Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Chronic Graft Versus Host Disease

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02195869
• Collaborator: (none)
• Enrollment: 45
• Locations: 10
• Arms: 4
• Actual Duration (Months): 38.1
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and clinical efficacy of ibrutinib in subjects with steroid dependent or refractory Chronic Graft Versus Host Disease.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: Ibrutinib	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease
• Actual Study Start Date: Jul 14, 2014
• Actual Primary Completion Date: Sep 15, 2017
• Actual Study Completion Date: Sep 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: Dose Level 1 Subjects receive daily dose of 420 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 1b: Dose Level 2 Subjects receive daily dose of 280 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 1b: Dose Level 3 Subjects receive daily dose of 140 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 2 Subjects receive daily dose of recommended phase 2 dose	Drug: Ibrutinib; Other Names: PCI32765

Outcome Measures

Primary Outcome Measures

1. Phase 1b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD. [28 treatment days after last subject enrolled in Phase 1 dose level(s).]

   Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib

2. Phase 2: Overall Response Rate as the Percentage of Participants With Response [Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.]

   Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site).

Secondary Outcome Measures

1. Sustained Response Rate as the Percentage of Participants With Sustained Response [Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.]

   For subjects who achieved an NIH-defined CR or PR, the proportion of subjects who achieved CR or PR that was sustained for at least 20 weeks (140 days). Intermittent SD was also acceptable.

2. To Evaluate the Clinical Efficacy of Ibrutinib in Steroid Dependent/Refractory cGVHD by Measuring: Duration of Response (DOR) [Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.]

   For subjects who achieved an NIH-defined CR or PR, the interval between the date of initial documentation of a response and the date of first documented evidence of PD, death, or date of censoring if applicable.

3. Corticosteroid Requirement Changes Over Time [Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.]

   Average daily corticosteroid dose assessed each week.

4. Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Summary Score [Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.]

   Subject reported improvement in symptom burden. The symptom burden will be measured according to the Lee cGVHD Symptom Scale. A change in >7 points on the Lee cGVHD Symptom Scale will be considered significant and relates to improvement in quality of life. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. A total summary score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. There are 7 subscales (Skin, Energy, Lung, Eye, Nutrition, Mouth and Psychological) with ratings as follow: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely; with a lower values representing a better outcome.

5. Phase 2b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD [From first dose with study drug until 30 days after the last dose of study drug, up to 36.7 months]

   Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Steroid dependent or refractory classic chronic GVHD disease.

• No more than 3 previous treatments for cGVHD.

• Receiving baseline systemic glucocorticoid therapy (at stable dose) for cGVHD at study entry.

• Men and women ≥18 years old.

• Karnofsky performance status ≥60.

Exclusion Criteria:

• Known or suspected active acute GVHD.

• Current treatment with sirolimus AND either cyclosporine or tacrolimus.

• History of treatment with a tyrosine kinase inhibitor (eg, imatinib), purine analogs or other cancer chemotherapy in the 4 weeks prior to starting study drug.

• Currently active, clinically significant cardiovascular disease.

• Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines or a recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.

• Progressive underlying malignant disease including post-transplant lymphoproliferative disease.

• History of other malignancy (not including the underlying malignancy that was the indication for transplant)

• Concomitant use of warfarin or other Vitamin K antagonists

• Known bleeding disorders or hemophilia.

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV).

• Concurrent use of a strong cytochrome P450(CYP) 3A inhibitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	University of California, San Francisco	San Francisco	California	United States	94143
3	Stanford University	Stanford	California	United States	94305
4	Emory University, Winship Cancer Institute	Atlanta	Georgia	United States	30322
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	University of Minnesota	Minneapolis	Minnesota	United States	55455
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
9	Vanderbilt University Medical Center, Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
10	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Pharmacyclics LLC.

Investigators

• Study Director: Lori Styles, MD, Pharmacyclics LLC.

Study Documents (Full-Text)

• Study Protocol - Oct 21, 2015
• Statistical Analysis Plan - Aug 31, 2016

More Information

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02195869
• Other Study ID Numbers: PCYC-1129-CA
• First Posted: Jul 21, 2014
• Last Update Posted: Jul 11, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Pharmacyclics LLC.: PCYC1129; PCYC1129CA; 1129; Ibrutinib; PCI32765; IMBRUVICA; Pharmacyclics; PCYC; GVHD; Steroid dependent; refractory; chronic; graft versus host disease; chronic graft versus host disease; immunology
• Additional relevant MeSH terms: Graft vs Host Disease

Study Results

Participant Flow

Arm/Group Title	Phase 1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Period Title: Overall Study
STARTED	42
All-Treated Population	42
COMPLETED	0
NOT COMPLETED	42

Baseline Characteristics

Arm/Group Title	Phase 1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	35 83.3%
>=65 years	7 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.5 (15.53)
Sex: Female, Male (Count of Participants)
Female	20 47.6%
Male	22 52.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.8%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	40 95.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.4%
White	39 92.9%
More than one race	0 0%
Unknown or Not Reported	1 2.4%
Region of Enrollment (participants) [Number]
United States	42 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD.
Description	Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib
Time Frame	28 treatment days after last subject enrolled in Phase 1 dose level(s).

Outcome Measure Data

Analysis Population Description

Endpoint only includes Phase 1 data.

Arm/Group Title	Phase 1b: Dose Level 1	Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules for dose level 1	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	6	0
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Phase 2: Overall Response Rate as the Percentage of Participants With Response
Description	Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site).
Time Frame	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Outcome Measure Data

Analysis Population Description

Efficacy analyses were performed using the All-treated Population (N = 42)

Arm/Group Title	Phase1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	42
Number (95% Confidence Interval) [percentage of participants]	69 164.3%

3. Secondary Outcome

Title	Sustained Response Rate as the Percentage of Participants With Sustained Response
Description	For subjects who achieved an NIH-defined CR or PR, the proportion of subjects who achieved CR or PR that was sustained for at least 20 weeks (140 days). Intermittent SD was also acceptable.
Time Frame	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Outcome Measure Data

Analysis Population Description

Phase 2 subjects include all subjects who participated in phase 1b. Subjects evaluated for sustained response includes participants who had achieved an NIH-defined CR or PR.

Arm/Group Title	Phase1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	29
Number (95% Confidence Interval) [percentage of participants]	69 164.3%

4. Secondary Outcome

Title	To Evaluate the Clinical Efficacy of Ibrutinib in Steroid Dependent/Refractory cGVHD by Measuring: Duration of Response (DOR)
Description	For subjects who achieved an NIH-defined CR or PR, the interval between the date of initial documentation of a response and the date of first documented evidence of PD, death, or date of censoring if applicable.
Time Frame	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Outcome Measure Data

Analysis Population Description

Phase 2 subjects includes all subjects who participated in Phase 1b

Arm/Group Title	Phase1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	29
Median (95% Confidence Interval) [Median]	NA

5. Secondary Outcome

Title	Corticosteroid Requirement Changes Over Time
Description	Average daily corticosteroid dose assessed each week.
Time Frame	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Outcome Measure Data

Analysis Population Description

Phase 2 subjects includes all subjects who participated in Phase 1b.

Arm/Group Title	Phase 1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	42
Week 1	0.31
Week 2	0.32
Week 3	0.32
Week 4	0.31
Week 5	0.31
Week 6	0.30
Week 7	0.30
Week 8	0.30
Week 9	0.27
Week 10	0.25
Week 11	0.25
Week 12	0.25
Week 13	0.24
Week 14	0.23
Week 15	0.23
Week 16	0.23
Week 17	0.21
Week 18	0.20
Week 19	0.20
Week 20	0.21
Week 21	0.22
Week 22	0.22
Week 23	0.22
Week 24	0.21
Week 25	0.19
Week 26	0.18
Week 27	0.18
Week 28	0.18
Week 29	0.16
Week 30	0.16
Week 31	0.16
Week 32	0.18
Week 33	0.17
Week 34	0.17
Week 35	0.18
Week 36	0.18
Week 37	0.16
Week 38	0.15
Week 39	0.15
Week 40	0.15
Week 41	0.15
Week 42	0.15
Week 43	0.13
Week 44	0.13
Week 45	0.13
Week 46	0.13
Week 47	0.13
Week 48	0.13
Week 49	0.12
Week 50	0.10
Week 51	0.10
Week 52	0.10
Week 53	0.10
Week 54	0.10
Week 55	0.10
Week 56	0.10
Week 57	0.10
Week 58	0.10
Week 59	0.10
Week 60	0.08
Week 61	0.08
Week 62	0.08
Week 63	0.08
Week 64	0.08
Week 65	0.08
Week 66	0.08
Week 67	0.08
Week 68	0.08
Week 69	0.08
Week 70	0.08
Week 71	0.07
Week 72	0.08
Week 73	0.08
Week 74	0.07
Week 75	0.07
Week 76	0.07
Week 77	0.07
Week 78	0.07
Week 79	0.07
Week 80	0.07
Week 81	0.07
Week 82	0.07
Week 83	0.07
Week 84	0.07
Week 85	0.08
Week 86	0.08
Week 87	0.08
Week 88	0.08
Week 89	0.08
Week 90	0.08
Week 91	0.08
Week 92	0.08
Week 93	0.08
Week 94	0.08
Week 95	0.08
Week 96	0.08
Week 97	0.08
Week 98	0.08
Week 99	0.08
Week 100	0.08
Week 101	0.09
Week 102	0.09
Week 103	0.09
Week 104	0.09
Week 105	0.08
Week 106	0.08
Week 107	0.08
Week 108	0.08
Week 109	0.08
Week 110	0.08
Week 111	0.08
Week 112	0.08
Week 113	0.08
Week 114	0.08
Week 115	0.12
Week 116	0.12
Week 117	0.08
Week 118	0.08
Week 119	0.08
Week 120	0.08
Week 121	0.08
Week 122	0.12
Week 123	0.08
Week 124	0.08
Week 125	0.08
Week 126	0.08
Week 127	0.08
Week 128	0.00
Week 129	0.00
Week 130	0.00
Week 131	0.00
Week 132	0.00
Week 133	0.00
Week 134	0.00
Week 135	0.00
Week 136	0.00
Week 137	0.00
Week 138	0.00
Week 139	0.00
Week 140	0.00
Week 141	0.00
Week 142	0.00
Week 143	0.00
Week 144	0.00
Week 145	0.00
Week 146	0.00
Week 147	0.00
Week 148	0.00
Week 149	0.00
Week 150	0.00
Week 151	0.00
Week 152	0.00
Week 153	0.00
Week 154	0.00
Week 155	0.00
Week 156	0.00
Week 157	0.00
Week 158	0.06
Week 159	0.06
Week 160	0.06

6. Secondary Outcome

Title	Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Summary Score
Description	Subject reported improvement in symptom burden. The symptom burden will be measured according to the Lee cGVHD Symptom Scale. A change in >7 points on the Lee cGVHD Symptom Scale will be considered significant and relates to improvement in quality of life. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. A total summary score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. There are 7 subscales (Skin, Energy, Lung, Eye, Nutrition, Mouth and Psychological) with ratings as follow: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely; with a lower values representing a better outcome.
Time Frame	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of ibrutinib at the recommended Phase 2 dose.

Arm/Group Title	Phase 1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	42
Number (95% Confidence Interval) [percentage of participants]	42.9 102.1%

7. Secondary Outcome

Title	Phase 2b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD
Description	Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib
Time Frame	From first dose with study drug until 30 days after the last dose of study drug, up to 36.7 months

Outcome Measure Data

Analysis Population Description

Phase 2 subjects includes all subjects who participated in Phase 1b

Arm/Group Title	Phase 1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
Measure Participants	42
Count of Participants [Participants]	42 100%

Adverse Events

Time Frame	From first dose of study drug to within 30 days of last dose or starting subsequent therapy for cGVHD, up to 36.7 months
Adverse Event Reporting Description	Adverse events were not collected by phase because the phase 1 part of the study confirmed the first dose level (420mg was acceptable for cGVHD subjects and it was used as the recommended Phase 2 dose (RP2D). The Safety Population was the same as the All-treated Population (ie, all subject who received at least 1 dose of ibrutinib at the RP2D)
Arm/Group Title	Phase1b/Phase 2
Arm/Group Description	Subjects receive daily dose of 420 mg of Ibrutinib capsules
All Cause Mortality
	Phase1b/Phase 2
	Affected / at Risk (%)	# Events
Total	7/42 (16.7%)
Serious Adverse Events
	Phase1b/Phase 2
	Affected / at Risk (%)	# Events
Total	22/42 (52.4%)
Blood and lymphatic system disorders
Anaemia	1/42 (2.4%)
Cardiac disorders
Atrial fibrilation	1/42 (2.4%)
Gastrointestinal disorders
Diarrhoea	1/42 (2.4%)
General disorders
Pyrexia	1/42 (2.4%)
Immune system disorders
Graft versus host disease	1/42 (2.4%)
Infections and infestations
Cellulitis	2/42 (4.8%)
Septic shock	2/42 (4.8%)
Bacteraemia	1/42 (2.4%)
Brain abscess	1/42 (2.4%)
Bronchopulmonary aspergillosis	1/42 (2.4%)
Clostridium difficile infection	1/42 (2.4%)
Pneumonia viral	1/42 (2.4%)
Rhinovirus infection	1/42 (2.4%)
Staphylococcal bacteraemia	1/42 (2.4%)
Urinary tract infection	1/42 (2.4%)
Injury, poisoning and procedural complications
Compression fracture	1/42 (2.4%)
Femur fracture	1/42 (2.4%)
Investigations
Electrocardiogram QT prolonged	1/42 (2.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/42 (2.4%)
Muscular weakness	1/42 (2.4%)
Myalgia	1/42 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	1/42 (2.4%)
Prolymphocytic leukaemia	1/42 (2.4%)
Nervous system disorders
Headache	2/42 (4.8%)
Syncope	1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	6/42 (14.3%)
Dyspnoea	2/42 (4.8%)
Pneumothorax	1/42 (2.4%)
Respiratory failure	1/42 (2.4%)
Skin and subcutaneous tissue disorders
Pain of skin	1/42 (2.4%)
Skin mass	1/42 (2.4%)
Vascular disorders
Deep vein thrombosis	1/42 (2.4%)
Hypertension	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Phase1b/Phase 2
	Affected / at Risk (%)	# Events
Total	41/42 (97.6%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders	17/42 (40.5%)
Increased tendency to bruise	10/42 (23.8%)
Anaemia	3/42 (7.1%)
Cardiac disorders
Cardiac Disorders	11/42 (26.2%)
Sinus tachycardia	4/42 (9.5%)
Tachycardia	3/42 (7.1%)
Eye disorders
Eye disorders	11/42 (26.2%)
Gastrointestinal disorders
Gastrointestinal disorders	38/42 (90.5%)
Diarrhoea	17/42 (40.5%)
Nausea	12/42 (28.6%)
Constipation	5/42 (11.9%)
Mouth Ulceration	5/42 (11.9%)
Vomiting	5/42 (11.9%)
Abdominal Pain	4/42 (9.5%)
Dry mouth	4/42 (9.5%)
Gastroesophogeal reflux disease	4/42 (9.5%)
Dysphagia	3/42 (7.1%)
Oral pain	3/42 (7.1%)
Stomatitis	3/42 (7.1%)
General disorders
General disorders and administration site conditions	30/42 (71.4%)
Fatique	24/42 (57.1%)
Pyrexia	7/42 (16.7%)
Oedema peripheral	6/42 (14.3%)
Influenza like illness	3/42 (7.1%)
Hepatobiliary disorders
Hepatobiliary disorders	4/42 (9.5%)
Hepatic function abnormal	4/42 (9.5%)
Immune system disorders
Immune system disorders	6/42 (14.3%)
Infections and infestations
Infections and infestations	25/42 (59.5%)
Upper respiratory tract infection	8/42 (19%)
Cellulitis	4/42 (9.5%)
Cytomegalovirus infection	3/42 (7.1%)
Urinary tract infections	3/42 (7.1%)
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	14/42 (33.3%)
Fall	7/42 (16.7%)
Contusion	5/42 (11.9%)
Laceration	3/42 (7.1%)
Investigations
Investigations	10/42 (23.8%)
Weight decreased	4/42 (9.5%)
Metabolism and nutrition disorders
Metabolism and nutrition disorders	16/42 (38.1%)
Hyperglycaemia	5/42 (11.9%)
Hypokalaemia	5/42 (11.9%)
Hypophosphataemia	5/42 (11.9%)
Decreased appetite	4/42 (9.5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	20/42 (47.6%)
Muscle spasms	14/42 (33.3%)
Myalgia	4/42 (9.5%)
Arthralgia	3/42 (7.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant unspecified (incl cysts and polyps)	4/42 (9.5%)
Nervous system disorders
Nervous system disorders	17/42 (40.5%)
Headache	7/42 (16.7%)
Dizziness	4/42 (9.5%)
Somnolence	3/42 (7.1%)
Psychiatric disorders
Psychiatric disorders	12/42 (28.6%)
Anxiety	4/42 (9.5%)
Delerium	3/42 (7.1%)
Insomnia	3/42 (7.1%)
Renal and urinary disorders
Renal and urinary disorders	5/42 (11.9%)
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	18/42 (42.9%)
Dyspnoea	7/42 (16.7%)
Cough	6/42 (14.3%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	19/42 (45.2%)
Night Sweats	3/42 (7.1%)
Vascular disorders
Vascular disorders	9/42 (21.4%)
Hypertension	3/42 (7.1%)
Hypotension	3/42 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Institution/Investigator will not publish without Sponsor prior review and approval.