Safety,Tolerability,Pharmacokinetics and Efficacy of CFZ533 in Moderate to Severe Myasthenia Gravis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02565576
• Collaborator: (none)
• Enrollment: 44
• Locations: 15
• Arms: 2
• Actual Duration (Months): 26.7
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on therapy to standard of care in patients with moderate to severe myasthenia gravis (MG).

Condition or Disease	Intervention/Treatment	Phase
Myasthenia Gravis, Generalized	Drug: Placebo; Drug: CFZ533	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Preliminarily Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of CFZ533 in Patients With Moderate to Severe Myasthenia Gravis
• Actual Study Start Date: Sep 29, 2015
• Actual Primary Completion Date: Jul 31, 2017
• Actual Study Completion Date: Dec 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: CFZ533 CFZ533	Drug: Placebo; Drug: CFZ533
Placebo Comparator: Placebo Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type. [week 25]

   QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005).

Secondary Outcome Measures

1. Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type. [From baseline to week 49]

   The Myasthenia Gravis Composite (MGC) score is another key efficacy outcome measure, ranging from 0 to 50. It is reliable and demonstrates concurrent and longitudinal construct validity in the MG practice care setting (Burns et al 2010). The MGC scale covers 10 important functional domains most frequently involved in patients with MG. The proportion of bulbar and respiratory items reflect the clinical importance of these domains in the disease, and are appropriately weighted. The assessment of each of the 10 test items provides immediate insight into the status of that particular functional domain. A decrease in this score shows an improvement.

2. Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score [at week 49]

   QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005).

3. Proportion of Patients Intolerant to Steroid Taper [week 49]

4. Number of Patients Who Discontinued Due to Inefficacy or Worsening [week 49]

5. Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) [week 25]

   The MG-ADL is an 8-item survey to assess functional performance of daily activities that are sometimes impaired by MG e.g. talking, breathing, swallowing etc. (Muppidi et al 2011). The higher score on MG-ADL scale (0-24 points) indicates worse functional performance of daily activities.

6. Mean Changes From Baseline in the QMG Score at Week 49 [week 49]

   QMG (quantitative myasthenia gravis) score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005). A decrease in the QMG score indicated an improvement. Results given as a change in the score as compared from baseline

7. Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15) [week 25]

   The MG-QOL15 is a 15-item survey, completed by MG patients and it is designed to assess some aspects of quality of life (QoL) related to MG (Burns et al 2011) e.g. assesment of mood, eating, speaking, driving a car etc.. The higher score on MG-QOL15 scale (0-60 points) indicates worse QoL.

8. Free CD40 on B Cells [week 1, week 25]

   CD40 receptor occupancy by CFZ533 in peripheral blood was assessed by flow cytometry analysis, measuring free or total CD40 receptors on whole blood B cells. Free CD40 on CD19-positive B cells, using PE-conjugated CFZ533 whose binding was prevented by bound, unconjugated CFZ533 (drug bound to CD40 on peripheral blood B cells). The more CD40 was occupied by unlabeled CFZ533, the less binding of labeled CFZ533, manifest as a lower mean fluorescence intensity (MFI) of CD40 on B cells. MFI from free CD40 on B cells was converted into Molecules of Equivalent Soluble Fluorochrome (MESF) using PE-MESF beads.

9. Total Soluble CD40 (sCD40) in Plasma [week1, week 25]

   PD

10. Plasma CFZ533 Concentration at Steady State Conditions (Week 17) [week 17]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of MG class IIa to IVa inclusive (Myasthenia Gravis Foundation of America Clinical Classification).

2. Quantitative Myasthenia Gravis (QMG) score of 10 or greater. If the QMG score is < 15 no more than 4 points may be derived from items 1 or 2 (ocular motility disturbance and ptosis).

3. Documented history of acetylcholine receptor (AChR) or Muscle Specific Kinase (MuSK) antibody positive.

4. Only one immunosuppressant or immunomodulatory drug at a stable dose is allowed during the study (i) azathioprine and mycophenolate mofetil must be stable for at least 4 months prior to randomization (ii) cyclosporine must be stable for at least 3 months prior to randomization.

5. If the patient is on oral corticosteroids, methotrexate or tacrolimus at screening, the dose must be stable for at least 1 month prior to randomization.

6. If the patient is on cholinesterase inhibitors at screening, the dose must be stable for at least 2 weeks prior to randomization.

7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, may be included in the study if they are using highly effective methods of contraception during the study and for 12 weeks after study treatment.

Exclusion Criteria:

1. MGFA grade I, IVb, or V disease.

2. Documented presence of unresected thymoma.

3. Patients having undergone thymectomy or thymo thymectomy (resection of thymoma) within 6 months of screening.

4. Patients having received any of the following treatments prior to randomization:

5. IVIg or plasma exchange within 8 weeks;

6. oral or IV cyclosphosphamide treatment within 3 months;

7. IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months;

8. belimumab within 6 months. For patients who received belimumab earlier, B cell count should be within normal range;

9. rituximab within 12 months. For patients who received rituximab earlier, B cell count should be within normal range;

10. any other biologic or an investigational drug within 1 month or five times thehalf-life, whichever is longer.

11. Live vaccines within 4 weeks of study drug infusion.

12. Patients who are at significant risk for TE as judged by the investigator or have any one of the following:

13. History of either thrombosis or 3 or more spontaneous abortions with or without the presence of anti-cardiolipin autoantibodies;

14. Presence of prolonged partial thromboplastin time (PTT).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Montreal	Quebec	Canada	H3A 2BA
2	Novartis Investigative Site	Quebec		Canada	G1J 1Z4
3	Novartis Investigative Site	Aarhus		Denmark	8000 C
4	Novartis Investigative Site	Copenhagen		Denmark	2100
5	Novartis Investigative Site	Berlin		Germany	13353
6	Novartis Investigative Site	Halle/S		Germany	06120
7	Novartis Investigative Site	Muenchen		Germany	81377
8	Novartis Investigative Site	Samara	Samara Region	Russian Federation	443095
9	Novartis Investigative Site	Barnaul		Russian Federation	656024
10	Novartis Investigative Site	Kazan		Russian Federation	420021
11	Novartis Investigative Site	Novosibirsk		Russian Federation	630087
12	Novartis Investigative Site	S-Petersburg		Russian Federation	194354
13	Novartis Investigative Site	Tainan	Taiwan ROC	Taiwan	70403
14	Novartis Investigative Site	Taipei		Taiwan	10002
15	Novartis Investigative Site	Taipei		Taiwan

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 19, 2016
• Statistical Analysis Plan - Nov 18, 2016

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02565576
• Other Study ID Numbers: CCFZ533X2204
• First Posted: Oct 1, 2015
• Last Update Posted: Jan 5, 2021
• Last Verified: Jul 1, 2019

• Keywords provided by Novartis Pharmaceuticals: CFZ533, Myasthenia Gravis
• Additional relevant MeSH terms: Myasthenia Gravis; Muscle Weakness

Study Results

Participant Flow

Recruitment Details	A total of 44 patients were randomized to receive either IV CFZ533 or IV placebo, of which 34 patients (77%) completed the study.
Pre-assignment Detail	Safety analysis set, and Full analysis: 44 patients (22 treated with CFZ533 and 22 with placebo) PK analysis set : 20 patients treated with CFZ533 PD analysis set: 42 patients (20 treated with CFZ533 and 20 with placebo)

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Period Title: Overall Study
STARTED	22	22
COMPLETED	17	17
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	CFZ533	Placebo	Total
Arm/Group Description	CFZ533 10 mg/kg	Placebo	Total of all reporting groups
Overall Participants	22	22	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.7 (13.54)	43.3 (13.92)	44.0 (13.59)
Sex: Female, Male (Count of Participants)
Female	12 54.5%	16 72.7%	28 63.6%
Male	10 45.5%	6 27.3%	16 36.4%
Race/Ethnicity, Customized (Count of Participants)
caucasian	19 86.4%	16 72.7%	35 79.5%
Asian (Chinese)	3 13.6%	5 22.7%	8 18.2%
other	0 0%	1 4.5%	1 2.3%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type.
Description	QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005).
Time Frame	week 25

Outcome Measure Data

Analysis Population Description

pharmacodynamic (PD) analysis set, participants with non-detectable AChR or MuSK autoantibodies were excluded from the PD analysis set.

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	18	18
Median (90% Confidence Interval) [score]	-4.07	-2.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CFZ533, Placebo
	Comments	Primary analysis was performed on the PD analysis set. Changes from baseline in QMG scores at Week 25 were analyzed using a Bayesian model. The model investigated effects for treatment (CFZ533 or placebo) and baseline QMG score. A difference of 3 points on the mean change in QMG score between CFZ533 and placebo was deemed a clinical meaningful effect.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	estimate of contrast posterior median
	Estimated Value	-1.14
	Confidence Interval	(2-Sided) 90%; -3.41 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type.
Description	The Myasthenia Gravis Composite (MGC) score is another key efficacy outcome measure, ranging from 0 to 50. It is reliable and demonstrates concurrent and longitudinal construct validity in the MG practice care setting (Burns et al 2010). The MGC scale covers 10 important functional domains most frequently involved in patients with MG. The proportion of bulbar and respiratory items reflect the clinical importance of these domains in the disease, and are appropriately weighted. The assessment of each of the 10 test items provides immediate insight into the status of that particular functional domain. A decrease in this score shows an improvement.
Time Frame	From baseline to week 49

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	18	18
Median (90% Confidence Interval) [score]	-8.00	-5.62

3. Secondary Outcome

Title	Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score
Description	QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005).
Time Frame	at week 49

Outcome Measure Data

Analysis Population Description

PD analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	18	19
improvement by ≥ 3 points in the QMG score	10 45.5%	9 40.9%
worsening by ≥ 3 points in the QMG score	2 9.1%	2 9.1%

4. Secondary Outcome

Title	Proportion of Patients Intolerant to Steroid Taper
Time Frame	week 49

Outcome Measure Data

Analysis Population Description

this data was not collected. No analysis could be performed for this outcome measure.

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	22	22
Count of Participants [Participants]	NA NaN	NA NaN

5. Secondary Outcome

Title	Number of Patients Who Discontinued Due to Inefficacy or Worsening
Time Frame	week 49

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	22	22
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL)
Description	The MG-ADL is an 8-item survey to assess functional performance of daily activities that are sometimes impaired by MG e.g. talking, breathing, swallowing etc. (Muppidi et al 2011). The higher score on MG-ADL scale (0-24 points) indicates worse functional performance of daily activities.
Time Frame	week 25

Outcome Measure Data

Analysis Population Description

PD analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	19	18
Mean (Standard Deviation) [score]	-2.6 (2.97)	-1.1 (3.23)

7. Secondary Outcome

Title	Mean Changes From Baseline in the QMG Score at Week 49
Description	QMG (quantitative myasthenia gravis) score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005). A decrease in the QMG score indicated an improvement. Results given as a change in the score as compared from baseline
Time Frame	week 49

Outcome Measure Data

Analysis Population Description

PD analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	18	19
Mean (Standard Deviation) [score on a scale]	-2.9 (5.16)	-2.6 (4.30)

8. Secondary Outcome

Title	Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15)
Description	The MG-QOL15 is a 15-item survey, completed by MG patients and it is designed to assess some aspects of quality of life (QoL) related to MG (Burns et al 2011) e.g. assesment of mood, eating, speaking, driving a car etc.. The higher score on MG-QOL15 scale (0-60 points) indicates worse QoL.
Time Frame	week 25

Outcome Measure Data

Analysis Population Description

PD analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	19	19
Mean (Standard Deviation) [score]	-9.7 (11.0)	-6.7 (10.86)

9. Secondary Outcome

Title	Free CD40 on B Cells
Description	CD40 receptor occupancy by CFZ533 in peripheral blood was assessed by flow cytometry analysis, measuring free or total CD40 receptors on whole blood B cells. Free CD40 on CD19-positive B cells, using PE-conjugated CFZ533 whose binding was prevented by bound, unconjugated CFZ533 (drug bound to CD40 on peripheral blood B cells). The more CD40 was occupied by unlabeled CFZ533, the less binding of labeled CFZ533, manifest as a lower mean fluorescence intensity (MFI) of CD40 on B cells. MFI from free CD40 on B cells was converted into Molecules of Equivalent Soluble Fluorochrome (MESF) using PE-MESF beads.
Time Frame	week 1, week 25

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	22	22
Free CD40 on B cells week 1 predose	34242.9 (18455.80)	31025.9 (16138.97)
Free CD40 on B cells week 25	5259.1 (11341.57)	24908.3 (5022.03)

10. Secondary Outcome

Title	Total Soluble CD40 (sCD40) in Plasma
Description	PD
Time Frame	week1, week 25

Outcome Measure Data

Analysis Population Description

pharmacodynamic analysis set, participants with measure

Arm/Group Title	CFZ533	Placebo
Arm/Group Description	CFZ533 10 mg/kg	Placebo
Measure Participants	22	22
week 1	0.1778 (0.13077)	0.1577 (0.17243)
week 25	191.1278 (69.67597)	0.1163 (0.18298)

11. Secondary Outcome

Title	Plasma CFZ533 Concentration at Steady State Conditions (Week 17)
Time Frame	week 17

Outcome Measure Data

Analysis Population Description

pharmacokinetic set, participants treated with CFZ533 only, with measure

Arm/Group Title	CFZ533
Arm/Group Description	CFZ533 10 mg/kg
Measure Participants	18
Mean (Standard Deviation) [micrograms/mL]	120 (40.5)

Adverse Events

Time Frame	up to week 49
Adverse Event Reporting Description	AE additional description
Arm/Group Title	CFZ533 10 mg/kg IV Infusion		Placebo IV Infusion
Arm/Group Description	CFZ533 10 mg/kg IV infusion		Placebo IV infusion
All Cause Mortality
	CFZ533 10 mg/kg IV Infusion		Placebo IV Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		2/22 (9.1%)
Serious Adverse Events
	CFZ533 10 mg/kg IV Infusion		Placebo IV Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/22 (31.8%)		4/22 (18.2%)
Blood and lymphatic system disorders
Febrile neutropenia	1/22 (4.5%)		0/22 (0%)
Cardiac disorders
Myocardial ischaemia	0/22 (0%)		1/22 (4.5%)
Eye disorders
Glaucoma	1/22 (4.5%)		0/22 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/22 (4.5%)		0/22 (0%)
Constipation	1/22 (4.5%)		0/22 (0%)
General disorders
Pyrexia	1/22 (4.5%)		0/22 (0%)
Hepatobiliary disorders
Hepatitis toxic	0/22 (0%)		1/22 (4.5%)
Infections and infestations
Influenza	2/22 (9.1%)		0/22 (0%)
Pneumonia	1/22 (4.5%)		0/22 (0%)
Nervous system disorders
Brachial plexopathy	0/22 (0%)		1/22 (4.5%)
Myasthenia gravis	2/22 (9.1%)		1/22 (4.5%)
Myasthenia gravis crisis	1/22 (4.5%)		0/22 (0%)
Radial nerve palsy	0/22 (0%)		1/22 (4.5%)
Other (Not Including Serious) Adverse Events
	CFZ533 10 mg/kg IV Infusion		Placebo IV Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/22 (90.9%)		21/22 (95.5%)
Blood and lymphatic system disorders
Anaemia	0/22 (0%)		2/22 (9.1%)
Iron deficiency anaemia	1/22 (4.5%)		0/22 (0%)
Leukocytosis	1/22 (4.5%)		0/22 (0%)
Leukopenia	2/22 (9.1%)		2/22 (9.1%)
Lymphocytosis	0/22 (0%)		1/22 (4.5%)
Lymphopenia	1/22 (4.5%)		2/22 (9.1%)
Neutropenia	1/22 (4.5%)		1/22 (4.5%)
Neutrophilia	1/22 (4.5%)		0/22 (0%)
Cardiac disorders
Angina pectoris	0/22 (0%)		1/22 (4.5%)
Atrial fibrillation	1/22 (4.5%)		0/22 (0%)
Palpitations	0/22 (0%)		1/22 (4.5%)
Congenital, familial and genetic disorders
Von Willebrand's disease	1/22 (4.5%)		0/22 (0%)
Eye disorders
Cataract	0/22 (0%)		1/22 (4.5%)
Vision blurred	1/22 (4.5%)		0/22 (0%)
Gastrointestinal disorders
Abdominal pain	0/22 (0%)		1/22 (4.5%)
Abdominal pain upper	0/22 (0%)		1/22 (4.5%)
Dental caries	0/22 (0%)		1/22 (4.5%)
Diarrhoea	1/22 (4.5%)		2/22 (9.1%)
Food poisoning	1/22 (4.5%)		0/22 (0%)
Gastroduodenitis	1/22 (4.5%)		0/22 (0%)
Gingival bleeding	0/22 (0%)		1/22 (4.5%)
Nausea	3/22 (13.6%)		2/22 (9.1%)
Pancreatitis chronic	0/22 (0%)		1/22 (4.5%)
General disorders
Asthenia	0/22 (0%)		2/22 (9.1%)
Chills	0/22 (0%)		1/22 (4.5%)
Discomfort	0/22 (0%)		1/22 (4.5%)
Fatigue	2/22 (9.1%)		0/22 (0%)
Feeling cold	1/22 (4.5%)		0/22 (0%)
Hyperthermia	0/22 (0%)		1/22 (4.5%)
Influenza like illness	1/22 (4.5%)		0/22 (0%)
Infusion site bruising	0/22 (0%)		1/22 (4.5%)
Malaise	0/22 (0%)		1/22 (4.5%)
Non-cardiac chest pain	1/22 (4.5%)		0/22 (0%)
Pyrexia	0/22 (0%)		2/22 (9.1%)
Hepatobiliary disorders
Hepatitis toxic	0/22 (0%)		1/22 (4.5%)
Infections and infestations
Acute sinusitis	0/22 (0%)		1/22 (4.5%)
Bronchitis	1/22 (4.5%)		0/22 (0%)
Conjunctivitis	0/22 (0%)		1/22 (4.5%)
Cystitis	1/22 (4.5%)		2/22 (9.1%)
Ear infection	0/22 (0%)		1/22 (4.5%)
Folliculitis	0/22 (0%)		1/22 (4.5%)
Gastrointestinal infection	1/22 (4.5%)		0/22 (0%)
Herpes virus infection	0/22 (0%)		1/22 (4.5%)
Herpes zoster	0/22 (0%)		2/22 (9.1%)
Influenza	1/22 (4.5%)		1/22 (4.5%)
Laryngitis viral	1/22 (4.5%)		0/22 (0%)
Nasopharyngitis	2/22 (9.1%)		3/22 (13.6%)
Oral candidiasis	1/22 (4.5%)		0/22 (0%)
Oral herpes	1/22 (4.5%)		1/22 (4.5%)
Oropharyngeal candidiasis	0/22 (0%)		1/22 (4.5%)
Pneumonia	2/22 (9.1%)		1/22 (4.5%)
Respiratory tract infection	1/22 (4.5%)		0/22 (0%)
Respiratory tract infection viral	2/22 (9.1%)		2/22 (9.1%)
Rhinitis	1/22 (4.5%)		0/22 (0%)
Skin candida	0/22 (0%)		1/22 (4.5%)
Systemic infection	1/22 (4.5%)		0/22 (0%)
Tonsillitis	0/22 (0%)		1/22 (4.5%)
Tooth infection	1/22 (4.5%)		0/22 (0%)
Tracheobronchitis	1/22 (4.5%)		0/22 (0%)
Upper respiratory tract infection	1/22 (4.5%)		4/22 (18.2%)
Urinary tract infection	1/22 (4.5%)		1/22 (4.5%)
Viral pharyngitis	1/22 (4.5%)		0/22 (0%)
Vulvovaginal candidiasis	0/22 (0%)		1/22 (4.5%)
Injury, poisoning and procedural complications
Ligament rupture	0/22 (0%)		1/22 (4.5%)
Muscle strain	0/22 (0%)		1/22 (4.5%)
Procedural headache	0/22 (0%)		1/22 (4.5%)
Procedural pain	0/22 (0%)		1/22 (4.5%)
Investigations
Activated partial thromboplastin time prolonged	1/22 (4.5%)		0/22 (0%)
Activated partial thromboplastin time shortened	1/22 (4.5%)		0/22 (0%)
Alanine aminotransferase increased	1/22 (4.5%)		0/22 (0%)
Blood bicarbonate decreased	0/22 (0%)		1/22 (4.5%)
Blood creatine phosphokinase increased	0/22 (0%)		1/22 (4.5%)
Blood creatinine increased	0/22 (0%)		1/22 (4.5%)
Blood lactate dehydrogenase increased	0/22 (0%)		1/22 (4.5%)
Blood pressure increased	0/22 (0%)		1/22 (4.5%)
C-reactive protein increased	1/22 (4.5%)		0/22 (0%)
Free haemoglobin present	2/22 (9.1%)		2/22 (9.1%)
Gamma-glutamyltransferase increased	1/22 (4.5%)		0/22 (0%)
Prothrombin time prolonged	1/22 (4.5%)		0/22 (0%)
Weight decreased	1/22 (4.5%)		0/22 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/22 (4.5%)		0/22 (0%)
Dyslipidaemia	1/22 (4.5%)		0/22 (0%)
Hypercholesterolaemia	1/22 (4.5%)		0/22 (0%)
Hypoglycaemia	0/22 (0%)		1/22 (4.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/22 (4.5%)		1/22 (4.5%)
Arthritis reactive	1/22 (4.5%)		0/22 (0%)
Joint swelling	0/22 (0%)		1/22 (4.5%)
Muscle spasms	0/22 (0%)		2/22 (9.1%)
Muscular weakness	2/22 (9.1%)		1/22 (4.5%)
Musculoskeletal pain	0/22 (0%)		1/22 (4.5%)
Myalgia	1/22 (4.5%)		0/22 (0%)
Neck pain	1/22 (4.5%)		0/22 (0%)
Osteochondrosis	0/22 (0%)		1/22 (4.5%)
Tendonitis	1/22 (4.5%)		0/22 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/22 (0%)		1/22 (4.5%)
Nervous system disorders
Dementia Alzheimer's type	1/22 (4.5%)		0/22 (0%)
Dizziness	2/22 (9.1%)		2/22 (9.1%)
Headache	4/22 (18.2%)		3/22 (13.6%)
Migraine	1/22 (4.5%)		0/22 (0%)
Myasthenia gravis	2/22 (9.1%)		1/22 (4.5%)
Nerve compression	0/22 (0%)		1/22 (4.5%)
Neuralgia	1/22 (4.5%)		0/22 (0%)
Paraesthesia	1/22 (4.5%)		0/22 (0%)
Post herpetic neuralgia	0/22 (0%)		1/22 (4.5%)
Psychiatric disorders
Depressed mood	1/22 (4.5%)		0/22 (0%)
Nervousness	1/22 (4.5%)		0/22 (0%)
Panic attack	0/22 (0%)		1/22 (4.5%)
Sleep disorder	1/22 (4.5%)		0/22 (0%)
Renal and urinary disorders
Calculus urinary	1/22 (4.5%)		0/22 (0%)
Haematuria	1/22 (4.5%)		0/22 (0%)
Reproductive system and breast disorders
Balanoposthitis	0/22 (0%)		1/22 (4.5%)
Breast pain	0/22 (0%)		1/22 (4.5%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/22 (4.5%)		0/22 (0%)
Cough	1/22 (4.5%)		0/22 (0%)
Laryngeal inflammation	0/22 (0%)		1/22 (4.5%)
Nasal congestion	0/22 (0%)		1/22 (4.5%)
Sinus disorder	1/22 (4.5%)		0/22 (0%)
Skin and subcutaneous tissue disorders
Acne	0/22 (0%)		1/22 (4.5%)
Dermatitis allergic	1/22 (4.5%)		0/22 (0%)
Erythema	1/22 (4.5%)		0/22 (0%)
Hyperhidrosis	0/22 (0%)		1/22 (4.5%)
Pruritus	1/22 (4.5%)		0/22 (0%)
Rash	0/22 (0%)		1/22 (4.5%)
Swelling face	1/22 (4.5%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.