Study to Investigate Whether AFQ056 Reduces Cocaine Use in Patients Diagnosed With Cocaine Use Disorder (CUD)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03242928
• Collaborator: (none)
• Enrollment: 68
• Locations: 8
• Arms: 2
• Actual Duration (Months): 24.4
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study assessed whether AFQ056 had a beneficial effect by reducing cocaine use in Cocaine Use Disorder (CUD) patients as assessed by Timeline Follow-Back cocaine self-report.

Condition or Disease	Intervention/Treatment	Phase
Cocaine-related Disorder	Drug: AFQ056; Drug: Placebo	Phase 2

Detailed Description

This was a randomized, subject- and Investigator-blinded, parallel-group, placebo-controlled study in subjects with CUD. The study consisted of a 17-day screening period followed by a 12-day baseline, a 98-day outpatient treatment period (14-day up-titration dose regimen followed by 84-day maintenance dose), and an End of Study evaluation visit approximately 14 days after the last study drug administration. The total duration for each subject in the study was approximately 20 weeks including screening and baseline.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Subject and Investigator Blinded, Placebo-controlled, Parallel Group Study to Investigate Whether AFQ056 Reduces Cocaine Use in Patients Diagnosed With Cocaine Use Disorder (CUD)
• Actual Study Start Date: Dec 4, 2017
• Actual Primary Completion Date: Dec 16, 2019
• Actual Study Completion Date: Dec 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching tablet of placebo taken orally BID	Drug: Placebo; Matching placebo tablets taken orally BID
Experimental: AFQ056 Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Drug: AFQ056; 50 mg and 100 mg tablets taken orally; Other Names: mavoglurant

Outcome Measures

Primary Outcome Measures

1. Proportion of Cocaine Use Days [Day 1 up to day 98]

   The cocaine consumption was recorded once daily (Yes/No) by the subject using the Timeline Follow-Back (TLFB) cocaine assessment tool during the treatment period. For each patient, the proportion of cocaine use days was calculated by dividing the number of days of cocaine use during the treatment period, i.e. 98 days for completers and number of days between Day 1 and day of last dose in case of premature discontinuation of study treatment.

Secondary Outcome Measures

1. Proportion of Positive Urine Measurements of Benzoylecgonine (BE) [Day 1 up to day 98]

   Urine samples were analyzed for the presence of cocaine's metabolite benzoylecgonine (BE) which is the main metabolite of cocaine present in urine. Two urine samples were provided per week to provide a quantitative measure.

2. Proportion of Days of Alcohol Consumption [Day 1 up to day 98]

   Alcohol consumption was recorded by the subjects using the Timeline Follow-Back (TLFB) alcohol self report. The number of standard drinks were recorded daily. The proportion of days of alcohol consumption during the study treatment period was was compared using an ANCOVA model with treatment as factor and past alcohol consumption as covariate. The past consumption of alcohol was the proportion of alcohol over the 28 days preceding the screening visit, which was assessed retrospectively using the TLFB.

3. AFQ056 Plasma Concentrations [Day 15 (0h, 2h), Day 29 (0, 2h), Day 57 (0h, 2h), Day 98 (0h,2h)]

   Plasma samples were collected to assess pharmacokinetics (PK)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Understand the study procedures and provide written informed consent before any assessment is performed.

• Subjects diagnosed with Cocaine Use Disorder according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Ed.).

• Must use cocaine through snorting (intranasally) as primary route of administration.

• Recent cocaine use confirmed by positive urine screen for 1 or more benzoylecgonine (BE).

• Must be seeking treatment for cocaine dependence and have a desire to reduce or cease cocaine use.

Exclusion Criteria:

• Has current diagnosis of Substance Use Disorder (according to the DSM 5) on alcohol, cannabis or other stimulants, except cocaine.

• Meets current or lifetime DSM 5 criteria for schizophrenia or any psychotic disorder, or organic mental disorder.

• Have current treatment for Substance Use Disorder (e.g.: disulfiram, acamprosate, methyl phenidate, modafinil, topiramate, immediate release dexamfetamine,or baclofen).

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test

• Have a history of any illness, condition, and use of medications that in the opinion of the investigator or designee might confound the results of the study or pose additional risk in administering the investigational agents to the subject or preclude successful completion of the study

• Current or/and previous treatment with concomitant medications that are strong or moderate inducers/inhibitors of CYP3A4 (e.g., clarithromycin, ketoconazole, ritonavir, etc.)

• History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result.

• Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV).

• Score "yes" on item 4 or item 5 of the Suicidal Ideation section of the CSSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior" (item also included in the Suicidal Behavior section), if this behavior occurred in the past 2 years.

• Controlled hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Buenos Aires		Argentina	1058
2	Novartis Investigative Site	Buenos Aires		Argentina	4634
3	Novartis Investigative Site	Buenos Aires		Argentina	C1405B0A
4	Novartis Investigative Site	San Juan de Alicante	Alicante	Spain	03550
5	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
6	Novartis Investigative Site	Barcelona		Spain	08036
7	Novartis Investigative Site	Basel		Switzerland	4025
8	Novartis Investigative Site	Zuerich		Switzerland	8001

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 15, 2017
• Statistical Analysis Plan - Apr 7, 2020

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03242928
• Other Study ID Numbers: CAFQ056X2201; 2017-000736-33
• First Posted: Aug 8, 2017
• Last Update Posted: Oct 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Cocaine Use Disorder; cocaine dependence,AFQ056,adult, cocaine use,CUD, drug abuse, drug addiction,
• Additional relevant MeSH terms: Disease; Cocaine-Related Disorders

Study Results

Participant Flow

Pre-assignment Detail	There were 68 patients who received study treatment.

Arm/Group Title	AFQ056	Placebo
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Matching tablet of placebo taken orally BID
Period Title: Overall Study
STARTED	31	37
COMPLETED	22	32
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	AFQ056	Placebo	Total
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Matching tablet of placebo taken orally BID	Total of all reporting groups
Overall Participants	31	37	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.4 (8.31)	35.5 (9.19)	35.4 (8.74)
Age, Customized (Number) [Number]
18 - 65 years	31 100%	37 100%	68 100%
Sex: Female, Male (Count of Participants)
Female	5 16.1%	7 18.9%	12 17.6%
Male	26 83.9%	30 81.1%	56 82.4%
Race/Ethnicity, Customized (participants) [Number]
White	31 100%	36 97.3%	67 98.5%
Asian	0 0%	1 2.7%	1 1.5%

Outcome Measures

1. Primary Outcome

Title	Proportion of Cocaine Use Days
Description	The cocaine consumption was recorded once daily (Yes/No) by the subject using the Timeline Follow-Back (TLFB) cocaine assessment tool during the treatment period. For each patient, the proportion of cocaine use days was calculated by dividing the number of days of cocaine use during the treatment period, i.e. 98 days for completers and number of days between Day 1 and day of last dose in case of premature discontinuation of study treatment.
Time Frame	Day 1 up to day 98

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set (PD): subjects with any available efficacy (PD) data, who received study drug for at least 14 days with no relevant protocol deviation

Arm/Group Title	AFQ056	Placebo
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Matching tablet of placebo taken orally BID
Measure Participants	29	36
Mean (Standard Error) [cocaine use days]	0.122 (0.027)	0.209 (0.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFQ056, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.021
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.087
	Confidence Interval	(2-Sided) 95%; -0.161 to -0.013
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Positive Urine Measurements of Benzoylecgonine (BE)
Description	Urine samples were analyzed for the presence of cocaine's metabolite benzoylecgonine (BE) which is the main metabolite of cocaine present in urine. Two urine samples were provided per week to provide a quantitative measure.
Time Frame	Day 1 up to day 98

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AFQ056	Placebo
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Matching tablet of placebo taken orally BID
Measure Participants	29	36
Mean (Standard Error) [positive urine samples]	0.666 (0.057)	0.843 (0.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFQ056, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.025
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.177
	Confidence Interval	(2-Sided) 95%; -0.331 to -0.023
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.077
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Days of Alcohol Consumption
Description	Alcohol consumption was recorded by the subjects using the Timeline Follow-Back (TLFB) alcohol self report. The number of standard drinks were recorded daily. The proportion of days of alcohol consumption during the study treatment period was was compared using an ANCOVA model with treatment as factor and past alcohol consumption as covariate. The past consumption of alcohol was the proportion of alcohol over the 28 days preceding the screening visit, which was assessed retrospectively using the TLFB.
Time Frame	Day 1 up to day 98

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set (PD): subjects with any available efficacy (PD) data, who received study drug for at least 14 days with no relevant protocol deviation

Arm/Group Title	AFQ056	Placebo
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days	Matching tablet of placebo taken orally BID
Measure Participants	29	36
Mean (Standard Error) [alcohol consumption days]	0.233 (0.030)	0.303 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFQ056, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.072
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.070
	Confidence Interval	(2-Sided) 95%; -0.146 to 0.006
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments

4. Secondary Outcome

Title	AFQ056 Plasma Concentrations
Description	Plasma samples were collected to assess pharmacokinetics (PK)
Time Frame	Day 15 (0h, 2h), Day 29 (0, 2h), Day 57 (0h, 2h), Day 98 (0h,2h)

Outcome Measure Data

Analysis Population Description

Number of samples available for analysis varied across time points

Arm/Group Title	AFQ056
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days
Measure Participants	29
Day 15 0 hour	41.2 (47.4)
Day 15 2 hour	78.0 (91.7)
Day 29 0 hour	83.5 (116)
Day 29 2 hour	148 (131)
Day 57 0 hour	108 (153)
Day 57 2 hour	141 (153)
Day 98 0 hour	89.8 (148)
Day 98 2 hour	116 (86.1)

Adverse Events

Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 14 days post treatment, up to maximum duration of approximately 16 weeks
Arm/Group Title	AFQ056		Placebo
Arm/Group Description	Mavoglurant was up titrated on a bid regimen followed by fixed-dose bid regimen: 50 mg bid from Day 1 to Day 7, 100 mg bid from Day 8 to Day 14, and then fixed-dose 200 mg bid for 84 days		Matching tablet of placebo taken orally BID
All Cause Mortality
	AFQ056		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/37 (0%)
Serious Adverse Events
	AFQ056		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		1/37 (2.7%)
Psychiatric disorders
Agitation	0/31 (0%)	0	1/37 (2.7%)	1
Other (Not Including Serious) Adverse Events
	AFQ056		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/31 (83.9%)		30/37 (81.1%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/31 (3.2%)	1	0/37 (0%)	0
Monocytosis	0/31 (0%)	0	1/37 (2.7%)	1
Cardiac disorders
Tachycardia	0/31 (0%)	0	1/37 (2.7%)	1
Ear and labyrinth disorders
Ear pain	1/31 (3.2%)	1	0/37 (0%)	0
Tinnitus	1/31 (3.2%)	1	0/37 (0%)	0
Eye disorders
Blepharospasm	1/31 (3.2%)	1	0/37 (0%)	0
Diplopia	1/31 (3.2%)	1	0/37 (0%)	0
Photophobia	1/31 (3.2%)	1	0/37 (0%)	0
Photopsia	3/31 (9.7%)	3	0/37 (0%)	0
Vision blurred	1/31 (3.2%)	1	0/37 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	1/31 (3.2%)	1	0/37 (0%)	0
Abdominal pain upper	3/31 (9.7%)	6	7/37 (18.9%)	12
Constipation	2/31 (6.5%)	2	1/37 (2.7%)	1
Diarrhoea	2/31 (6.5%)	3	5/37 (13.5%)	5
Dry mouth	2/31 (6.5%)	4	0/37 (0%)	0
Dyspepsia	3/31 (9.7%)	3	2/37 (5.4%)	2
Gingival bleeding	1/31 (3.2%)	2	0/37 (0%)	0
Nausea	6/31 (19.4%)	8	3/37 (8.1%)	3
Odynophagia	1/31 (3.2%)	1	0/37 (0%)	0
Paraesthesia oral	1/31 (3.2%)	1	0/37 (0%)	0
Regurgitation	1/31 (3.2%)	1	0/37 (0%)	0
Toothache	0/31 (0%)	0	6/37 (16.2%)	6
Vomiting	3/31 (9.7%)	6	1/37 (2.7%)	1
General disorders
Asthenia	1/31 (3.2%)	1	1/37 (2.7%)	1
Discomfort	1/31 (3.2%)	1	0/37 (0%)	0
Fatigue	2/31 (6.5%)	4	3/37 (8.1%)	3
Influenza like illness	1/31 (3.2%)	1	0/37 (0%)	0
Malaise	2/31 (6.5%)	4	1/37 (2.7%)	1
Pain	1/31 (3.2%)	1	0/37 (0%)	0
Physical deconditioning	1/31 (3.2%)	1	0/37 (0%)	0
Pyrexia	1/31 (3.2%)	1	1/37 (2.7%)	1
Thirst	1/31 (3.2%)	1	0/37 (0%)	0
Vessel puncture site pain	0/31 (0%)	0	1/37 (2.7%)	1
Immune system disorders
Seasonal allergy	1/31 (3.2%)	1	2/37 (5.4%)	2
Infections and infestations
Hordeolum	0/31 (0%)	0	1/37 (2.7%)	1
Influenza	4/31 (12.9%)	7	2/37 (5.4%)	2
Laryngitis	0/31 (0%)	0	1/37 (2.7%)	1
Nasopharyngitis	2/31 (6.5%)	2	8/37 (21.6%)	10
Pharyngitis	1/31 (3.2%)	1	0/37 (0%)	0
Pulpitis dental	0/31 (0%)	0	1/37 (2.7%)	1
Rhinitis	3/31 (9.7%)	3	0/37 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/31 (3.2%)	3	0/37 (0%)	0
Limb injury	0/31 (0%)	0	1/37 (2.7%)	1
Road traffic accident	1/31 (3.2%)	1	0/37 (0%)	0
Skin abrasion	0/31 (0%)	0	1/37 (2.7%)	1
Skin laceration	0/31 (0%)	0	1/37 (2.7%)	1
Toxicity to various agents	1/31 (3.2%)	1	0/37 (0%)	0
Investigations
Alanine aminotransferase increased	2/31 (6.5%)	2	2/37 (5.4%)	3
Amylase increased	0/31 (0%)	0	1/37 (2.7%)	1
Aspartate aminotransferase increased	0/31 (0%)	0	1/37 (2.7%)	1
Blood creatine phosphokinase increased	2/31 (6.5%)	2	0/37 (0%)	0
Blood creatinine abnormal	0/31 (0%)	0	1/37 (2.7%)	1
Blood creatinine increased	0/31 (0%)	0	1/37 (2.7%)	1
Blood triglycerides increased	3/31 (9.7%)	3	2/37 (5.4%)	2
Gamma-glutamyltransferase increased	1/31 (3.2%)	1	1/37 (2.7%)	2
Lymphocyte count increased	1/31 (3.2%)	1	0/37 (0%)	0
Neutrophil count increased	0/31 (0%)	0	1/37 (2.7%)	1
Platelet count increased	0/31 (0%)	0	1/37 (2.7%)	1
Red blood cell count increased	1/31 (3.2%)	1	0/37 (0%)	0
White blood cell count increased	1/31 (3.2%)	1	1/37 (2.7%)	1
Metabolism and nutrition disorders
Decreased appetite	0/31 (0%)	0	1/37 (2.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	4/31 (12.9%)	4	5/37 (13.5%)	6
Muscle tightness	0/31 (0%)	0	1/37 (2.7%)	1
Muscle twitching	0/31 (0%)	0	1/37 (2.7%)	1
Myalgia	1/31 (3.2%)	1	0/37 (0%)	0
Neck pain	1/31 (3.2%)	1	0/37 (0%)	0
Pain in extremity	1/31 (3.2%)	1	1/37 (2.7%)	1
Rhabdomyolysis	1/31 (3.2%)	1	0/37 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma	1/31 (3.2%)	1	0/37 (0%)	0
Nervous system disorders
Dizziness	7/31 (22.6%)	17	4/37 (10.8%)	4
Headache	6/31 (19.4%)	13	10/37 (27%)	24
Muscle contractions involuntary	1/31 (3.2%)	1	0/37 (0%)	0
Paraesthesia	2/31 (6.5%)	3	0/37 (0%)	0
Psychomotor hyperactivity	1/31 (3.2%)	1	0/37 (0%)	0
Resting tremor	1/31 (3.2%)	1	0/37 (0%)	0
Somnolence	4/31 (12.9%)	4	1/37 (2.7%)	1
Psychiatric disorders
Anxiety	3/31 (9.7%)	4	4/37 (10.8%)	5
Aversion	1/31 (3.2%)	3	0/37 (0%)	0
Depressed mood	1/31 (3.2%)	1	2/37 (5.4%)	3
Depression	1/31 (3.2%)	3	0/37 (0%)	0
Depressive symptom	1/31 (3.2%)	1	0/37 (0%)	0
Disorientation	0/31 (0%)	0	1/37 (2.7%)	2
Euphoric mood	1/31 (3.2%)	1	0/37 (0%)	0
Feeling guilty	1/31 (3.2%)	1	0/37 (0%)	0
Hallucination	1/31 (3.2%)	1	0/37 (0%)	0
Hallucination, auditory	1/31 (3.2%)	1	0/37 (0%)	0
Hallucination, olfactory	1/31 (3.2%)	3	0/37 (0%)	0
Hallucination, visual	2/31 (6.5%)	3	0/37 (0%)	0
Ideas of reference	0/31 (0%)	0	2/37 (5.4%)	2
Illusion	2/31 (6.5%)	2	0/37 (0%)	0
Initial insomnia	1/31 (3.2%)	2	1/37 (2.7%)	1
Insomnia	5/31 (16.1%)	9	2/37 (5.4%)	11
Irritability	1/31 (3.2%)	1	2/37 (5.4%)	2
Nightmare	2/31 (6.5%)	2	1/37 (2.7%)	1
Paranoia	1/31 (3.2%)	1	0/37 (0%)	0
Sleep disorder	3/31 (9.7%)	4	0/37 (0%)	0
Stress	0/31 (0%)	0	1/37 (2.7%)	1
Renal and urinary disorders
Acute kidney injury	1/31 (3.2%)	1	0/37 (0%)	0
Nocturia	1/31 (3.2%)	1	0/37 (0%)	0
Renal pain	0/31 (0%)	0	1/37 (2.7%)	1
Reproductive system and breast disorders
Dysmenorrhoea	0/31 (0%)	0	1/37 (2.7%)	1
Pelvic pain	1/31 (3.2%)	1	0/37 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/31 (3.2%)	1	0/37 (0%)	0
Cough	1/31 (3.2%)	1	1/37 (2.7%)	1
Epistaxis	1/31 (3.2%)	2	0/37 (0%)	0
Nasal congestion	0/31 (0%)	0	1/37 (2.7%)	1
Nasal mucosal ulcer	0/31 (0%)	0	1/37 (2.7%)	1
Oropharyngeal pain	1/31 (3.2%)	2	1/37 (2.7%)	2
Rhinitis allergic	1/31 (3.2%)	1	0/37 (0%)	0
Skin and subcutaneous tissue disorders
Acne	0/31 (0%)	0	1/37 (2.7%)	2
Hyperhidrosis	1/31 (3.2%)	1	1/37 (2.7%)	1
Pruritus	2/31 (6.5%)	7	0/37 (0%)	0
Vascular disorders
Haematoma	1/31 (3.2%)	1	2/37 (5.4%)	2
Peripheral coldness	1/31 (3.2%)	1	0/37 (0%)	0
Vasospasm	1/31 (3.2%)	1	0/37 (0%)	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 (i.e., data from all sites) in the clinical trial.