Restoring Masticatory Function as Treatment for Chronic Pain: a Randomized Placebo-controlled Trial
Phase: NA
Conditions: Temporomandibular Joint Dysfunction Syndrome, Chronic Pain
Sponsor: Urbano Santana Penin, MD, DDS, PhD

	  
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Title page 
MAP Protocol. Restoring physiological jaw closure and MAsticatory function as treatment 
for chronic facial Pain: a randomized clinical trial 
Public title: Improving chewing function to treat chronic pain 
ACRONYM: MAP 
 
Universal Trial Number (UTN): U1111-1134-0832  
ClinicalTrials.gov Identifier: NCT02144233 
International Standard Randomized Controlled Trial Number Register (ISRCTN Register): 
ISRCTN61654487 - http://www.controlled-trials.com/ISRCTN61654487/   
 
Protocol number: 2 
Protocol date: 2017 March 1st 
 
 
 
Authorized signature 
 
 
 
 
 
Name: Professor Urbano Santana-Penín 
(Chair of Trial Steering Committee for final protocols and amended final protocols) 
 
 
Trial Steering Committee 
Urbano Santana-Penín (USP) 
José López-Cedrún (JLC), 
María J. Mora (MJM) 
Urbano Santana-Mora (USM) 
 
Key words. Mesh Terms: 
Musculoskeletal Diseases [C05] 
 
 
 
 
Jaw Diseases [C05.500]  
 
 
 
Mandibular Diseases [C05.500.607] 
 
 
 
 
Craniomandibular Disorders [C05.500.607.221] 
 
 
 
 
Temporomandibular Joint Disorders [C05.500.607.221.897]  
 
 
 
Temporomandibular Joint Dysfunction Syndrome [C05.500.607.221.897.897] 
Occlusal Adjustment [E06.658.578.200] 
Facial Pain [C10.597.617.364] 
Chronic Pain [C10.597.617.258] 
Mastication [G10.261.326.240.500] 

	  
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MAP TRIAL 
Name of person authorized to sign final protocol and protocol amendments for the sponsor (Chair of Trial 
Steering Committee) 
 
Name: Prof Dr Urbano Santana-Penín 
 
 
 
urbano.santana@usc.es 
Professor and chair,  
 
 
 
 
 
Tel Instit.: +34 881812350 
Orofacial Pain and Prosthodontics Department 
 
 
Tel: +34 647 344 093 
Faculty of Medicine and Dentistry  
 
 
 
Fax: +34 981 562226 
Santiago de Compostela University 
C/ Entrarríos s/n 
15782 SANTIAGO DE COMPOSTELA, SPAIN 
 
Principal Investigators in bold and Investigators responsible for the conduct of the MAP Trial 
 
Dr José López-Cedrún (JLC), 
 
 
 
 
lopezcedrun@centromaxilofacial.com 
Head of the Oral and Maxillofacial Surgery Department  
 
Tel: +34 981178000 Ext 292021 
Complejo Hospitalario Universitario A Coruña   
 
 
Fax: 0034 981178052 
Calle Jubias 84, 15006 A CORUÑA, Spain  
 
Professor María J. Mora (MJM)  
 
 
 
mariajesus.mora@usc.es 
Head of the Stomatology Unit 
University Hospital Complex of Santiago de Compostela, and 
Tel: +34 981951919 
University of Santiago de Compostela, A Coruña, Spain 
15782 SANTIAGO DE COMPOSTELA, SPAIN 
 
Dr Urbano Santana-Mora (USM).  Clinical Instructor. 
 
urbanoalejandro.santana@rai.usc.es 
Orofacial Pain and Prosthodontics Department 
 
 
Tel: +34 881812350 
Faculty of Medicine and Dentistry  
 
 
 
Fax: +34 981 562226 
Santiago de Compostela University 
C/ Entrarríos s/n 
15782 SANTIAGO DE COMPOSTELA, SPAIN 
 
Dr Javier Collado López (JCL) 
Oral and Maxillofacial Surgery Department  
jcolmax@gmail.com 
Complejo Hospitalario Universitario A Coruña    
981 178000 
Calle Jubias 84, 15006 A CORUÑA, Spain 
 
Dr María Pombo Castro (MPC) 
Oral and Maxillofacial Surgery Department  
mariacorme@hotmail.com 
Complejo Hospitalario Universitario A Coruña    
981 178000 
Calle Jubias 84, 15006 A CORUÑA, Spain 
Dr Fernanda Lorenzo Franco (FLF) 
Oral and Maxillofacial Surgery Department  
JMbares@terra.com 
Complejo Hospitalario Universitario A Coruña    
981 178000 
Calle Jubias 84, 15006 A CORUÑA, Spain 
Dr Rocío P. García. Clinical Instructor. 
rochi_perez@hotmail.es 
Orofacial Pain and Prosthodontics Department 
 
 
Tel: +34 881812349 
Facultad de Medicina y Odontología 
 
 
 
Fax: +34 981 562226 
Universidad de Santiago de Compostela  
C/ Entrerríos s/n 
15782 SANTIAGO DE COMPOSTELA, SPAIN 
 
Dr Iria L. Darriba. Clinical Instructor. 
irialopezdarriba@gmail.com 
Orofacial Pain and Prosthodontics Department 
 
 
Tel: +34 881812349 
Facultad de Medicina y Odontología 
 
 
 
Fax: +34 981 562226 
Universidad de Santiago de Compostela  
C/ Entrerríos s/n 
15782 SANTIAGO DE COMPOSTELA, SPAIN 

	  
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Trial manager and monitor 
Urbano Santana-Mora (USM) 
Protocol Steering Committee:  
Same as the Trial Steering Committee (see title page) 
Data management team:  
Teresa Pazos Fernández (TPF), JLC 
Dr María Pombo Castro (MPC) 
 
Trial Management Committee:  
JLC, USP 
Other individuals or groups overseeing the trial: 
Prof. James H. Ware (JHW) 
Written (committed) Chair: 
USP 
Serum Utilization Committee: 
Ms Teresa Pazos Fernández (Nurse), Dr Rivas Lombardero (Head of Lab) and JLC. 
Data and Safety Monitoring Board (DSMB): (please see item 21a) 
Prof. Dr. Pentti Alanen (Chair).  
alanenpentti@gmail.com 
Prof. Dr. Julián Álvarez Escudero (Expert in Pain Medicine)  julian.alvarez.escudero@sergas.es  
Prof. Dr. Joao C. Pinho (Expert in TMD).  
pinhojc@gmail.com 
Prof. Dr. Carmen Carollo (Statistician).  
mdelcarmen.carollo@usc.es 
Dr. Francisco Gude (Statistician).  
francisco.gude.sampedro@sergas.es 
 
 
 

	  
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Trial Coordinator and Sponsor's Representative 
Prof Dr Urbano Santana-Penin 
Facial Pain and Prosthodontics, Faculty of Medicine and Dentistry, University of Santiago de Compostela, 
C/ Entrerrios s/n. 15782 Santiago de Compostela, Spain.  
Tel: +34 647344093.  
Fax: +34 981562226.  
E-mail: urbano.santana@usc.es 
Principal Coordinating Investigator 
Dr José López-Cedrún 
Head of the Oral and Maxillofacial Surgery Department, University Hospital Complex of A Coruña, 
Calle Jubias 84, 15006 La Coruña, Spain.  
Phone: +34 981178000 Ext 292021.  
FAX: +34 981178052 
E-mail: lopezcedrun@centromaxilofacial.com 
Trial Statistician 
Prof. James H. Ware 
Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, US. 
E-mail: ware@hsph.harvard.edu  
 
 

	  
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Background  
Chronic temporomandibular joint (TMJ) disorders (TMD) are the main cause of facial pain, and the second 
cause of musculoskeletal pain after low-back pain. The cause of TMD is unknown and therapy is usually 
empirical. Systematic reviews have shown that more research is needed to elucidate the benefits of occlusal 
adjustment for TMD. The risk factors for chronic unilateral TMD include dental (occlusal) premature 
contacts and habitual chewing on the affected side; therefore, a new occlusal therapy is proposed to restore 
physiological jaw closure and chewing function. 
Aims 
The primary endpoint will be the average change in pain score from baseline to the six-month assessments. 
Efficacy will be demonstrated by superior pain relief with the active treatment compared with the placebo. 
Methods  
Study design 
A phase 3, randomized, single (extensible to up three) centre, 6-month parallel-group, patient- and observer-
blinded, placebo-controlled clinical trial to assess the efficacy of occlusal adjustment on recovery of 
physiological jaw closure and chewing function in patients with TMD. 
Study population  
Inclusion criteria: TMD patients, aged 18-65 years with full dentates and normo-occlusion suffering 
significant pain (pain scores ≥4 and ≤9; method: visual analogue/numerical rating scale (VAS/NRS); 0 = no 
pain, 10 = worst imaginable pain). Main exclusion criterion is the requirement of excessive enamel removal to 
equilibrate the dental articulation (occlusion). 
Intervention 
Active therapy will consist of the elimination of premature tooth contacts and the reduction of the steeper 
lateral anterior guidance. Placebo therapy will be conducted in a manner identical to the active adjustment, 
but no enamel will be removed. 
Outcomes  
Main outcome: self-reported pain intensity on the affected side measured by the VAS and/or NRS scale. 
Secondary outcomes: maximum comfortable mouth opening (using a Boley gauge), chewing function 
(observed on the habitual chewing side) and quality of life using self-administered tests. Time frame: baseline 
and both 3- and 6-months follow-up. 
Sample size estimation 
Based on data from a previous study, we assume a standard deviation of 2.4 for this variable.  We will test the 
null hypothesis of no treatment effect at the two-sided 0.05 level.  With a fixed sample size design, a total 
sample size of 88 subjects (extended to 110 for drop-outs) with complete follow-up would provide power of 
0.8 to detect changes in pain score of 1.5 units between the active and placebo treatment groups. 

	  
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Interim analysis plan and stopping rules 
The Data and Safety Monitoring Board will be responsible for activating early stopping. The study will 
employ an interim analysis plan with a single interim analysis after 70% of participants have completed the 
six-month follow-up visit. Using the Lan-DeMets version of the O’Brien-Fleming stopping rule, the critical 
value for statistical significance at the interim analysis (under both intention-to-treat and per-protocol sets) 
will be +2.438, corresponding to a nominal two-sided P value of 0.0146. 
  
Statistical analysis plan  
For analysis of baseline characteristics, qualitative variables will be expressed as frequencies and percentages 
(25th -75th percentiles) and continuous variables as means (standard deviation). Fisher´s exact or McNemar 
tests will be used to compare the distributions of binary variables; Student t test or measurements repeated 
analysis of variance will be used to compare normal variables, and the Wilcoxon or Mann-Whitney U test for 
non-normally distributed continuous variables.  
All analyses will be conducted by two independent statisticians according to the intention-to- treat approach 
(the primary outcome was also analyzed as per protocol).  
The objective of this analysis is to adjust regression models that explain the outcomes of interest as a function 
of time and group. Based on the properties of the analized variables, the model fit of the analyses based on the 
linear mixed-effects model or the beta mean regression model with mixed effects, using the Akaike 
Information Criterion or the Bayes Information Criterion. Plots of residuals were used to check that the model 
assumptions were met and to assess goodness of fit. Statistical significance level was set at 0.05. All the 
analyses were conducted using the software R (R Development Core Team), including the “lme4” and the 
“gamlss” packages or IBM SPSS24. 
Sponsor 
University of Santiago de Compostela, Praza Obradoiro s/n, 15782 Santiago de Compostela, Spain   
Funder 
Ministry of Science and Innovation of the Government of Spain (Grant nº PI11/02507). 
European Development Fund (EDF). Fondo Europeo de Desarrollo Regional (FEDER) . “Una manera de 
hacer Europa” 
Autonomic Committee of the Research Ethics of Galicia: CAEI approval number 2009/017; updated on 
November 29, 2013). 
Date trial started  
11th August, 2014. 
Expected end date 
July, 2017. 
 
The authors state that there are no conflicts of interest to report.