Clinical trial NCT02500641
Conditions: Gout
Keywords: Biological Markers Cardiovascular disease Humans Pulse Wave Velocity Cardiovascular risk factors Allopurinol Pulse Wave Analysis Thiazoles Inflammation Uric acid Febuxostat Oxidative stress Tumor Necrosis Factor Arthritis Hyperuricemia
Sponsor: Menarini International Operations Luxembourg SA
Start date: 2015-08-17; Completion date: 2017-05-10
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There is a mounting and clear association between hyperuricaemia, gout and the presence of traditional cardiovascular (CV) risk factors and CV event-equivalent conditions such as chronic kidney disease, metabolic syndrome, and diabetes. Gout is associated with increased risk of CV events such as myocardial infarction and CV death. Furthermore hyperuricaemia is clearly associated with an increased arterial stiffness, a marker of pre-clinical atherosclerosis. Carotid-femoral pulse wave velocity (PWV) is the "gold standard" measurement of arterial stiffness and it is considered, in this trial, as a valid surrogate endpoint with clearly established relevance to predict cardiovascular disease (CVD) clinical outcome In this randomised trial conducted on adult subjects with a history of gout, we use surrogate endpoints to investigate the efficacy of febuxostat compared with allopurinol to predict (CVD) clinical outcome.

Eligible subjects were randomised in a 1:1 ratio to the following treatment groups:

* Test product: febuxostat 80 mg or 120 mg once daily (120 mg daily, if serum urate was \>6 mg/dL after 2 weeks of treatment at 80 mg daily).
* Active comparator: allopurinol 100 mg once daily (up to a maximum dose of 600 mg daily escalated in 100 mg increments every 2 weeks, if serum urate acid (sUA) was \>6 mg/dL after 2 weeks of treatment at the previous dose).

The study duration was 39 weeks, which included the:

* Run-in/screening period: 1 week (extendable up to a maximum of 30 days according to variability of sUA levels);
* Treatment period: 36 weeks;
* Safety follow-up period: 2 weeks.

Detailed description:
The study physician, responsible for randomization and drug supply handling, is unblinded to study medications and therefore will not be involved in the main efficacy evaluations of each patient randomized in the study.

Conversely, the study physician/s responsible for the main efficacy evaluation (Pulse Wave Velocity) will be blind to study treatments.

Key efficacy variables will be performed by an independent centralized laboratory.

Trial was conducted in a detailed and orderly manner in accordance with established research principles, International Conference on Harmonization (ICH), Good Clinical Practice (GCP) Guidelines and with Clinical Research Organization (CRO) Standard Operating Procedures (SOPs). As part of a concerted effort to fulfill these obligations, the authorised CRO study monitor visited investigative sites prior to and during the trial in addition to maintaining telephone and written communication. Data from each subject were reviewed and source verified as the study progressed.

In accordance with audit plans, this trial may have been selected for audits. The investigators committed to permit independent audits by auditors assigned by the Sponsor at a reasonable notice. Audits included, but were not limited to, drug supply, presence of required documents, the informed consent process, protection of rights and well-being of subjects and verification of Electronic case report form (eCRF) entries against source documents.

Regulatory authorities worldwide had the right to inspect the investigative sites during or after the trial. In such cases, the investigators were required to contact the Sponsor immediately and to fully cooperate with the inspectors.

Copies of written correspondence between the investigators, CRO, Sponsor, Competent Authorities, Institutional Review Board (IRB) and Independent Ethic Committee (IEC) are on file with the Sponsor and investigators.

Adverse events were according to the Medical Dictionary for Regulatory Activities (MedDRA, version 18.0) thesaurus.

Statistical analysis were conducted according the Statistical Analysis Plan (SAP) describing the analytical principles and statistical techniques employed in order to address the objectives specified in the Protocol.

A Data Management Plan was present for missing data, to address situations where variables are reported as missing, unavailable, non-reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results.

Arms: arm 1: Febuxostat 80/120 mg film coated tablets.The initial daily dose is 80 mg given orally. In case a patient has serum urate level 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained during the study treatment period.

To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg quaque die (QD ) or in case of colchicine intolerance, Naproxen 550 mg bis in die (BID) with Omeprazole (20-40 mg once daily), if indicated to be used. arm 2: Allopurinol 100/300 mg tablets.The initial daily allopurinol dose is 100 mg given orally, to be escalated of 100 mg every 2 weeks in patients with serum urate concentration \>6 mg/dl.

The maximum dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg daily.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD or in case of colchicine intolerance, Naproxen 550 mg BID with Omeprazole (20-40 mg once daily), if indicated to be used.
Interventions: intervention 1: Febuxostat 80/120mg/day intervention 2: Allopurinol 100 up to 600mg/day intervention 3: Colchicine intervention 4: Naproxen intervention 5: Omeprazole
Intervention descriptions: intervention 1: Starting dose and dose regimen of Febuxostat : the initial daily dose is 80 mg. In case the patient has the serum urate concentration \> 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained for the duration of the study. intervention 2: Starting dose and dose regimen of allopurinol : the initial daily allopurinol dose is 100 mg, to be increased by 100 mg every 2 weeks in patients with serum urate concentration \>6 mg/dl. The maximum daily dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg. intervention 3: Colchicine 0.5 mg tablets.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD intervention 4: Naproxen sodium 550 mg film coated tablets. In case of colchicine intolerance patients will be treated for at least 6 months with Naproxen 550 mg BID and Omeprazole (20-40 mg once daily), if indicated to be used. intervention 5: Omeprazole 20 mg capsules, co-administered to patients for gastric protection.

Protocol documents:
Prot_001.pdf: 
  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 1 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 2 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 4 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 5 of 68
$			&>7(-	
	
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
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		&&		*-	G&*-!
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
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 6 of 68

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
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2.2
STUDY FLOW CHART .............................................................................................................................................. 22
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)
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
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	 ................................................................................................................................. 26

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,
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
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
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
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
 
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/
 !& &%("
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!
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	 ............................................................................................................................................... 34
!!
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 7 of 68
!(

 .................................................................................................................................................... 35
!)
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 .......................................................................................................... 36
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!
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0
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 14 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 15 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 16 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 17 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 18 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 19 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 20 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 21 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 22 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 23 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 24 of 68


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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 25 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 26 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 27 of 68

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	A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 28 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 29 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 30 of 68
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	 
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  	
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	
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
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
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	
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	

6K*E


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 31 of 68
•

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•
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
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
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•

%
	
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67 3
#
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6F 3
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=< $
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=6 % 
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 A    
 G5?< 	 
 
 
	

  1  E  	
 
 		 


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
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 %% 

7?@=6=F
E


	
'26G6*	

;;?<



'26G=*A


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 32 of 68
•

 6=< 	 	 
 A    
 66@G? 	 
 
 
	

  1  E  	
 
 		 

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 
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
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 %% 

7?@=6=F
E


	
'26G6*	

;;?<

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
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•
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6<<	A

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

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 
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 
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
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
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	
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 
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





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 33 of 68
•
-
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 34 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 35 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 36 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 37 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 38 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 39 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 40 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 41 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 42 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 43 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 44 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 45 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 46 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 47 of 68
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 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 48 of 68
B1
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		 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 49 of 68
%
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 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 50 of 68
   -
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 51 of 68

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


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 52 of 68
3
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 53 of 68

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 
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 54 of 68



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	


		& 





  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 55 of 68
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	  
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 
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	
 
 
 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 56 of 68
8
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%B.#%2 
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 57 of 68
8
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 58 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 59 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 60 of 68
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		 


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 61 of 68
$  		 
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 
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


  
Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 62 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 63 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 64 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 65 of 68
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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 67 of 68

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Sponsor:Menarini International Operations Luxembourg S.A.  
Study Code MEIN/14/FEB-PWV/001
Protocol Version FINAL 1.4, 
Amedment 2    30/03/2016 
30/03/2016, Final Version 1.4, Am 2                                                                               
Page 68 of 68
APPENDICES 
Appendix  1: Declaration of Helsinki 
Appendix  2: the  Joint Task Force of the European Society of Cardiology and other European Societies on 
cardiovascular disease prevention in clinical practice 
Appendix  5: “Preliminary criteria for the classification of the acute arthritis of primary gout - ACR 1977”  
  
Appendix  6a:  Hepatic Adverse Event additional information form  
Appendix  6b:  Cutaneous Adverse Event additional information form  
Appendix  3: SmPC Febuxostat: (ADENURIC®). 
Appendix  4: SmPC Allopurinol (Allopurinol TEVA) . 

SAP_000.pdf: 
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5.4 Medical history, physical examination ....................................................................................................... 16
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