A Study to Evaluate the Safety of Long-term Treatment With Siltuximab in Patients With Multicentric Castleman's Disease

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01400503
• Collaborator: (none)
• Enrollment: 60
• Locations: 26
• Arm: 1
• Actual Duration (Months): 71
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the long-term safety of siltuximab in patients with multicentric Castleman's disease (MCD).

Condition or Disease	Intervention/Treatment	Phase
Multicentric Castleman's Disease	Drug: Siltuximab	Phase 2

Detailed Description

This is an open-label (all people know the identity of the intervention), multicenter (study conducted in multiple sites), non-randomized (patients are not assigned by chance to treatment groups), Phase 2b study. Up to 75 patients with MCD will be eligible for the study, the majority of whom will be on active therapy with siltuximab at the time of enrollment. Patients will be either siltuximab-naive or have not progressed on siltuximab in the opinion of the investigator. Duration of disease control and survival will be assessed. Data collection for patients who discontinue treatment will be limited to survival, occurrence of malignancies, and subsequent therapies for MCD, which will be assessed twice per year until the patient has been lost to follow up or has withdrawn consent for the study, whichever occurs first. An interim analysis will be conducted (no later than 2 years after the start of enrollment) to further evaluate the benefit and safety of long-term treatment with siltuximab in patients with MCD. A data will occur at 6 years after the start of enrollment and for those patients remaining on treatment after the data cutoff, data collection will be limited to pregnancies and serious adverse events (SAEs), including information on study agent administration and concomitant medications associated with an SAE. Safety evaluations for adverse events, clinical laboratory tests, vital signs, and physical examination will be performed throughout the study. The end of study is the date of the last assessment for the last patient.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter Study to Evaluate the Safety of Long-term Treatment With Siltuximab in Subjects With Multicentric Castleman's Disease
• Actual Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Siltuximab Siltuximab 11 mg/kg, intravenous infusion, given as a 1-hour infusion every 3 weeks.	Drug: Siltuximab; Type=exact number, unit=mg/kg, number=11, form=intravenous solution, route=intravenous. Siltuximab given as a 1-hour infusion every 3 weeks.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [Up to 6 years]

   An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Secondary Outcome Measures

1. Percentage of Previously Responding Participants Who Maintained Disease Control [Up to 6 years]

   Percentage of participants maintaining disease control (defined as stable or better response) was defined as the percentage of previously responding participants who had not progressed during the long-term safety extension based on investigator assessment. A worsening in any of the measures will be considered as a progression of the disease.

2. Percentage of Siltuximab-naive Participants Who Experienced Disease Control [Up to 6 years]

   Percentage of participants experiencing disease control was defined as the percentage of siltuximab-naïve participants who had stable or better response during the long-term safety extension based on investigator's judgment. Disease control was defined as stable or better response assessed by the investigators.

3. Duration of Disease Control [Up to 6 years]

   Duration of disease control (DODC) was defined as the time from the first siltuximab administration in this study to disease progression as assessed by the investigator. Disease control was defined as stable or better response assessed by the investigators. Kaplan-Meier method was used to estimate the duration of disease control.

4. Overall Survival [Up to 6 years]

   Overall survival was defined as the time between the first study siltuximab administration and death due to any cause. Kaplan-Meier method was used to estimate the overall survival.

5. Number of Participants Positive for Antibodies to Siltuximab [Up to 6 years]

   Serum samples were screened for antibodies binding to siltuximab and number of participants positive for antibodies to siltuximab was reported.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has multicentric Castleman's disease

• Have previously been enrolled in Study C0328T03 or CNTO328MCD2001 (either treatment arm)

• Have had their last administration of study treatment (siltuximab or placebo) less than 6 weeks (window of plus 2 weeks) prior to first dose

• Patients must not have had disease progression while receiving siltuximab. For those patients originally assigned to placebo in the CNTO328MCD2001 study, patients who have received less than 4 months of siltuximab following crossover will also be eligible

• Have adequate clinical laboratory parameters within 2 weeks prior to the first dose of siltuximab for this study

Exclusion Criteria:

• Unmanageable toxicity, an adverse event, progression of disease, or withdrawal of consent as reason for discontinuing treatment from previous sponsor-initiated siltuximab study

• Vaccination with live, attenuated vaccines within 4 weeks of first dose of this study

• Known unmanageable allergies, hypersensitivity, intolerance to monoclonal antibodies, to murine, chimeric, human proteins or their excipients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Tampa	Florida	United States
3		Lansing	Michigan	United States
4		Chapel Hill	North Carolina	United States
5		Greenville	South Carolina	United States
6		Houston	Texas	United States
7		Seattle	Washington	United States
8		Leuven		Belgium
9		Sao Paulo		Brazil
10		Toronto		Canada
11		Beijing		China
12		Chengdu		China
13		Cairo		Egypt
14		Montpellier		France
15		Tours Cedex 9		France
16		Vandoeuvre Les Nancy		France
17		Berlin		Germany
18		Sha Tin		Hong Kong
19		Ramat Gan		Israel
20		Seoul		Korea, Republic of
21		Auckland		New Zealand
22		Oslo		Norway
23		Singapore		Singapore
24		Madrid		Spain
25		Taipei		Taiwan
26		Manchester		United Kingdom

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

• Study Protocol - Apr 4, 2014
• Statistical Analysis Plan - Mar 21, 2017

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01400503
• Other Study ID Numbers: CR018469; CNTO328MCD2002; 2010-022837-27
• First Posted: Jul 22, 2011
• Last Update Posted: May 22, 2018
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janssen Research & Development, LLC: Multicentric Castleman's Disease; Multicentric; Castleman; Siltuximab; Long term safety
• Additional relevant MeSH terms: Castleman Disease; Siltuximab

Study Results

Participant Flow

Pre-assignment Detail	Participants enrolled in this study CNTO328MCD2002 included participants who were previously enrolled in study C0328T03 (NCT00412321) or CNTO328MCD2001 (NCT01024036) (either placebo or siltuximab treatment arm). A total of 60 participants from previous MCD studies C0328T03 and CNTO328MCD2001 were found eligible to be enrolled in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Period Title: Overall Study
STARTED	60
COMPLETED	0
NOT COMPLETED	60

Baseline Characteristics

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.1 (14.51)
Sex: Female, Male (Count of Participants)
Female	20 33.3%
Male	40 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 8.3%
Not Hispanic or Latino	55 91.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%
Asian	23 38.3%
Native Hawaiian or Other Pacific Islander	2 3.3%
Black or African American	3 5%
White	31 51.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	23 38.3%
Black or African American	3 5%
Hispanic or Latino	5 8.3%
Other	3 5%
White Non-Hispanic	26 43.3%
Region of Enrollment (Count of Participants)
Belgium	1 1.7%
Brazil	1 1.7%
Canada	1 1.7%
China	6 10%
Egypt	1 1.7%
France	3 5%
Germany	1 1.7%
Hong Kong	3 5%
New Zealand	2 3.3%
Norway	2 3.3%
Singapore	3 5%
Korea, Republic Of	4 6.7%
Spain	2 3.3%
Taiwan, Province Of China	1 1.7%
United Kingdom	2 3.3%
United States	27 45%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all enrolled participants in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	60
Count of Participants [Participants]	60 100%

2. Secondary Outcome

Title	Percentage of Previously Responding Participants Who Maintained Disease Control
Description	Percentage of participants maintaining disease control (defined as stable or better response) was defined as the percentage of previously responding participants who had not progressed during the long-term safety extension based on investigator assessment. A worsening in any of the measures will be considered as a progression of the disease.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Population included subset of safety analysis set who previously responded to siltuximab treatment ie, did not report disease progression while receiving siltuximab in study C0328T03 or CNTO328MCD2001.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	57
Number [percentage of participants]	96.5 160.8%

3. Secondary Outcome

Title	Percentage of Siltuximab-naive Participants Who Experienced Disease Control
Description	Percentage of participants experiencing disease control was defined as the percentage of siltuximab-naïve participants who had stable or better response during the long-term safety extension based on investigator's judgment. Disease control was defined as stable or better response assessed by the investigators.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Population included subset of safety analysis set who were previously Siltuximab-naive i.e., received placebo in study CNTO328MCD2001 and never received siltuximab prior to enrollment in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	3
Number [percentage of participants]	100 166.7%

4. Secondary Outcome

Title	Duration of Disease Control
Description	Duration of disease control (DODC) was defined as the time from the first siltuximab administration in this study to disease progression as assessed by the investigator. Disease control was defined as stable or better response assessed by the investigators. Kaplan-Meier method was used to estimate the duration of disease control.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all enrolled participants in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	60
Median (95% Confidence Interval) [years]	NA

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time between the first study siltuximab administration and death due to any cause. Kaplan-Meier method was used to estimate the overall survival.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all enrolled participants in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	60
Median (95% Confidence Interval) [years]	NA

6. Secondary Outcome

Title	Number of Participants Positive for Antibodies to Siltuximab
Description	Serum samples were screened for antibodies binding to siltuximab and number of participants positive for antibodies to siltuximab was reported.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Safety analysis set included all enrolled participants in this study.

Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
Measure Participants	60
Count of Participants [Participants]	3 5%

Adverse Events

Time Frame	Up to 6 years
Adverse Event Reporting Description	Safety analysis set included all enrolled participants in this study.
Arm/Group Title	Siltuximab
Arm/Group Description	Participants received siltuximab 11 milligram per kilogram (mg/kg) as a 1-hour intravenous infusion every 3 weeks until disease progression, withdrew, experienced unacceptable toxicity,or until the 6-year data cutoff, whichever occurred first.
All Cause Mortality
	Siltuximab
	Affected / at Risk (%)	# Events
Total	0/60 (0%)
Serious Adverse Events
	Siltuximab
	Affected / at Risk (%)	# Events
Total	25/60 (41.7%)
Blood and lymphatic system disorders
Anaemia	1/60 (1.7%)
Lymphadenopathy	1/60 (1.7%)
Polycythaemia	1/60 (1.7%)
Endocrine disorders
Hyperthyroidism	1/60 (1.7%)
Eye disorders
Vitreous Haemorrhage	1/60 (1.7%)
Gastrointestinal disorders
Food Poisoning	1/60 (1.7%)
Nausea	2/60 (3.3%)
Umbilical Hernia	1/60 (1.7%)
Vomiting	1/60 (1.7%)
General disorders
Chest Pain	1/60 (1.7%)
Hepatobiliary disorders
Cholelithiasis	1/60 (1.7%)
Infections and infestations
Abscess Limb	1/60 (1.7%)
Anal Abscess	1/60 (1.7%)
Cellulitis	1/60 (1.7%)
Cystitis	1/60 (1.7%)
Device Related Infection	1/60 (1.7%)
Infection	2/60 (3.3%)
Lower Respiratory Tract Infection	1/60 (1.7%)
Parotitis	1/60 (1.7%)
Peritonitis	1/60 (1.7%)
Pneumonia	2/60 (3.3%)
Pyelonephritis	1/60 (1.7%)
Vulval Abscess	1/60 (1.7%)
Wound Infection Staphylococcal	1/60 (1.7%)
Injury, poisoning and procedural complications
Ankle Fracture	1/60 (1.7%)
Avulsion Fracture	1/60 (1.7%)
Chest Injury	1/60 (1.7%)
Contusion	1/60 (1.7%)
Fractured Sacrum	1/60 (1.7%)
Ilium Fracture	1/60 (1.7%)
Pubis Fracture	1/60 (1.7%)
Rib Fracture	2/60 (3.3%)
Tibia Fracture	2/60 (3.3%)
Metabolism and nutrition disorders
Dehydration	1/60 (1.7%)
Musculoskeletal and connective tissue disorders
Back Pain	1/60 (1.7%)
Spinal Column Stenosis	1/60 (1.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign Neoplasm of Testis	1/60 (1.7%)
Uterine Leiomyoma	1/60 (1.7%)
Nervous system disorders
Cerebrospinal Fluid Leakage	1/60 (1.7%)
Syncope	1/60 (1.7%)
Renal and urinary disorders
Bladder Pain	1/60 (1.7%)
Bladder Spasm	1/60 (1.7%)
Dysuria	1/60 (1.7%)
Micturition Disorder	1/60 (1.7%)
Renal Colic	1/60 (1.7%)
Ureteral Disorder	1/60 (1.7%)
Urinary Retention	2/60 (3.3%)
Reproductive system and breast disorders
Haemorrhagic Ovarian Cyst	1/60 (1.7%)
Uterine Haemorrhage	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/60 (1.7%)
Pleural Effusion	1/60 (1.7%)
Pneumothorax	1/60 (1.7%)
Skin and subcutaneous tissue disorders
Henoch-Schonlein Purpura	1/60 (1.7%)
Surgical and medical procedures
Mastectomy	1/60 (1.7%)
Vascular disorders
Hypertension	1/60 (1.7%)
Hypertensive Crisis	1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Siltuximab
	Affected / at Risk (%)	# Events
Total	60/60 (100%)
Blood and lymphatic system disorders
Anaemia	7/60 (11.7%)
Leukopenia	5/60 (8.3%)
Lymphadenopathy	3/60 (5%)
Lymphopenia	3/60 (5%)
Neutropenia	9/60 (15%)
Thrombocytopenia	7/60 (11.7%)
Cardiac disorders
Atrioventricular Block First Degree	2/60 (3.3%)
Cardiac Disorder	2/60 (3.3%)
Palpitations	2/60 (3.3%)
Ear and labyrinth disorders
Ear Pain	6/60 (10%)
Tinnitus	5/60 (8.3%)
Tympanic Membrane Perforation	2/60 (3.3%)
Vertigo	6/60 (10%)
Eye disorders
Cataract	4/60 (6.7%)
Dry Eye	2/60 (3.3%)
Eye Irritation	2/60 (3.3%)
Periorbital Oedema	2/60 (3.3%)
Vision Blurred	7/60 (11.7%)
Gastrointestinal disorders
Abdominal Discomfort	2/60 (3.3%)
Abdominal Distension	2/60 (3.3%)
Abdominal Pain	14/60 (23.3%)
Abdominal Pain Lower	2/60 (3.3%)
Abdominal Pain Upper	10/60 (16.7%)
Anal Fistula	2/60 (3.3%)
Aphthous Ulcer	5/60 (8.3%)
Chronic Gastritis	2/60 (3.3%)
Constipation	17/60 (28.3%)
Dental Caries	2/60 (3.3%)
Diarrhoea	23/60 (38.3%)
Dry Mouth	2/60 (3.3%)
Dyspepsia	8/60 (13.3%)
Dysphagia	3/60 (5%)
Flatulence	2/60 (3.3%)
Gastrooesophageal Reflux Disease	9/60 (15%)
Gingival Pain	2/60 (3.3%)
Haematochezia	3/60 (5%)
Haemorrhoids	2/60 (3.3%)
Hiatus Hernia	3/60 (5%)
Mouth Ulceration	2/60 (3.3%)
Nausea	22/60 (36.7%)
Oral Pain	3/60 (5%)
Stomatitis	3/60 (5%)
Tongue Ulceration	2/60 (3.3%)
Toothache	4/60 (6.7%)
Vomiting	16/60 (26.7%)
General disorders
Asthenia	3/60 (5%)
Catheter Site Pain	2/60 (3.3%)
Chest Discomfort	2/60 (3.3%)
Chest Pain	3/60 (5%)
Cyst	2/60 (3.3%)
Fatigue	31/60 (51.7%)
Generalised Oedema	4/60 (6.7%)
Influenza Like Illness	2/60 (3.3%)
Localised Oedema	3/60 (5%)
Malaise	8/60 (13.3%)
Oedema	2/60 (3.3%)
Oedema Peripheral	13/60 (21.7%)
Pain	7/60 (11.7%)
Peripheral Swelling	5/60 (8.3%)
Pyrexia	6/60 (10%)
Hepatobiliary disorders
Cholelithiasis	2/60 (3.3%)
Gallbladder Polyp	2/60 (3.3%)
Hepatic Function Abnormal	11/60 (18.3%)
Hyperbilirubinaemia	7/60 (11.7%)
Immune system disorders
Seasonal Allergy	5/60 (8.3%)
Infections and infestations
Acute Sinusitis	2/60 (3.3%)
Bronchitis	2/60 (3.3%)
Cellulitis	3/60 (5%)
Conjunctivitis	3/60 (5%)
Cystitis	4/60 (6.7%)
Ear Infection	6/60 (10%)
Fungal Infection	3/60 (5%)
Furuncle	2/60 (3.3%)
Gastroenteritis	8/60 (13.3%)
Herpes Simplex	2/60 (3.3%)
Herpes Zoster	5/60 (8.3%)
Influenza	6/60 (10%)
Laryngitis	3/60 (5%)
Localised Infection	2/60 (3.3%)
Lower Respiratory Tract Infection	3/60 (5%)
Nasopharyngitis	11/60 (18.3%)
Onychomycosis	2/60 (3.3%)
Oral Candidiasis	2/60 (3.3%)
Oral Herpes	2/60 (3.3%)
Otitis Media	4/60 (6.7%)
Pharyngitis	3/60 (5%)
Pneumonia	4/60 (6.7%)
Rash Pustular	5/60 (8.3%)
Respiratory Tract Infection	4/60 (6.7%)
Rhinitis	3/60 (5%)
Sinusitis	10/60 (16.7%)
Skin Infection	3/60 (5%)
Tinea Infection	2/60 (3.3%)
Tooth Abscess	3/60 (5%)
Tooth Infection	2/60 (3.3%)
Upper Respiratory Tract Infection	40/60 (66.7%)
Urinary Tract Infection	11/60 (18.3%)
Viral Infection	2/60 (3.3%)
Injury, poisoning and procedural complications
Ankle Fracture	2/60 (3.3%)
Arthropod Bite	3/60 (5%)
Contusion	5/60 (8.3%)
Hand Fracture	2/60 (3.3%)
Laceration	2/60 (3.3%)
Ligament Sprain	5/60 (8.3%)
Procedural Pain	4/60 (6.7%)
Skin Abrasion	5/60 (8.3%)
Tibia Fracture	2/60 (3.3%)
Tooth Fracture	3/60 (5%)
Investigations
Alanine Aminotransferase Increased	4/60 (6.7%)
Aspartate Aminotransferase Increased	4/60 (6.7%)
Blood Creatinine Increased	4/60 (6.7%)
Blood Fibrinogen Decreased	3/60 (5%)
Blood Phosphorus Increased	2/60 (3.3%)
Haemoglobin Increased	4/60 (6.7%)
Serum Ferritin Decreased	4/60 (6.7%)
Weight Decreased	4/60 (6.7%)
Weight Increased	11/60 (18.3%)
Metabolism and nutrition disorders
Decreased Appetite	13/60 (21.7%)
Enzyme Abnormality	5/60 (8.3%)
Gout	6/60 (10%)
Hypercholesterolaemia	13/60 (21.7%)
Hyperglycaemia	4/60 (6.7%)
Hyperkalaemia	4/60 (6.7%)
Hypertriglyceridaemia	17/60 (28.3%)
Hyperuricaemia	10/60 (16.7%)
Hypoglycaemia	3/60 (5%)
Hypokalaemia	10/60 (16.7%)
Hypomagnesaemia	5/60 (8.3%)
Hyponatraemia	2/60 (3.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	20/60 (33.3%)
Back Pain	19/60 (31.7%)
Bone Pain	2/60 (3.3%)
Flank Pain	3/60 (5%)
Joint Stiffness	2/60 (3.3%)
Joint Swelling	2/60 (3.3%)
Muscle Spasms	7/60 (11.7%)
Muscular Weakness	6/60 (10%)
Musculoskeletal Chest Pain	2/60 (3.3%)
Musculoskeletal Pain	11/60 (18.3%)
Myalgia	4/60 (6.7%)
Neck Pain	7/60 (11.7%)
Pain in Extremity	14/60 (23.3%)
Plantar Fasciitis	2/60 (3.3%)
Rotator Cuff Syndrome	2/60 (3.3%)
Spinal Column Stenosis	2/60 (3.3%)
Synovial Cyst	2/60 (3.3%)
Tendonitis	2/60 (3.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Pain	4/60 (6.7%)
Nervous system disorders
Amnesia	2/60 (3.3%)
Dizziness	14/60 (23.3%)
Headache	14/60 (23.3%)
Hypoaesthesia	5/60 (8.3%)
Memory Impairment	2/60 (3.3%)
Neuropathy Peripheral	4/60 (6.7%)
Paraesthesia	6/60 (10%)
Peripheral Motor Neuropathy	5/60 (8.3%)
Peripheral Sensory Neuropathy	15/60 (25%)
Polyneuropathy	2/60 (3.3%)
Somnolence	3/60 (5%)
Tremor	2/60 (3.3%)
Psychiatric disorders
Anxiety	5/60 (8.3%)
Depression	8/60 (13.3%)
Insomnia	11/60 (18.3%)
Nightmare	2/60 (3.3%)
Renal and urinary disorders
Azotaemia	4/60 (6.7%)
Dysuria	3/60 (5%)
Haematuria	3/60 (5%)
Nephrolithiasis	2/60 (3.3%)
Pollakiuria	3/60 (5%)
Renal Impairment	6/60 (10%)
Urinary Retention	2/60 (3.3%)
Reproductive system and breast disorders
Erectile Dysfunction	3/60 (5%)
Menorrhagia	2/60 (3.3%)
Pelvic Pain	3/60 (5%)
Prostatitis	2/60 (3.3%)
Prostatomegaly	2/60 (3.3%)
Respiratory, thoracic and mediastinal disorders
Cough	19/60 (31.7%)
Dyspnoea	13/60 (21.7%)
Dyspnoea Exertional	3/60 (5%)
Epistaxis	4/60 (6.7%)
Nasal Congestion	3/60 (5%)
Oropharyngeal Pain	15/60 (25%)
Pneumonitis	3/60 (5%)
Productive Cough	5/60 (8.3%)
Rhinitis Allergic	2/60 (3.3%)
Sinus Congestion	3/60 (5%)
Upper-Airway Cough Syndrome	4/60 (6.7%)
Wheezing	3/60 (5%)
Skin and subcutaneous tissue disorders
Acne	2/60 (3.3%)
Blister	2/60 (3.3%)
Dermatitis	2/60 (3.3%)
Dermatitis Acneiform	3/60 (5%)
Dermatitis Allergic	3/60 (5%)
Dry Skin	8/60 (13.3%)
Eczema	7/60 (11.7%)
Hyperhidrosis	9/60 (15%)
Night Sweats	9/60 (15%)
Pruritus	19/60 (31.7%)
Pruritus Generalised	3/60 (5%)
Psoriasis	2/60 (3.3%)
Rash	21/60 (35%)
Rash Maculo-Papular	16/60 (26.7%)
Rash Pruritic	3/60 (5%)
Scar Pain	2/60 (3.3%)
Seborrhoeic Dermatitis	2/60 (3.3%)
Skin Hyperpigmentation	3/60 (5%)
Skin Induration	2/60 (3.3%)
Skin Lesion	2/60 (3.3%)
Urticaria	4/60 (6.7%)
Vitiligo	2/60 (3.3%)
Vascular disorders
Flushing	7/60 (11.7%)
Hot Flush	4/60 (6.7%)
Hypertension	15/60 (25%)
Hypotension	6/60 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.