22/297 (7.41%)
General disorders
Asthenia * 1	75/298 (25.17%)	75/297 (25.25%)
Fatigue * 1	80/298 (26.85%)	70/297 (23.57%)
Mucosal inflammation * 1	39/298 (13.09%)	31/297 (10.44%)
Pyrexia * 1	35/298 (11.74%)	35/297 (11.78%)
Oedema peripheral * 1	30/298 (10.07%)	23/297 (7.74%)
Injection site pain * 1	0/298 (0.00%)	18/297 (6.06%)
Oedema * 1	15/298 (5.03%)	10/297 (3.37%)
Pain * 1	15/298 (5.03%)	12/297 (4.04%)
Infections and infestations
Nasopharyngitis * 1	40/298 (13.42%)	24/297 (8.08%)
Upper respiratory tract infection * 1	30/298 (10.07%)	30/297 (10.10%)
Urinary tract infection * 1	22/298 (7.38%)	10/297 (3.37%)
Pharyngitis * 1	11/298 (3.69%)	15/297 (5.05%)
Injury, poisoning and procedural complications
Incision site pain * 1	24/298 (8.05%)	33/297 (11.11%)
Procedural pain * 1	16/298 (5.37%)	18/297 (6.06%)
Radiation skin injury * 1	34/298 (11.41%)	41/297 (13.80%)
Investigations
Alanine aminotransferase increased * 1	19/298 (6.38%)	16/297 (5.39%)
Metabolism and nutrition disorders
Decreased appetite * 1	59/298 (19.80%)	58/297 (19.53%)
Musculoskeletal and connective tissue disorders
Myalgia * 1	54/298 (18.12%)	61/297 (20.54%)
Arthralgia * 1	60/298 (20.13%)	53/297 (17.85%)
Musculoskeletal pain * 1	22/298 (7.38%)	18/297 (6.06%)
Back pain * 1	25/298 (8.39%)	26/297 (8.75%)
Pain in extremity * 1	26/298 (8.72%)	29/297 (9.76%)
Bone pain * 1	10/298 (3.36%)	19/297 (6.40%)
Nervous system disorders
Headache * 1	44/298 (14.77%)	50/297 (16.84%)
Peripheral sensory neuropathy * 1	27/298 (9.06%)	33/297 (11.11%)
Dysgeusia * 1	22/298 (7.38%)	24/297 (8.08%)
Dizziness * 1	28/298 (9.40%)	29/297 (9.76%)
Neuropathy peripheral * 1	18/298 (6.04%)	24/297 (8.08%)
Psychiatric disorders
Insomnia * 1	31/298 (10.40%)	26/297 (8.75%)
Reproductive system and breast disorders
Amenorrhoea * 1	10/298 (3.36%)	15/297 (5.05%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	24/298 (8.05%)	35/297 (11.78%)
Epistaxis * 1	18/298 (6.04%)	19/297 (6.40%)
Dyspnoea * 1	22/298 (7.38%)	21/297 (7.07%)
Oropharyngeal pain * 1	19/298 (6.38%)	19/297 (6.40%)
Skin and subcutaneous tissue disorders
Alopecia * 1	188/298 (63.09%)	187/297 (62.96%)
Rash * 1	44/298 (14.77%)	48/297 (16.16%)
Nail disorder * 1	31/298 (10.40%)	29/297 (9.76%)
Palmar-plantar erythrodysaesthesia syndrome * 1	18/298 (6.04%)	20/297 (6.73%)
Pruritus * 1	27/298 (9.06%)	26/297 (8.75%)
Erythema * 1	8/298 (2.68%)	21/297 (7.07%)
Skin hyperpigmentation * 1	24/298 (8.05%)	20/297 (6.73%)
Dermatitis * 1	15/298 (5.03%)	14/297 (4.71%)
Vascular disorders
Hot flush * 1	31/298 (10.40%)	30/297 (10.10%)
Hypertension * 1	14/298 (4.70%)	24/297 (8.08%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (19.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 May 1;5(5):e190339. doi: 10.1001/jamaoncol.2019.0339. Epub 2019 May 9.

Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. doi: 10.1016/S1470-2045(12)70329-7. Epub 2012 Aug 9.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00950300
• Other Study ID Numbers: BO22227; 2008-007326-19 ( EudraCT Number )
• First Submitted: July 30, 2009
• First Posted: July 31, 2009
• Results First Submitted: November 4, 2016
• Results First Posted: January 23, 2017
• Last Update Posted: January 23, 2018