PCYC-1104-CA: Safety and Efficacy of PCI-32765 in Participants With Relapsed/Refractory Mantle Cell Lymphoma (MCL)

• Sponsor: Pharmacyclics LLC. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01236391
• Collaborator: Janssen Pharmaceuticals (Industry)
• Enrollment: 115
• Locations: 18
• Arm: 1
• Duration (Months): 35
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this study was to evaluate the efficacy of ibrutinib in participants with relapsed or refractory MCL.

The secondary objective was to evaluate the safety of a fixed daily dosing regimen (560 mg daily) of PCI-32765 in this population.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: PCI-32765	Phase 2

Detailed Description

This is a Phase 2, open-label, nonrandomized, multicenter, monotherapy study in subjects with histologically documented MCL who have relapsed after ≥ 1 (but not > 5) prior treatment regimens. All subjects meeting eligibility criteria will receive PCI-32765 capsules at a dosage of 560 mg/day once daily for a 28-day cycle until disease progression, unacceptable toxicity, or enrollment in a long-term extension study, whichever occurs earlier.

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Phase 2 Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Relapsed or Refractory Mantle Cell Lymphoma
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Participants received PCI-32765 560 mg daily Participants were enrolled and received 560 mg/day dose, stratified into 2 groups based on prior bortezomib exposure.	Drug: PCI-32765; 560 mg daily

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving Response [The median follow-up time on study for all treated participants is 15.3 (range 1.9 - 22.3) months]

   The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. CR is a complete disappearance of all disease, no new lesions, lymph nodes must have regressed and be PET negative, spleen and liver should not be palpable and without nodules, and bone marrow must be negative. PR is a >/= 50% decrease in the sum of the product of diameters of the target lesions, and >/= 50% decrease of splenic and hepatic nodules from baseline, no new lesions and no increase in the size of liver, spleen or non-target lesions.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (AEs) [From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure]

   Number of participants who had experienced at least one treatment emergent AE

2. PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 [Performed During the First Month of Receiving PCI-32765]

   Area under the plasma concentration-time curve using data collected at 0, 1, 2, 4, 6-8, and 24 hours post dose (AUC0-24h)

3. Mean Change From Baseline to Cycle 5 in EORTC QLQ-C30 Global Health Status Score [From Baseline to Cycle 5 (Week 20)]

   Mean change from baseline to Cycle 5 in the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) Global Health Status Score according to EORTC QLQ-C30 Scoring Manual (3rd Edition, 2001). For global health status, positive changes indicated better health status or functioning, and negative changes indicated worsening of health status or functioning. Scale scores range from 0 to 100. A change in 5 to 10 points in either direction represents a small change; 10 to 20 points represents a moderate change and greater than 20 points represents a large change.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Men and women ≥ 18 years of age

• ECOG performance status of ≤ 2

• Pathologically confirmed MCL, with documentation of either overexpression of cyclin D1 or t(11;14), and measurable disease on cross sectional imaging that is ≥ 2 cm in the longest diameter and measurable in 2 perpendicular dimensions

• Documented failure to achieve at least partial response (PR) with, or documented disease progression disease after, the most recent treatment regimen

• At least 1, but no more than 5, prior treatment regimens for MCL (Note: Subjects having received ≥2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered to be bortezomib-exposed.)

• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Major exclusion criteria:

• Prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of study drug

• Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at undue risk

• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction

• Any of the following laboratory abnormalities:

1. Absolute neutrophil count (ANC) < 750 cells/mm3 (0.75 x 109/L) unless there is documented bone marrow involvement

2. Platelet count < 50,000 cells/mm3 (50 x 109/L) independent of transfusion support unless there is documented bone marrow involvement

3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)

4. Creatinine > 2.0 x ULN

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305
2	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
3	Cll Research and Treatment Program	New Hyde Park	New York	United States	11042
4	New York Presbyterian Hospital/Cornell Medical Center	New York	New York	United States	94305
5	The Ohio Sate university	Columbus	Ohio	United States	43210
6	Oregon Health & Science University	Portland	Oregon	United States	97239
7	MD Anderson Cancer Center	Houston	Texas	United States	77030
8	University of Virginia School of Medicine Hospital	Charlottesville	Virginia	United States	22908
9	University of Wisconsin	Madison	Wisconsin	United States	53792
10	Klinikum der Universitat Munchen - Campus Grosshadern	Munchen		Germany	D - 81377
11	Universitatsklinikum Ulm, Klinik fur Innere Medizin II	ULM		Germany	89081
12	Oddzail Kliniczny Onkologil	Bydgoszcz		Poland	85-796
13	Malopolskie Centrum Medyczne	Krakow		Poland	30-510
14	MTZ Clinical Research Sp. z o.o.	Warsaw		Poland	02-106
15	Centre for Experimental Cancer Medicine	London		United Kingdom	EC1M6BQ
16	Christie Hospital	Manchester		United Kingdom	M20 4BX
17	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH
18	Southampton General Hospital	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Pharmacyclics LLC.
• Janssen Pharmaceuticals

Investigators

• Study Director: Darrin Beaupre, MD, PhD, Pharmacyclics LLC.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• www.pharmacyclics.com

Publications

None provided.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT01236391
• Other Study ID Numbers: PCYC-1104-CA; PCI-32765
• First Posted: Nov 8, 2010
• Last Update Posted: Aug 28, 2015
• Last Verified: Aug 1, 2015

• Keywords provided by Pharmacyclics LLC.: Pharmacyclics; Mantle; Mantle Cell; Lymphoma; Non-Hodgkins; Bortezomib; Velcade; Naive; PCYC
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell

Study Results

Participant Flow

Pre-assignment Detail	One hundred fifteen subjects were enrolled and 111 subjects received at least 1 dose of ibrutinib and constitute the all treated population and the safety analysis set.

Arm/Group Title	PCI-32765
Arm/Group Description	Participants received 560 mg daily
Period Title: Overall Study
STARTED	111
COMPLETED	95
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	PCI-32765
Arm/Group Description	PCI-32765: 560 mg daily
Overall Participants	111
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	41 36.9%
>=65 years	70 63.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.1 (8.6)
Sex: Female, Male (Count of Participants)
Female	26 23.4%
Male	85 76.6%
Region of Enrollment (participants) [Number]
United States	78 70.3%
Poland	10 9%
Germany	3 2.7%
United Kingdom	20 18%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Response
Description	The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator. CR is a complete disappearance of all disease, no new lesions, lymph nodes must have regressed and be PET negative, spleen and liver should not be palpable and without nodules, and bone marrow must be negative. PR is a >/= 50% decrease in the sum of the product of diameters of the target lesions, and >/= 50% decrease of splenic and hepatic nodules from baseline, no new lesions and no increase in the size of liver, spleen or non-target lesions.
Time Frame	The median follow-up time on study for all treated participants is 15.3 (range 1.9 - 22.3) months

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of PCI-32765 and constitute the all treated population

Arm/Group Title	PCI-32765
Arm/Group Description	PCI-32765: 560 mg daily
Measure Participants	111
Number (95% Confidence Interval) [percentage of participants with response]	67.6 60.9%

2. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (AEs)
Description	Number of participants who had experienced at least one treatment emergent AE
Time Frame	From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCI-32765
Arm/Group Description	PCI-32765: 560 mg daily
Measure Participants	111
Number [participants]	111 100%

3. Secondary Outcome

Title	PCI-32765 and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765
Description	Area under the plasma concentration-time curve using data collected at 0, 1, 2, 4, 6-8, and 24 hours post dose (AUC0-24h)
Time Frame	Performed During the First Month of Receiving PCI-32765

Outcome Measure Data

Analysis Population Description

PK samples were collected in a subset of participants (n=48) in this trial (n=111). PK parameters reported here reflects those that were PK evaluable from the 48 participants.

Arm/Group Title	PCI-32765 - Day 8	PCI-45227 (Metabolite)- Day 8
Arm/Group Description	PCI-32765: 560 mg daily	PCI-32765: 560 mg daily
Measure Participants	43	44
Mean (Standard Deviation) [AUC0-24h (ng*h/mL)]	953 (705)	1263 (707)

4. Secondary Outcome

Title	Mean Change From Baseline to Cycle 5 in EORTC QLQ-C30 Global Health Status Score
Description	Mean change from baseline to Cycle 5 in the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) Global Health Status Score according to EORTC QLQ-C30 Scoring Manual (3rd Edition, 2001). For global health status, positive changes indicated better health status or functioning, and negative changes indicated worsening of health status or functioning. Scale scores range from 0 to 100. A change in 5 to 10 points in either direction represents a small change; 10 to 20 points represents a moderate change and greater than 20 points represents a large change.
Time Frame	From Baseline to Cycle 5 (Week 20)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EORTC QLQ-C30
Arm/Group Description	Participants received PCI-32765 560 mg daily and completed the EORTC QLQ-C30 questionnaire at Pre-Dose and at Cycle 5
Measure Participants	69
Mean (Standard Deviation) [scores on a scale]	0.6 (22.4)

Adverse Events

Time Frame	From first dose of PCI-32765 to within 30 days of last dose
Arm/Group Title	PCI-32765
Arm/Group Description	PCI-32765: 560 mg daily
All Cause Mortality
	PCI-32765
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	PCI-32765
	Affected / at Risk (%)	# Events
Total	62/111 (55.9%)
Blood and lymphatic system disorders
Febrile neutropenia	3/111 (2.7%)
Anaemia	2/111 (1.8%)
Neutropenia	1/111 (0.9%)
Pancytopenia	1/111 (0.9%)
Retroperitoneal lymphadenopathy	1/111 (0.9%)
Thrombocytopenia	1/111 (0.9%)
Cardiac disorders
Atrial fibrillation	5/111 (4.5%)
Atrial flutter	1/111 (0.9%)
Cardiac arrest	1/111 (0.9%)
Cardiac failure	1/111 (0.9%)
Coronary artery occlusion	1/111 (0.9%)
Gastrointestinal disorders
Abdominal pain	3/111 (2.7%)
Ileus paralytic	2/111 (1.8%)
Diarrhoea	1/111 (0.9%)
Ileus	1/111 (0.9%)
Small intestinal obstruction	1/111 (0.9%)
General disorders
Oedema peripheral	3/111 (2.7%)
Pyrexia	3/111 (2.7%)
Non-cardiac chest pain	2/111 (1.8%)
Chills	1/111 (0.9%)
Device leakage	1/111 (0.9%)
General physical health deterioration	1/111 (0.9%)
Infections and infestations
Pneumonia	6/111 (5.4%)
Urinary tract infection	4/111 (3.6%)
Bronchitis	2/111 (1.8%)
Cellulitis	2/111 (1.8%)
Sepsis	2/111 (1.8%)
Anal abscess	1/111 (0.9%)
Cellulitis orbital	1/111 (0.9%)
Clostridium difficile colitis	1/111 (0.9%)
Enterocolitis infectious	1/111 (0.9%)
Gastroenteritis	1/111 (0.9%)
Herpes zoster ophthalmic	1/111 (0.9%)
Lower respiratory tract infection	1/111 (0.9%)
Pneumocystis jiroveci pneumonia	1/111 (0.9%)
Pneumonia bacterial	1/111 (0.9%)
Pneumonia klebsiella	1/111 (0.9%)
Respiratory tract infection	1/111 (0.9%)
Staphylococcal bacteraemia	1/111 (0.9%)
Streptococcal infection	1/111 (0.9%)
Wound infection	1/111 (0.9%)
Injury, poisoning and procedural complications
Subdural haematoma	3/111 (2.7%)
Spinal compression fracture	2/111 (1.8%)
Metabolism and nutrition disorders
Dehydration	2/111 (1.8%)
Musculoskeletal and connective tissue disorders
Flank pain	2/111 (1.8%)
Arthralgia	1/111 (0.9%)
Groin pain	1/111 (0.9%)
Neck mass	1/111 (0.9%)
Osteoarthritis	1/111 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mantle cell lymphoma	8/111 (7.2%)
Bladder cancer	1/111 (0.9%)
Malignant pleural effusion	1/111 (0.9%)
Metastatic neoplasm	1/111 (0.9%)
Nervous system disorders
Headache	1/111 (0.9%)
Transient global amnesia	1/111 (0.9%)
Psychiatric disorders
Confusional state	2/111 (1.8%)
Renal and urinary disorders
Renal failure acute	3/111 (2.7%)
Haematuria	2/111 (1.8%)
Renal failure	1/111 (0.9%)
Urinary tract obstruction	1/111 (0.9%)
Reproductive system and breast disorders
Uterovaginal prolapse	1/111 (0.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/111 (1.8%)
Respiratory failure	2/111 (1.8%)
Chronic obstructive pulmonary disease	1/111 (0.9%)
Hypoxia	1/111 (0.9%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/111 (0.9%)
Vascular disorders
Hypotension	1/111 (0.9%)
Other (Not Including Serious) Adverse Events
	PCI-32765
	Affected / at Risk (%)	# Events
Total	111/111 (100%)
Blood and lymphatic system disorders
Neutropenia	20/111 (18%)
Thrombocytopenia	20/111 (18%)
Anaemia	14/111 (12.6%)
Leukopenia	7/111 (6.3%)
Leukocytosis	3/111 (2.7%)
Febrile neutropenia	1/111 (0.9%)
Iron deficiency anaemia	1/111 (0.9%)
Lymphadenopathy	1/111 (0.9%)
Lymphocytosis	1/111 (0.9%)
Lymphopenia	1/111 (0.9%)
Splenomegaly	1/111 (0.9%)
Cardiac disorders
Atrial fibrillation	7/111 (6.3%)
Sinus tachycardia	5/111 (4.5%)
Sinus bradycardia	2/111 (1.8%)
Atrioventricular block first degree	1/111 (0.9%)
Cardiac failure	1/111 (0.9%)
Mitral valve incompetence	1/111 (0.9%)
Myocardial infarction	1/111 (0.9%)
Palpitations	1/111 (0.9%)
Supraventricular tachycardia	1/111 (0.9%)
Torsade de pointes	1/111 (0.9%)
Ventricular tachycardia	1/111 (0.9%)
Ear and labyrinth disorders
Ear pain	2/111 (1.8%)
Hyperacusis	1/111 (0.9%)
Hypoacusis	1/111 (0.9%)
Tinnitus	1/111 (0.9%)
Vertigo	1/111 (0.9%)
Endocrine disorders
Hypothyroidism	2/111 (1.8%)
Eye disorders
Lacrimation increased	8/111 (7.2%)
Cataract	6/111 (5.4%)
Conjunctivitis	6/111 (5.4%)
Dry eye	5/111 (4.5%)
Ocular hyperaemia	2/111 (1.8%)
Vision blurred	2/111 (1.8%)
Visual acuity reduced	2/111 (1.8%)
Vitreous floaters	2/111 (1.8%)
Conjunctival haemorrhage	1/111 (0.9%)
Diabetic retinopathy	1/111 (0.9%)
Eye inflammation	1/111 (0.9%)
Eyelid ptosis	1/111 (0.9%)
Periorbital oedema	1/111 (0.9%)
Photophobia	1/111 (0.9%)
Retinal detachment	1/111 (0.9%)
Scleral haemorrhage	1/111 (0.9%)
Gastrointestinal disorders
Diarrhoea	55/111 (49.5%)
Nausea	34/111 (30.6%)
Constipation	28/111 (25.2%)
Vomiting	25/111 (22.5%)
Abdominal pain	17/111 (15.3%)
Stomatitis	13/111 (11.7%)
Dyspepsia	12/111 (10.8%)
Abdominal pain upper	6/111 (5.4%)
Dry mouth	6/111 (5.4%)
Flatulence	5/111 (4.5%)
Gastritis	5/111 (4.5%)
Abdominal distension	4/111 (3.6%)
Gastrooesophageal reflux disease	4/111 (3.6%)
Oral pain	4/111 (3.6%)
Abdominal discomfort	3/111 (2.7%)
Dysphagia	3/111 (2.7%)
Epigastric discomfort	3/111 (2.7%)
Gingival oedema	2/111 (1.8%)
Mouth ulceration	2/111 (1.8%)
Proctalgia	2/111 (1.8%)
Tongue ulceration	2/111 (1.8%)
Barrett's oesophagus	1/111 (0.9%)
Cheilitis	1/111 (0.9%)
Eructation	1/111 (0.9%)
Faecal incontinence	1/111 (0.9%)
Frequent bowel movements	1/111 (0.9%)
Gastric antral vascular ectasia	1/111 (0.9%)
Glossodynia	1/111 (0.9%)
Haematochezia	1/111 (0.9%)
Haemorrhoids	1/111 (0.9%)
Irritable bowel syndrome	1/111 (0.9%)
Lip blister	1/111 (0.9%)
Lip swelling	1/111 (0.9%)
Lip ulceration	1/111 (0.9%)
Lower gastrointestinal haemorrhage	1/111 (0.9%)
Mouth haemorrhage	1/111 (0.9%)
Odynophagia	1/111 (0.9%)
Palatal disorder	1/111 (0.9%)
Pancreatitis chronic	1/111 (0.9%)
Periodontal disease	1/111 (0.9%)
Proctitis	1/111 (0.9%)
Rectal fissure	1/111 (0.9%)
Rectal haemorrhage	1/111 (0.9%)
General disorders
Fatigue	46/111 (41.4%)
Oedema peripheral	30/111 (27%)
Pyrexia	18/111 (16.2%)
Asthenia	12/111 (10.8%)
Influenza like illness	8/111 (7.2%)
Chills	6/111 (5.4%)
Chest pain	4/111 (3.6%)
Mucosal inflammation	4/111 (3.6%)
Non-cardiac chest pain	3/111 (2.7%)
Pain	3/111 (2.7%)
Local swelling	2/111 (1.8%)
Axillary pain	1/111 (0.9%)
Chest discomfort	1/111 (0.9%)
Crepitations	1/111 (0.9%)
Device leakage	1/111 (0.9%)
Feeling abnormal	1/111 (0.9%)
Generalised oedema	1/111 (0.9%)
Gravitational oedema	1/111 (0.9%)
Induration	1/111 (0.9%)
Injection site erythema	1/111 (0.9%)
Injection site extravasation	1/111 (0.9%)
Injection site haematoma	1/111 (0.9%)
Injection site pain	1/111 (0.9%)
Injection site reaction	1/111 (0.9%)
Malaise	1/111 (0.9%)
Oedema	1/111 (0.9%)
Performance status decreased	1/111 (0.9%)
Xerosis	1/111 (0.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/111 (1.8%)
Hepatic function abnormal	1/111 (0.9%)
Immune system disorders
Seasonal allergy	3/111 (2.7%)
Hypersensitivity	2/111 (1.8%)
Allergy to arthropod bite	1/111 (0.9%)
Drug hypersensitivity	1/111 (0.9%)
Infections and infestations
Upper respiratory tract infection	26/111 (23.4%)
Sinusitis	14/111 (12.6%)
Urinary tract infection	14/111 (12.6%)
Pneumonia	10/111 (9%)
Nasopharyngitis	9/111 (8.1%)
Bronchitis	8/111 (7.2%)
Cellulitis	8/111 (7.2%)
Folliculitis	5/111 (4.5%)
Herpes zoster	5/111 (4.5%)
Rhinitis	5/111 (4.5%)
Oral herpes	4/111 (3.6%)
Skin infection	4/111 (3.6%)
Clostridium difficile colitis	3/111 (2.7%)
Gastroenteritis	3/111 (2.7%)
Lower respiratory tract infection	3/111 (2.7%)
Paronychia	3/111 (2.7%)
Staphylococcal infection	3/111 (2.7%)
Tooth infection	3/111 (2.7%)
Bacteraemia	2/111 (1.8%)
Clostridial infection	2/111 (1.8%)
Diverticulitis	2/111 (1.8%)
Eye infection	2/111 (1.8%)
Herpes simplex	2/111 (1.8%)
Infection	2/111 (1.8%)
Localised infection	2/111 (1.8%)
Otitis media	2/111 (1.8%)
Respiratory tract infection	2/111 (1.8%)
Viral infection	2/111 (1.8%)
Wound infection	2/111 (1.8%)
Bronchiolitis	1/111 (0.9%)
Citrobacter infection	1/111 (0.9%)
Conjunctivitis infective	1/111 (0.9%)
Cryptococcosis	1/111 (0.9%)
Eye infection bacterial	1/111 (0.9%)
Gastroenteritis viral	1/111 (0.9%)
Genital infection fungal	1/111 (0.9%)
Haemophilus infection	1/111 (0.9%)
Herpes virus infection	1/111 (0.9%)
Herpes zoster ophthalmic	1/111 (0.9%)
Histoplasmosis	1/111 (0.9%)
Implant site infection	1/111 (0.9%)
Incision site infection	1/111 (0.9%)
Influenza	1/111 (0.9%)
Klebsiella infection	1/111 (0.9%)
Lip infection	1/111 (0.9%)
Lower respiratory tract infection bacterial	1/111 (0.9%)
Nail infection	1/111 (0.9%)
Onychomycosis	1/111 (0.9%)
Oral candidiasis	1/111 (0.9%)
Papilloma viral infection	1/111 (0.9%)
Pharyngitis streptococcal	1/111 (0.9%)
Pneumonia bacterial	1/111 (0.9%)
Rash pustular	1/111 (0.9%)
Rectal abscess	1/111 (0.9%)
Streptococcal infection	1/111 (0.9%)
Tinea pedis	1/111 (0.9%)
Urinary tract infection pseudomonal	1/111 (0.9%)
Viral upper respiratory tract infection	1/111 (0.9%)
Injury, poisoning and procedural complications
Contusion	19/111 (17.1%)
Fall	8/111 (7.2%)
Laceration	3/111 (2.7%)
Excoriation	2/111 (1.8%)
Traumatic haematoma	2/111 (1.8%)
Arthropod bite	1/111 (0.9%)
Eye injury	1/111 (0.9%)
Head injury	1/111 (0.9%)
Ligament sprain	1/111 (0.9%)
Open wound	1/111 (0.9%)
Post procedural constipation	1/111 (0.9%)
Post-traumatic pain	1/111 (0.9%)
Procedural pain	1/111 (0.9%)
Skeletal injury	1/111 (0.9%)
Skin wound	1/111 (0.9%)
Subdural haematoma	1/111 (0.9%)
Thermal burn	1/111 (0.9%)
Urinary retention postoperative	1/111 (0.9%)
Wound	1/111 (0.9%)
Investigations
Blood creatinine increased	6/111 (5.4%)
Alanine aminotransferase increased	3/111 (2.7%)
Aspartate aminotransferase increased	3/111 (2.7%)
Weight decreased	3/111 (2.7%)
Weight increased	3/111 (2.7%)
Blood bilirubin increased	2/111 (1.8%)
Cardiac murmur	2/111 (1.8%)
Glomerular filtration rate decreased	2/111 (1.8%)
International normalised ratio increased	2/111 (1.8%)
Activated partial thromboplastin time prolonged	1/111 (0.9%)
Aspergillus test positive	1/111 (0.9%)
Blood alkaline phosphatase increased	1/111 (0.9%)
Blood bilirubin abnormal	1/111 (0.9%)
Blood cholesterol increased	1/111 (0.9%)
Blood immunoglobulin G decreased	1/111 (0.9%)
Blood iron decreased	1/111 (0.9%)
Blood phosphorus decreased	1/111 (0.9%)
Breath sounds abnormal	1/111 (0.9%)
C-reactive protein increased	1/111 (0.9%)
Haemophilus test positive	1/111 (0.9%)
Heart rate irregular	1/111 (0.9%)
Liver function test abnormal	1/111 (0.9%)
Macular reflex abnormal	1/111 (0.9%)
Mean cell volume increased	1/111 (0.9%)
Platelet count decreased	1/111 (0.9%)
Urine output decreased	1/111 (0.9%)
White blood cell count increased	1/111 (0.9%)
Metabolism and nutrition disorders
Decreased appetite	24/111 (21.6%)
Hyperuricaemia	15/111 (13.5%)
Dehydration	12/111 (10.8%)
Hypokalaemia	9/111 (8.1%)
Hyponatraemia	6/111 (5.4%)
Hyperglycaemia	4/111 (3.6%)
Hypomagnesaemia	4/111 (3.6%)
Enzyme abnormality	2/111 (1.8%)
Hypocalcaemia	2/111 (1.8%)
Hypoglycaemia	2/111 (1.8%)
Alcohol intolerance	1/111 (0.9%)
Fluid overload	1/111 (0.9%)
Gout	1/111 (0.9%)
Hypercholesterolaemia	1/111 (0.9%)
Hyperkalaemia	1/111 (0.9%)
Hyperphosphataemia	1/111 (0.9%)
Hypoalbuminaemia	1/111 (0.9%)
Hypophosphataemia	1/111 (0.9%)
Musculoskeletal and connective tissue disorders
Muscle spasms	16/111 (14.4%)
Back pain	14/111 (12.6%)
Myalgia	14/111 (12.6%)
Pain in extremity	12/111 (10.8%)
Arthralgia	11/111 (9.9%)
Musculoskeletal pain	6/111 (5.4%)
Muscular weakness	5/111 (4.5%)
Flank pain	2/111 (1.8%)
Groin pain	2/111 (1.8%)
Joint stiffness	2/111 (1.8%)
Mobility decreased	2/111 (1.8%)
Musculoskeletal chest pain	2/111 (1.8%)
Musculoskeletal stiffness	2/111 (1.8%)
Neck pain	2/111 (1.8%)
Bone pain	1/111 (0.9%)
Intervertebral disc degeneration	1/111 (0.9%)
Joint contracture	1/111 (0.9%)
Musculoskeletal discomfort	1/111 (0.9%)
Myopathy	1/111 (0.9%)
Osteoporosis	1/111 (0.9%)
Soft tissue disorder	1/111 (0.9%)
Synovial cyst	1/111 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/111 (0.9%)
Oral papilloma	1/111 (0.9%)
Skin cancer	1/111 (0.9%)
Skin papilloma	1/111 (0.9%)
Squamous cell carcinoma	1/111 (0.9%)
Squamous cell carcinoma of skin	1/111 (0.9%)
Nervous system disorders
Dizziness	16/111 (14.4%)
Headache	12/111 (10.8%)
Peripheral sensory neuropathy	6/111 (5.4%)
Paraesthesia	4/111 (3.6%)
Memory impairment	3/111 (2.7%)
Amnesia	2/111 (1.8%)
Lethargy	2/111 (1.8%)
Somnolence	2/111 (1.8%)
Balance disorder	1/111 (0.9%)
Dizziness postural	1/111 (0.9%)
Head discomfort	1/111 (0.9%)
Hypersomnia	1/111 (0.9%)
Hypoaesthesia	1/111 (0.9%)
Migraine	1/111 (0.9%)
Migraine with aura	1/111 (0.9%)
Neuralgia	1/111 (0.9%)
Neuropathy peripheral	1/111 (0.9%)
Nystagmus	1/111 (0.9%)
Peroneal nerve palsy	1/111 (0.9%)
Presyncope	1/111 (0.9%)
Sciatica	1/111 (0.9%)
Sensory disturbance	1/111 (0.9%)
Tension headache	1/111 (0.9%)
Tremor	1/111 (0.9%)
Psychiatric disorders
Insomnia	11/111 (9.9%)
Anxiety	6/111 (5.4%)
Depression	6/111 (5.4%)
Agitation	3/111 (2.7%)
Confusional state	3/111 (2.7%)
Abnormal behaviour	1/111 (0.9%)
Euphoric mood	1/111 (0.9%)
Libido decreased	1/111 (0.9%)
Mania	1/111 (0.9%)
Panic attack	1/111 (0.9%)
Renal and urinary disorders
Haematuria	5/111 (4.5%)
Renal failure acute	4/111 (3.6%)
Pollakiuria	3/111 (2.7%)
Dysuria	2/111 (1.8%)
Renal impairment	2/111 (1.8%)
Urinary incontinence	2/111 (1.8%)
Azotaemia	1/111 (0.9%)
Hydronephrosis	1/111 (0.9%)
Micturition urgency	1/111 (0.9%)
Nocturia	1/111 (0.9%)
Obstructive uropathy	1/111 (0.9%)
Urinary tract obstruction	1/111 (0.9%)
Urinary tract pain	1/111 (0.9%)
Reproductive system and breast disorders
Haematospermia	2/111 (1.8%)
Oedema genital	2/111 (1.8%)
Breast pain	1/111 (0.9%)
Penile pain	1/111 (0.9%)
Vaginal haemorrhage	1/111 (0.9%)
Vulvovaginal pain	1/111 (0.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	29/111 (26.1%)
Cough	20/111 (18%)
Epistaxis	12/111 (10.8%)
Oropharyngeal pain	10/111 (9%)
Pleural effusion	6/111 (5.4%)
Rhinitis allergic	4/111 (3.6%)
Dysphonia	3/111 (2.7%)
Sinus congestion	3/111 (2.7%)
Lung consolidation	2/111 (1.8%)
Productive cough	2/111 (1.8%)
Haemoptysis	1/111 (0.9%)
Hiccups	1/111 (0.9%)
Increased upper airway secretion	1/111 (0.9%)
Lung infiltration	1/111 (0.9%)
Nasal congestion	1/111 (0.9%)
Nasal inflammation	1/111 (0.9%)
Paranasal sinus hypersecretion	1/111 (0.9%)
Pulmonary embolism	1/111 (0.9%)
Rales	1/111 (0.9%)
Respiratory tract congestion	1/111 (0.9%)
Restrictive pulmonary disease	1/111 (0.9%)
Rhinorrhoea	1/111 (0.9%)
Sinus disorder	1/111 (0.9%)
Skin and subcutaneous tissue disorders
Rash	17/111 (15.3%)
Petechiae	10/111 (9%)
Pruritus	8/111 (7.2%)
Rash maculo-papular	8/111 (7.2%)
Skin lesion	8/111 (7.2%)
Dry skin	6/111 (5.4%)
Ecchymosis	6/111 (5.4%)
Alopecia	5/111 (4.5%)
Increased tendency to bruise	5/111 (4.5%)
Night sweats	5/111 (4.5%)
Rash macular	4/111 (3.6%)
Erythema	3/111 (2.7%)
Onychoclasis	3/111 (2.7%)
Purpura	3/111 (2.7%)
Rash erythematous	3/111 (2.7%)
Blister	2/111 (1.8%)
Dermatitis acneiform	2/111 (1.8%)
Ingrowing nail	2/111 (1.8%)
Skin discolouration	2/111 (1.8%)
Acne	1/111 (0.9%)
Decubitus ulcer	1/111 (0.9%)
Dermatitis	1/111 (0.9%)
Dermatitis allergic	1/111 (0.9%)
Dermatitis contact	1/111 (0.9%)
Haemorrhage subcutaneous	1/111 (0.9%)
Hyperhidrosis	1/111 (0.9%)
Intertrigo	1/111 (0.9%)
Nail disorder	1/111 (0.9%)
Nail ridging	1/111 (0.9%)
Skin fissures	1/111 (0.9%)
Skin hyperpigmentation	1/111 (0.9%)
Skin hypopigmentation	1/111 (0.9%)
Skin ulcer	1/111 (0.9%)
Sunburn	1/111 (0.9%)
Urticaria	1/111 (0.9%)
Vascular disorders
Hypertension	11/111 (9.9%)
Hypotension	6/111 (5.4%)
Orthostatic hypotension	2/111 (1.8%)
Blood pressure fluctuation	1/111 (0.9%)
Flushing	1/111 (0.9%)
Varicose vein	1/111 (0.9%)

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.