A Study to Compare Subcutaneous (SC) Versus Intravenous (... | NCT00950300

NCT00950300

ID	Type	Description	Link
2008-007326-19	EudraCT Number

Status Module

Description Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Herceptin IV + Chemotherapy	Active Comparator	Participants will receive Herceptin via IV infusion for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin IV will be given on Day 1 of each 21-day cycle, as 8 milligrams per kilogram (mg/kg) for a loading dose during Cycle 1 and as 6 mg/kg during subsequent cycles.	Drug: 5-Fluorouracil Drug: Cyclophosphamide Drug: Docetaxel Drug: Epirubicin Drug: Herceptin IV [trastuzumab]
Herceptin SC + Chemotherapy	Experimental	Participants will receive Herceptin via SC injection for 8 cycles prior to surgery and an additional 10 cycles after surgery. Docetaxel will be co-administered during Cycles 1 to 4; chemotherapy during Cycles 5 to 8 will include 5-fluorouracil, cyclophosphamide, and epirubicin. Herceptin SC will be given on Day 1 of each 21-day cycle, as a 600-milligram (mg) fixed dose.	Drug: 5-Fluorouracil Drug: Cyclophosphamide Drug: Docetaxel Drug: Epirubicin Drug: Herceptin SC [trastuzumab]

Interventions

Name	Type	Description	Arm Group Labels	Other Names
5-Fluorouracil	Drug	Participants will receive 5-fluorouracil, 500 milligrams per meter-squared (mg/m^2) via IV bolus or infusion, on Day 1 of every 21-day cycle during Cycles 5 to 8.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery	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).	Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
Percentage of Participants With Pathological Complete Response (pCR)	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.	After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

Secondary Outcomes

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

Eligibility Module

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Centro Medico San Roque; Oncology Dept		San Miguel de Tucumán		T4000IAK	Argentina
Caipo; Oncology

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
30998824	Derived	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.
22884505

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Herceptin IV + Chemotherapy	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Herceptin IV + Chemotherapy	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.
BG001	Herceptin SC + Chemotherapy	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG00057.8± 30.3 OG00178.7± 43.9

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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%.					Geometric mean ratio	1.33			2-Sided	90	1.24	1.44			Ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

Primary

Percentage of Participants With Pathological Complete Response (pCR)

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.

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.

Posted

Number

95% Confidence Interval

percentage of participants

After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.

Secondary

Observed Ctrough of Trastuzumab After Surgery

Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL.

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.

Posted

Mean

Standard Deviation

μg/mL

Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Predicted Ctrough of Trastuzumab Prior to Surgery

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.

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

Posted

Mean

Standard Deviation

μg/mL

Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Predicted Ctrough of Trastuzumab After Surgery

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.

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

Posted

Mean

Standard Deviation

μg/mL

Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery

Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough >20 μg/mL was reported.

Primary PKPP Population

Posted

Number

participants

Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery

Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough >20 μg/mL was reported.

Secondary PKPP Population

Posted

Number

participants

Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery

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.

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

Posted

Mean

Standard Deviation

μg/mL

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery

PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.

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

Posted

Mean

Standard Deviation

days

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery

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).

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

Posted

Mean

Standard Deviation

d*μg/mL

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.

Secondary

Cmax of Trastuzumab After Surgery

PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL.

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

Posted

Mean

Standard Deviation

μg/mL

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Tmax of Trastuzumab After Surgery

PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.

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

Posted

Mean

Standard Deviation

days

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

AUC21d of Trastuzumab After Surgery

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.

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

Posted

Mean

Standard Deviation

d*μg/mL

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001

Secondary

Percentage of Participants With Total Pathological Complete Response (tpCR)

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.

EPP Population

Posted

Number

95% Confidence Interval

percentage of participants

After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy

Secondary

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

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.

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

Posted

Number

95% Confidence Interval

percentage of participants

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.

Secondary

Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline

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.

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

Posted

Median

Full Range

weeks

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.

Secondary

Percentage of Participants Who Experienced a Protocol-Defined Event

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.

ITT Population

Posted

Number

percentage of participants

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001

Secondary

Event-Free Survival (EFS)

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.

ITT Population

Posted

Median

Full Range

months

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy

Secondary

Percentage of Participants Who Died

The percentage of participants who died at any time during the study was reported.

ITT Population

Posted

Number

percentage of participants

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)

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Overall Survival (OS)

OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.

ITT Population

Posted

Median

Full Range

months

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.
OG001	Herceptin SC + Chemotherapy	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.

Secondary

Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab

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).

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.

Posted

Number

participants

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

ID	Title	Description
OG000	Herceptin IV + Chemotherapy	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.

Secondary

Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20)

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).

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.

Posted

Number

participants

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

ID	Title	Description
OG000	Herceptin SC + Chemotherapy	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Herceptin IV + Chemotherapy	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.			45	298	277	298
EG001	Herceptin SC + Chemotherapy	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.			65	297	283	297

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Respiratory tract infection viral	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Lymphorrhoea	Vascular disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Endometrial cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Goitre	Endocrine disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Emphysema	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00010 affected298 at risk EG00113 affected297 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0009 affected298 at risk EG0017 affected297 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Tonsillitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Pneumonia	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0004 affected298 at risk EG0012 affected297 at risk
Atypical pneumonia	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Cellulitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Febrile infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Gastroenteritis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
H1N1 influenza	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Hepatitis B	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Periorbital cellulitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Postoperative wound infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Respiratory tract infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Septic shock	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Urinary tract infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Cystitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Abscess	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Encephalitis viral	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Herpes zoster	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Infected lymphocele	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Post procedural infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Pyelonephritis acute	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Sepsis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Wound infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Haemorrhoids	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Nausea	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Vomiting	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Pyrexia	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
General physical health deterioration	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Sudden death	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Arrhythmia	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Myocardial infarction	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Angina pectoris	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Coronary artery disease	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Anxiety	Psychiatric disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Depression	Psychiatric disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Schizophrenia	Psychiatric disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Haematoma	Vascular disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Thrombophlebitis	Vascular disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Hypersensitivity	Immune system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0002 affected298 at risk EG0010 affected297 at risk
Post procedural haematoma	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Incision site haematoma	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Lumbar vertebral fracture	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Pulmonary radiation injury	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Radiation pneumonitis	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Pregnancy	Pregnancy, puerperium and perinatal conditions	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0012 affected297 at risk
Dizziness	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Renal colic	Renal and urinary disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Menorrhagia	Reproductive system and breast disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Ovarian haemorrhage	Reproductive system and breast disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Ovarian mass	Reproductive system and breast disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Vaginal prolapse	Reproductive system and breast disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Tumour marker increased	Investigations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Erythema multiforme	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Mastitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk
Tonsillitis bacterial	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Death	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0010 affected297 at risk
Ejection fraction	Investigations	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Spinal pain	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG0011 affected297 at risk
Breast abscess	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG0001 affected298 at risk EG0011 affected297 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG000188 affected298 at risk EG001187 affected297 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00044 affected298 at risk EG00148 affected297 at risk
Nail disorder	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00031 affected298 at risk EG00129 affected297 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00018 affected298 at risk EG00120 affected297 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00027 affected298 at risk EG00126 affected297 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG0008 affected298 at risk EG00121 affected297 at risk
Nausea	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG000147 affected298 at risk EG001145 affected297 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG000109 affected298 at risk EG001101 affected297 at risk
Vomiting	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00069 affected298 at risk EG00169 affected297 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00051 affected298 at risk EG00157 affected297 at risk
Constipation	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00045 affected298 at risk EG00143 affected297 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00030 affected298 at risk EG00133 affected297 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00027 affected298 at risk EG00121 affected297 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00016 affected298 at risk EG00122 affected297 at risk
Asthenia	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00075 affected298 at risk EG00175 affected297 at risk
Fatigue	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00080 affected298 at risk EG00170 affected297 at risk
Mucosal inflammation	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00039 affected298 at risk EG00131 affected297 at risk
Pyrexia	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00035 affected298 at risk EG00135 affected297 at risk
Oedema peripheral	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00030 affected298 at risk EG00123 affected297 at risk
Injection site pain	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG0000 affected298 at risk EG00118 affected297 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG000135 affected298 at risk EG001128 affected297 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00046 affected298 at risk EG00130 affected297 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00041 affected298 at risk EG00134 affected297 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00054 affected298 at risk EG00161 affected297 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00060 affected298 at risk EG00153 affected297 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00022 affected298 at risk EG00118 affected297 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00025 affected298 at risk EG00126 affected297 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00026 affected298 at risk EG00129 affected297 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00010 affected298 at risk EG00119 affected297 at risk
Headache	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00044 affected298 at risk EG00150 affected297 at risk
Peripheral sensory neuropathy	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00027 affected298 at risk EG00133 affected297 at risk
Dysgeusia	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00022 affected298 at risk EG00124 affected297 at risk
Dizziness	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00028 affected298 at risk EG00129 affected297 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA (19.1)	Non-systematic Assessment	EG00018 affected298 at risk EG00124 affected297 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (19.1)	Non-systematic Assessment	EG00059 affected298 at risk EG00158 affected297 at risk
Nasopharyngitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG00040 affected298 at risk EG00124 affected297 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG00030 affected298 at risk EG00130 affected297 at risk
Urinary tract infection	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG00022 affected298 at risk EG00110 affected297 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00024 affected298 at risk EG00135 affected297 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00018 affected298 at risk EG00119 affected297 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00022 affected298 at risk EG00121 affected297 at risk
Incision site pain	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG00024 affected298 at risk EG00133 affected297 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG00016 affected298 at risk EG00118 affected297 at risk
Radiation skin injury	Injury, poisoning and procedural complications	MedDRA (19.1)	Non-systematic Assessment	EG00034 affected298 at risk EG00141 affected297 at risk
Hot flush	Vascular disorders	MedDRA (19.1)	Non-systematic Assessment	EG00031 affected298 at risk EG00130 affected297 at risk
Hypertension	Vascular disorders	MedDRA (19.1)	Non-systematic Assessment	EG00014 affected298 at risk EG00124 affected297 at risk
Insomnia	Psychiatric disorders	MedDRA (19.1)	Non-systematic Assessment	EG00031 affected298 at risk EG00126 affected297 at risk
Alanine aminotransferase increased	Investigations	MedDRA (19.1)	Non-systematic Assessment	EG00019 affected298 at risk EG00116 affected297 at risk
Skin hyperpigmentation	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00024 affected298 at risk EG00120 affected297 at risk
Dermatitis	Skin and subcutaneous tissue disorders	MedDRA (19.1)	Non-systematic Assessment	EG00015 affected298 at risk EG00114 affected297 at risk
Oedema	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00015 affected298 at risk EG00110 affected297 at risk
Pain	General disorders	MedDRA (19.1)	Non-systematic Assessment	EG00015 affected298 at risk EG00112 affected297 at risk
Pharyngitis	Infections and infestations	MedDRA (19.1)	Non-systematic Assessment	EG00011 affected298 at risk EG00115 affected297 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (19.1)	Non-systematic Assessment	EG00019 affected298 at risk EG00119 affected297 at risk
Amenorrhoea	Reproductive system and breast disorders	MedDRA (19.1)	Non-systematic Assessment	EG00010 affected298 at risk EG00115 affected297 at risk

Ancestor Terms

ID	Term
D014498	Uracil
D011744	Pyrimidinones
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D010752	Phosphoramide Mustards
D009588	Nitrogen Mustard Compounds
D009150	Mustard Compounds
D006846	Hydrocarbons, Halogenated
D006838	Hydrocarbons
D009930	Organic Chemicals
D063088	Phosphoramides
D009943	Organophosphorus Compounds
D043823	Taxoids
D043822	Cyclodecanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic
D006844	Hydrocarbons, Cyclic
D004224	Diterpenes
D013729	Terpenes
D004317	Doxorubicin
D003630	Daunorubicin
D018943	Anthracyclines
D009279	Naphthacenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D011083	Polycyclic Compounds
D000617	Aminoglycosides
D006027	Glycosides
D002241	Carbohydrates
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D005472	Fluorouracil
D003520	Cyclophosphamide
D000077143	Docetaxel
D015251	Epirubicin
D000068878	Trastuzumab