An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide

• Sponsor: Puma Biotechnology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02400476
• Collaborator: (none)
• Enrollment: 563
• Locations: 58
• Arms: 6
• Actual Duration (Months): 74.6
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide or other prophylactic measures.

Condition or Disease	Intervention/Treatment	Phase
Early Stage HER2+ Breast Cancer	Drug: Neratinib; Drug: Loperamide; Drug: Colestipol; Drug: Budesonide	Phase 2

Detailed Description

This is an open-label, Phase 2 study that will investigate the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with loperamide, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, or neratinib dose escalation, who have previously undergone a course of trastuzumab therapy in the adjuvant setting.

Patients will receive:

• Neratinib 240 mg orally once daily with food for thirteen 28-day cycles.

• Loperamide daily for two 28-day cycles and then as needed.

• Amendment 3, an anti-inflammatory treatment for one cycle and loperamide to be administered daily for two 28-day cycles and then as needed. Closed to enrollment.

• Amendment 4, colestipol for one cycle and loperamide to be administered one cycle and then as needed. Closed to enrollment.

• Amendment 5, colestipol for one cycle and loperamide as needed. Closed to enrollment.

• Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib for Week 2 (C1D8-C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to end of treatment). Loperamide as needed. Closed to enrollment.

• Amendment 7/7.1, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter (C2D1 to end of treatment). Loperamide as needed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 563 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide
• Actual Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Apr 22, 2021
• Actual Study Completion Date: Apr 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide
Experimental: Budesonide and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide; Drug: Budesonide; 9 mg extended release tablets once daily with or without food for 28 days
Experimental: Colestipol and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide; Drug: Colestipol; 2 g twice daily with or without food for one 28 day cycle
Experimental: Colestipol with Loperamide as needed 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide; Drug: Colestipol; 2 g twice daily with or without food for one 28 day cycle
Experimental: Neratinib Dose Escalation 1 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide
Experimental: Neratinib Dose Escalation 2 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only.	Drug: Neratinib; Other Names: Nerlynx ; Drug: Loperamide

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0. [From first dose of investigational product through 28 days after last dose, up to 15.5 months.]

   The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

Secondary Outcome Measures

1. Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0. [From first dose of investigational product through 28 days after last dose, up to 15.5 months.]

   Assess the percentage of patients with diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

2. Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest [From first dose of investigational product through 28 days after last dose, up to 15.5 months.]

   Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries (SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA preferred terms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age ≥18; male or female

• Early breast cancer (stage I-3c)

• Documented HER2+ tumor: HER2 immunohistochemistry (IHC) 3+ or ISH+

• Prior course of adjuvant trastuzumab given >2 weeks and ≤1 year from enrollment

• No evidence of local/regional recurrence or metastatic disease

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

• Male patients with female partners of childbearing potential must agree and commit to use a condom and women of childbearing potential must not be pregnant and must agree and commit to the use of a highly effective non-hormonal method of contraception

• Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or ECHO

Exclusion Criteria:

• Major surgery < 30 days

• Chemotherapy, investigational agents, other cancer therapy (except hormonal therapy) < 14 days

• Corrected QT Interval (QTc) >0.450 seconds (males) or >0.470 (females) or other active cardiac disease

• Significant chronic GI disorder with diarrhea as a major symptom

• Active, unresolved infections

• Currently pregnant or breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Oncology	Birmingham	Alabama	United States	35205
2	Compassionate Care Research Group Inc.	Corona	California	United States	92879
3	St. Joseph Heritage Healthcare	Fullerton	California	United States	92835
4	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
5	Emad Ibrahim, M.D., Inc.	Redlands	California	United States	92373
6	Torrance Memorial Physician Network Cancer Care Associates	Redondo Beach	California	United States	90277
7	Compassionate Care Research Group Inc.	Riverside	California	United States	92501
8	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
9	The Oncology Institute of Hope and Innovation	Santa Ana	California	United States	92705
10	Cancer Center of Santa Barbara with Sansum Clinic	Santa Barbara	California	United States	93105
11	Central Coast Medical Oncology Corporation	Santa Maria	California	United States	93454
12	Memorial Healthcare System	Hollywood	Florida	United States	33021
13	Florida Cancer Research Institute, LLC	Plantation	Florida	United States	33324
14	Hematology-Oncology Associates of the Treasure Coast	Port Saint Lucie	Florida	United States	34952
15	Baptist Health Urgent Care Sawgrass	Sunrise	Florida	United States	33322
16	Cancer Treatment Centers of America	Newnan	Georgia	United States	30265
17	Decatur Memorial Hospital Cancer Care Specialists of Central Illinois	Decatur	Illinois	United States	62526
18	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
19	Norton Cancer Institute	Louisville	Kentucky	United States	40202
20	Central Maine Medical Center	Lewiston	Maine	United States	04240
21	University of Maryland, Greenebaum Comprehensive Cancer Center	Baltimore	Maryland	United States	21201
22	North Mississippi Medical Center Hematology and Oncology Services	Tupelo	Mississippi	United States	38801
23	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
24	Great Plains Health (Callahan Cancer Center)	North Platte	Nebraska	United States	69101
25	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
26	Jersey Shore University Medical Center	Neptune	New Jersey	United States	07753
27	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
28	MD Anderson Cancer Center at Cooper	Voorhees	New Jersey	United States	08035
29	Clinical Research Alliance, Inc	Lake Success	New York	United States	11042
30	Good Samaritan Hospital Samaritan Pastega Regional Cancer Center	Corvallis	Oregon	United States	97330
31	Providence Portland Medical Center	Portland	Oregon	United States	97213
32	Magee-Womens Hospital of UPMC	Pittsburgh	Pennsylvania	United States	15213
33	Charleston Hematology Oncology Associates	Charleston	South Carolina	United States	29414
34	Saint Joseph / Candler SC Cancer Specialists	Hilton Head Island	South Carolina	United States	29926
35	Coastal Bend Cancer Center	Corpus Christi	Texas	United States	78412
36	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
37	Community Cancer Trials of Utah	Ogden	Utah	United States	84405
38	Utah Cancer Specialists	Salt Lake City	Utah	United States	84106
39	Inova Schar Cancer Institute	Fairfax	Virginia	United States	22031
40	Sydney Adventist Hospital	Wahroonga	New South Wales	Australia
41	Ashford Cancer Centre Research	Kurralta Park	South Australia	Australia	5037
42	BCRC-WA, Hollywood Private Hospital	Nedlands	Western Australia	Australia	6009
43	Univ. Klinik für Innere Medizin, Klin. Abt. Onkologie	Graz		Austria	8036
44	Medical University of Innsbruck-Department of Gynecology	Innsbruck		Austria	A-6020
45	Uniklinikum Salzburg, Landeskrankenhaus, Univ. Klinik fur Innere Medizin III der PMU	Salzburg		Austria	A-5020
46	Medical University of Vienna, Department of Oncology	Vienna		Austria	1090
47	Medical University of Vienna,Department of Obstetrics and Gynecology	Vienna		Austria	1090
48	Sunnybrook Research Insitute	Toronto	Ontario	Canada	M4N3M5
49	McGill University Health Centre, Cedars Cancer Centre	Montreal	Quebec	Canada	H4A 3J1
50	CHU Group Hospitalier Pitié-Salpêtrière, Service d'oncologie Médicale	Paris		France	5013
51	Institut Gustave Roussy	Villejuif		France	94800
52	Praxis für interdisziplinäre Onkologie & Hämatologie	Freiburg		Germany	79110
53	Mammazentrum HH am Krankenhaus Jerusalem	Hamburg		Germany	20357
54	Universitaetsklinikum Schleswig-Holstein	Kiel		Germany	24105
55	Universitaetsklinikum Schleswig-Holstein (UKSH), Klinik fuer Gynaekologie und Geburtshilfe, Studienzentrale Gynäkologische Onkologie (SGC) Kiel	Kiel		Germany	D-24106
56	Sana Klinikum Offenbach GmbH - Frauenklinik	Offenbach		Germany	63069
57	Hospital Clinico San Carlos	Madrid		Spain	28040
58	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013

Sponsors and Collaborators

• Puma Biotechnology, Inc.

Investigators

• Study Director: Chief Scientific Officer, Puma Biotechnology, Inc.

Study Documents (Full-Text)

• Study Protocol - Jul 25, 2019
• Statistical Analysis Plan - Aug 30, 2019
• Informed Consent Form - Aug 15, 2019

More Information

Publications

None provided.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT02400476
• Other Study ID Numbers: PUMA-NER-6201; 2015-004374-15
• First Posted: Mar 27, 2015
• Last Update Posted: May 6, 2022
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Puma Biotechnology, Inc.: HER2 +; Breast Cancer; Neratinib; Nerlynx; Loperamide; Colestipol; Budesonide
• Additional relevant MeSH terms: Breast Neoplasms; Diarrhea; Budesonide; Loperamide; Antidiarrheals; Colestipol

Study Results

Participant Flow

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Period Title: Overall Study
STARTED	137	64	136	104	60	62
COMPLETED	76	52	95	74	45	46
NOT COMPLETED	61	12	41	30	15	16

Baseline Characteristics

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2	Total
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide	Total of all reporting groups
Overall Participants	137	64	136	104	60	62	563
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	116 84.7%	58 90.6%	117 86%	93 89.4%	51 85%	52 83.9%	487 86.5%
>=65 years	21 15.3%	6 9.4%	19 14%	11 10.6%	9 15%	10 16.1%	76 13.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.39 (11.06)	49.11 (10.55)	52.49 (11.08)	51.94 (10.23)	51.90 (10.71)	53.82 (10.15)	52.31 (10.76)
Sex: Female, Male (Count of Participants)
Female	137 100%	64 100%	133 97.8%	104 100%	60 100%	62 100%	560 99.5%
Male	0 0%	0 0%	3 2.2%	0 0%	0 0%	0 0%	3 0.5%
Race/Ethnicity, Customized (Count of Participants)
White	113 82.5%	50 78.1%	96 70.6%	80 76.9%	53 88.3%	52 83.9%	444 78.9%
Black or African American	11 8%	5 7.8%	9 6.6%	8 7.7%	1 1.7%	2 3.2%	36 6.4%
Asian	8 5.8%	4 6.3%	13 9.6%	9 8.7%	3 5%	1 1.6%	38 6.7%
American Indian or Alaska Native	1 0.7%	0 0%	1 0.7%	0 0%	0 0%	0 0%	2 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.6%	3 2.2%	0 0%	0 0%	0 0%	4 0.7%
Other	3 2.2%	2 3.1%	9 6.6%	0 0%	1 1.7%	3 4.8%	18 3.2%
Unknown	0 0%	1 1.6%	2 1.5%	1 1%	0 0%	1 1.6%	5 0.9%
Missing	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.6%	1 0.2%
Not Reported	1 0.7%	1 1.6%	3 2.2%	6 5.8%	2 3.3%	2 3.2%	15 2.7%
Region of Enrollment (participants) [Number]
Canada	0 0%	0 0%	4 2.9%	10 9.6%	6 10%	7 11.3%	27 4.8%
Austria	0 0%	0 0%	0 0%	0 0%	0 0%	4 6.5%	4 0.7%
United States	132 96.4%	52 81.3%	115 84.6%	83 79.8%	20 33.3%	11 17.7%	413 73.4%
Australia	5 3.6%	12 18.8%	17 12.5%	11 10.6%	23 38.3%	18 29%	86 15.3%
France	0 0%	0 0%	0 0%	0 0%	0 0%	6 9.7%	6 1.1%
Germany	0 0%	0 0%	0 0%	0 0%	0 0%	2 3.2%	2 0.4%
Spain	0 0%	0 0%	0 0%	0 0%	11 18.3%	14 22.6%	25 4.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.
Description	The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Measure Participants	137	64	136	104	60	62
Number (95% Confidence Interval) [Percentage of participants]	30.7 22.4%	28.1 43.9%	20.6 15.1%	32.7 31.4%	13.3 22.2%	27.4 44.2%

2. Secondary Outcome

Title	Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.
Description	Assess the percentage of patients with diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Measure Participants	137	64	136	104	60	62
Percentage of Patients w Grade 1 Diarrhea	24.1 17.6%	23.4 36.6%	27.9 20.5%	32.7 31.4%	40.0 66.7%	37.1 59.8%
Percentage of Patients w Grade 2 Diarrhea	24.8 18.1%	34.4 53.8%	34.6 25.4%	29.8 28.7%	45.0 75%	33.9 54.7%
Percentage of Patients w Grade 3 Diarrhea	30.7 22.4%	28.1 43.9%	20.6 15.1%	32.7 31.4%	13.3 22.2%	27.4 44.2%

3. Secondary Outcome

Title	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest
Description	Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries (SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA preferred terms.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of neratinib.

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Measure Participants	137	64	136	104	60	62
Percentage of Patients with SAEs	6.57 4.8%	6.25 9.8%	6.62 4.9%	2.88 2.8%	8.33 13.9%	8.06 13%
Percentage of Patients with AESI-Gastrointestinal Toxicities (Diarrhoea and Stomatitis Broad Search)	81.75 59.7%	87.5 136.7%	83.82 61.6%	96.15 92.5%	98.33 163.9%	98.39 158.7%
Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	12.41 9.1%	7.81 12.2%	4.41 3.2%	4.81 4.6%	8.33 13.9%	4.84 7.8%
Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Broad Search)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	5.84 4.3%	6.25 9.8%	10.29 7.6%	7.69 7.4%	10.00 16.7%	4.84 7.8%
Percentage of Patients with AESI - Dermatologic Toxicities (Rash and Nail Disorders)	12.41 9.1%	37.50 58.6%	23.53 17.3%	18.27 17.6%	11.67 19.5%	30.65 49.4%
Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	80.29 58.6%	85.94 134.3%	83.09 61.1%	95.19 91.5%	98.33 163.9%	98.39 158.7%
Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	10.95 8%	7.81 12.2%	3.68 2.7%	3.85 3.7%	8.33 13.9%	4.84 7.8%
Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Narrow Search)	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	2.92 2.1%	0 0%	1.47 1.1%	0.96 0.9%	1.67 2.8%	0 0%

Adverse Events

Time Frame	From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Arm/Group Title	Loperamide		Budesonide and Loperamide		Colestipol and Loperamide		Colestipol With Loperamide as Needed		Neratinib Dose Escalation 1		Neratinib Dose Escalation 2
Arm/Group Description	240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide		240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days		240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle		240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle		120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide		160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
All Cause Mortality
	Loperamide		Budesonide and Loperamide		Colestipol and Loperamide		Colestipol With Loperamide as Needed		Neratinib Dose Escalation 1		Neratinib Dose Escalation 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Serious Adverse Events
	Loperamide		Budesonide and Loperamide		Colestipol and Loperamide		Colestipol With Loperamide as Needed		Neratinib Dose Escalation 1		Neratinib Dose Escalation 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/137 (6.6%)		4/64 (6.3%)		9/136 (6.6%)		3/104 (2.9%)		5/60 (8.3%)		5/62 (8.1%)
Eye disorders
Retinal detachment	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Gastrointestinal disorders
Abdominal pain	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Colitis	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Diarrhoea	2/137 (1.5%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Nausea	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Pancreatitis	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Stomatitis	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
General disorders
Fat necrosis	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Pyrexia	0/137 (0%)		1/64 (1.6%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Hepatobiliary disorders
Cholecystitis	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Cholecystitis acute	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Cholelithiasis	0/137 (0%)		1/64 (1.6%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Infections and infestations
Appendicitis	0/137 (0%)		0/64 (0%)		0/136 (0%)		1/104 (1%)		0/60 (0%)		0/62 (0%)
Bacteraemia	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Breast cellulitis	0/137 (0%)		1/64 (1.6%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Cellulitis	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		1/104 (1%)		0/60 (0%)		0/62 (0%)
Device related infection	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Gastroenteritis	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		1/104 (1%)		0/60 (0%)		0/62 (0%)
Gastroenteritis viral	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Influenza	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Listeriosis	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		1/62 (1.6%)
Lower respiratory tract infection	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Post procedural infection	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Sepsis	1/137 (0.7%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Upper respiratory tract infection	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Urinary tract infection	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Wound infection	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Injury, poisoning and procedural complications
Rib fracture	0/137 (0%)		1/64 (1.6%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Investigations
Alanine aminotransferase increased	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Aspartate aminotransferase increased	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Electrocardiogram QT prolonged	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Dehydration	1/137 (0.7%)		0/64 (0%)		1/136 (0.7%)		1/104 (1%)		1/60 (1.7%)		0/62 (0%)
Hypokalaemia	1/137 (0.7%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Nervous system disorders
Seizure	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Syncope	0/137 (0%)		0/64 (0%)		2/136 (1.5%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Psychiatric disorders
Confusional state	0/137 (0%)		0/64 (0%)		1/136 (0.7%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Skin and subcutaneous tissue disorders
Rash	0/137 (0%)		1/64 (1.6%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Rash erythematous	1/137 (0.7%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		0/60 (0%)		0/62 (0%)
Other (Not Including Serious) Adverse Events
	Loperamide		Budesonide and Loperamide		Colestipol and Loperamide		Colestipol With Loperamide as Needed		Neratinib Dose Escalation 1		Neratinib Dose Escalation 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	137/137 (100%)		64/64 (100%)		136/136 (100%)		104/104 (100%)		60/60 (100%)		62/62 (100%)
Blood and lymphatic system disorders
Anaemia	8/137 (5.8%)		5/64 (7.8%)		1/136 (0.7%)		5/104 (4.8%)		0/60 (0%)		0/62 (0%)
Ear and labyrinth disorders
Vertigo	0/137 (0%)		4/64 (6.3%)		3/136 (2.2%)		0/104 (0%)		1/60 (1.7%)		0/62 (0%)
Gastrointestinal disorders
Abdominal discomfort	7/137 (5.1%)		2/64 (3.1%)		7/136 (5.1%)		5/104 (4.8%)		2/60 (3.3%)		0/62 (0%)
Abdominal distension	21/137 (15.3%)		5/64 (7.8%)		22/136 (16.2%)		15/104 (14.4%)		6/60 (10%)		10/62 (16.1%)
Abdominal pain	36/137 (26.3%)		12/64 (18.8%)		26/136 (19.1%)		27/104 (26%)		13/60 (21.7%)		15/62 (24.2%)
Abdominal pain upper	5/137 (3.6%)		7/64 (10.9%)		16/136 (11.8%)		7/104 (6.7%)		3/60 (5%)		8/62 (12.9%)
Constipation	78/137 (56.9%)		48/64 (75%)		93/136 (68.4%)		39/104 (37.5%)		22/60 (36.7%)		15/62 (24.2%)
Diarrhoea	109/137 (79.6%)		55/64 (85.9%)		113/136 (83.1%)		99/104 (95.2%)		59/60 (98.3%)		61/62 (98.4%)
Dry mouth	18/137 (13.1%)		6/64 (9.4%)		12/136 (8.8%)		5/104 (4.8%)		4/60 (6.7%)		3/62 (4.8%)
Dyspepsia	12/137 (8.8%)		10/64 (15.6%)		16/136 (11.8%)		13/104 (12.5%)		7/60 (11.7%)		6/62 (9.7%)
Flatulence	5/137 (3.6%)		6/64 (9.4%)		5/136 (3.7%)		2/104 (1.9%)		1/60 (1.7%)		3/62 (4.8%)
Gastrooesophageal reflux disease	10/137 (7.3%)		5/64 (7.8%)		10/136 (7.4%)		6/104 (5.8%)		2/60 (3.3%)		4/62 (6.5%)
Nausea	78/137 (56.9%)		32/64 (50%)		83/136 (61%)		64/104 (61.5%)		27/60 (45%)		28/62 (45.2%)
Stomatitis	7/137 (5.1%)		4/64 (6.3%)		14/136 (10.3%)		13/104 (12.5%)		6/60 (10%)		6/62 (9.7%)
Vomiting	36/137 (26.3%)		16/64 (25%)		43/136 (31.6%)		25/104 (24%)		9/60 (15%)		5/62 (8.1%)
General disorders
Asthenia	6/137 (4.4%)		1/64 (1.6%)		1/136 (0.7%)		4/104 (3.8%)		3/60 (5%)		2/62 (3.2%)
Fatigue	73/137 (53.3%)		34/64 (53.1%)		65/136 (47.8%)		41/104 (39.4%)		28/60 (46.7%)		19/62 (30.6%)
Pyrexia	6/137 (4.4%)		2/64 (3.1%)		10/136 (7.4%)		3/104 (2.9%)		2/60 (3.3%)		1/62 (1.6%)
Infections and infestations
Cellulitis	3/137 (2.2%)		1/64 (1.6%)		0/136 (0%)		2/104 (1.9%)		3/60 (5%)		0/62 (0%)
Influenza	2/137 (1.5%)		0/64 (0%)		3/136 (2.2%)		4/104 (3.8%)		3/60 (5%)		0/62 (0%)
Nasopharyngitis	5/137 (3.6%)		4/64 (6.3%)		2/136 (1.5%)		3/104 (2.9%)		1/60 (1.7%)		1/62 (1.6%)
Upper respiratory tract infection	5/137 (3.6%)		7/64 (10.9%)		7/136 (5.1%)		5/104 (4.8%)		6/60 (10%)		2/62 (3.2%)
Urinary tract infection	10/137 (7.3%)		2/64 (3.1%)		8/136 (5.9%)		9/104 (8.7%)		6/60 (10%)		5/62 (8.1%)
Investigations
Alanine aminotransferase increased	9/137 (6.6%)		4/64 (6.3%)		4/136 (2.9%)		3/104 (2.9%)		4/60 (6.7%)		2/62 (3.2%)
Aspartate aminotransferase increased	4/137 (2.9%)		1/64 (1.6%)		3/136 (2.2%)		2/104 (1.9%)		3/60 (5%)		2/62 (3.2%)
Blood glucose increased	0/137 (0%)		0/64 (0%)		0/136 (0%)		0/104 (0%)		3/60 (5%)		0/62 (0%)
Weight decreased	10/137 (7.3%)		4/64 (6.3%)		11/136 (8.1%)		4/104 (3.8%)		1/60 (1.7%)		3/62 (4.8%)
Metabolism and nutrition disorders
Decreased appetite	26/137 (19%)		11/64 (17.2%)		24/136 (17.6%)		26/104 (25%)		8/60 (13.3%)		8/62 (12.9%)
Dehydration	7/137 (5.1%)		6/64 (9.4%)		5/136 (3.7%)		4/104 (3.8%)		2/60 (3.3%)		2/62 (3.2%)
Hypokalaemia	4/137 (2.9%)		1/64 (1.6%)		8/136 (5.9%)		2/104 (1.9%)		1/60 (1.7%)		0/62 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/137 (7.3%)		14/64 (21.9%)		15/136 (11%)		13/104 (12.5%)		9/60 (15%)		4/62 (6.5%)
Back pain	10/137 (7.3%)		5/64 (7.8%)		9/136 (6.6%)		10/104 (9.6%)		4/60 (6.7%)		2/62 (3.2%)
Muscle spasms	15/137 (10.9%)		8/64 (12.5%)		14/136 (10.3%)		15/104 (14.4%)		12/60 (20%)		8/62 (12.9%)
Myalgia	3/137 (2.2%)		4/64 (6.3%)		6/136 (4.4%)		5/104 (4.8%)		2/60 (3.3%)		3/62 (4.8%)
Pain in extremity	7/137 (5.1%)		3/64 (4.7%)		7/136 (5.1%)		5/104 (4.8%)		2/60 (3.3%)		3/62 (4.8%)
Nervous system disorders
Dizziness	19/137 (13.9%)		6/64 (9.4%)		21/136 (15.4%)		20/104 (19.2%)		9/60 (15%)		8/62 (12.9%)
Headache	26/137 (19%)		12/64 (18.8%)		20/136 (14.7%)		24/104 (23.1%)		13/60 (21.7%)		8/62 (12.9%)
Neuropathy peripheral	4/137 (2.9%)		3/64 (4.7%)		3/136 (2.2%)		6/104 (5.8%)		0/60 (0%)		1/62 (1.6%)
Paraesthesia	3/137 (2.2%)		1/64 (1.6%)		3/136 (2.2%)		0/104 (0%)		5/60 (8.3%)		0/62 (0%)
Psychiatric disorders
Anxiety	5/137 (3.6%)		4/64 (6.3%)		3/136 (2.2%)		3/104 (2.9%)		3/60 (5%)		2/62 (3.2%)
Insomnia	6/137 (4.4%)		8/64 (12.5%)		10/136 (7.4%)		8/104 (7.7%)		3/60 (5%)		4/62 (6.5%)
Reproductive system and breast disorders
Breast pain	4/137 (2.9%)		7/64 (10.9%)		8/136 (5.9%)		6/104 (5.8%)		1/60 (1.7%)		0/62 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	7/137 (5.1%)		7/64 (10.9%)		9/136 (6.6%)		8/104 (7.7%)		1/60 (1.7%)		0/62 (0%)
Dyspnoea	9/137 (6.6%)		4/64 (6.3%)		4/136 (2.9%)		4/104 (3.8%)		3/60 (5%)		1/62 (1.6%)
Epistaxis	2/137 (1.5%)		2/64 (3.1%)		9/136 (6.6%)		4/104 (3.8%)		3/60 (5%)		4/62 (6.5%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	2/137 (1.5%)		4/64 (6.3%)		5/136 (3.7%)		1/104 (1%)		1/60 (1.7%)		4/62 (6.5%)
Dry skin	6/137 (4.4%)		8/64 (12.5%)		7/136 (5.1%)		10/104 (9.6%)		4/60 (6.7%)		9/62 (14.5%)
Onychoclasis	5/137 (3.6%)		3/64 (4.7%)		6/136 (4.4%)		4/104 (3.8%)		3/60 (5%)		6/62 (9.7%)
Rash	7/137 (5.1%)		12/64 (18.8%)		15/136 (11%)		10/104 (9.6%)		1/60 (1.7%)		8/62 (12.9%)
Vascular disorders
Hot flush	8/137 (5.8%)		6/64 (9.4%)		17/136 (12.5%)		7/104 (6.7%)		7/60 (11.7%)		4/62 (6.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.