The Facial Nerve Palsy And Cortisone Evaluation (FACE) Study in Children: A Randomized Double-blind, Placebo-controlled, Multicenter Trial
Phase: PHASE4
Conditions: Facial Palsy, Facial Nerve Diseases, Borrelia Infection of Central Nervous System, Bell Palsy
Sponsor: Dalarna County Council, Sweden

 
 
 CLINICAL STUDY PROTOCOL 
 
The Facial nerve palsy And Cortisone Evaluation (FACE) study in children:   
A randomized double-blind, placebo-controlled, multicenter trial 
 
Development Phase  
 
               Sponsor Project No: 
FACE-01 
EudraCT number: 2017-004187-35 
Investigational Product: Prednisolone 
  
Sponsor: Dalarnas county council  
(Region Dalarna) 
 
Sponsor Representative: Björn Äng,  research manager (Forskningsdirektör )   
Region Dalarna 
Vasagatan 27 
 791 37 Falun 
Sweden 
Telephone number: +46-23 492000 
Mobile +46 705518850 
E-mail address:                               
bjorn.ang@regiondalarna.se 
 
 
 
Coordinating Investigator Barbro Hedin Skogman, MD, PhD  
Center for Clinical Research Dalarna (CKF) 
Nissers väg 3 
S-791 82 Falun 
Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile +46 (0)70 309 11 01 
E-mail address: barbro.hedinskogman@ltdalarna.se 
 
 
 
 
The clinical study will be conducted, and essential documentation archived, in 
compliance with the requirements of the ICH Guideline for Good Clinical Practice. 

  
 
 
 
 
 
 
 
 
 
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SYNOPSIS 
Title of study:  
The Facial nerve palsy And Cortisone Evaluation (FACE) study in children:  a randomized double-blind, 
placebo-controlled, multicenter trial 
  
Name of Sponsor/Company: 
Dalarnas county council (Region Dalarna) 
 
Name of investigational product: 
Prednisolone 
Investigator(s) and study center(s):  
Barbro Hedin Skogman, coordinating investigator 
16-20 study centers with a principal investigator at each center (see separate document) 
Planned study period:  
2018-2024 
Phase of development:  
Development Phase IV 
Primary objective: 
To evaluate the efficacy of cortisone versus placebo treatment in children with acute facial nerve palsy.  
 
Secondary objective: 
 
To evaluate the total recovery rate at 1 month as compared to the total recovery rate at 12 months, in order to 
evaluate if prediction of recovery at 1 month is feasible and/or useful in children with acute facial nerve palsy. 
 
To evaluate subjective symptoms and influence in daily life in children with acute facial nerve palsy. 
 
To evaluate the safety profile for cortisone in children with acute facial nerve palsy. 
 
Methodology:  
Randomized double-blind, placebo-controlled, multicenter trial 
Number of subjects (planned):  
500 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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SYNOPSIS 
Inclusion criteria:  
1. 
1-17 years of age 
2. 
Acute peripheral unilateral facial nerve palsy 
3. 
Less than 72 hours of duration of symptoms 
4. 
Signed informed consent 
 
 
 
 
 
 
 
 
Exclusion criteria:  
1. 
Head trauma < 1 month 
2. 
Central or bilateral facial nerve palsy 
3. 
Malformations in head and neck 
4. 
Conditions not compatible with cortisone treatment (hypertension, diabetes mellitus, psychiatric 
disorder, active or latent tuberculosis, intolerance of lactose) 
5. 
Current or past oncological diagnosis 
6. 
Other serious medical conditions (meningitis, encephalitis, stroke) 
7. 
Acute otitis media  
8. 
Signs of herpes simplex or varicella zoster infection (vesicles in the ear region)  
9. 
Pregnancy or breastfeeding 
10. Use of any systemic or inhaled steroids within 2 weeks prior onset of symptoms 
11. Immunization with live vaccine 1 month prior onset of symptoms 
12. Requirement of live vaccine within 2 months from start of experimental treatment (prednisolone or 
placebo) 
13. Evaluation of primary endpoint at 12 not feasible for any reason 
14. Previously included into the FACE study 
 
Investigational product, dosage and mode of administration:  
Prednisolone capsules 5 mg, dosage 1 mg/kg body weight (maximum 50 mg) x 1, per oral 
Duration of treatment:  
10 days 
Active control, dosage and mode of administration:  
Placebo capsules, same number of capsules as investigational product for each child, maximum 10 capsules x 1, 
per oral 

  
 
 
 
 
 
 
 
 
 
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SYNOPSIS 
Primary Endpoint: 
 
The total recovery rate at 12 months follow-up in the two treatment groups measured with the House-Brackmann 
scale. 
 
Secondary Endpoints: 
The total recovery rate at 12 months follow-up in the two treatment groups measured with the Sunnybrook scale.  
 
The total recovery rate at 1 month follow-up as compared to the total recovery rate at 12 months follow-up, 
measured with Sunnybrook and House-Brackmann scale (prediction). 
 
Quality of daily life at 1 and 12 months follow-up measured with the Facial Clinimetric Evaluation (FaCE) scale 
and the Facial Disability Index (FDI) and at the 12 months follow-up measured with the Synkinesis Assessment 
Questionnaire (SAQ). 
 
Number of Adverse Events possibly or probably related to the study drug during the 12 months follow-up. 
 
Statistical methods:  
Intention-to-treat will be applied when analyzing results from the primary outcome.  
 
Comparisons between groups for dichotomous endpoints (recovery/no recovery) will be performed using 
Fisher’s exact test and for categorical endpoints (scale) using Mann-Whitney U-test. For correlations between 
scales, Pearson’s correlation test, or Cohen's kappa if appropriate, will be used.  
 
When predicting recovery at 1 month to 12 months, diagnostic performance will be calculated on total recovery 
defined as House-Brackmann grade 1.  
 
Analysis of early predictors will be performed to understand variance of subgroups. Furthermore, logistic 
regression analysis will be used to evaluate recovery in relation to baseline data.  
 
 

  
 
 
 
 
 
 
 
 
 
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1 
TABLE OF CONTENTS 
 
PAGE 
1 
TABLE OF CONTENTS ........................................................................................................ 5 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 7 
3 
GENERAL INFORMATION/STUDY ADMINISTRATIVE STRUCTURE ...................... 8 
4 
SIGNATURE PAGES .............................................................................................................. 9 
5 
BACKGROUND INFORMATION ...................................................................................... 11 
5.1 
STUDY RATIONALE ................................................................................................................... 11 
5.2 
STUDY TIME TABLE ................................................................................................................... 12 
6 
STUDY OBJECTIVES .......................................................................................................... 12 
6.1 
PRIMARY OBJECTIVE .................................................................................................................. 12 
6.2 
SECONDARY OBJECTIVES ........................................................................................................... 12 
7 
ENDPOINTS ........................................................................................................................ 13 
7.1 
PRIMARY ENDPOINT ................................................................................................................. 13 
7.2 
SECONDARY ENDPOINTS .......................................................................................................... 13 
8 
STUDY DESIGN................................................................................................................... 14 
8.1 
STUDY OUTLINE ............................................................................................................................. 14 
8.2 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................................. 14 
8.3 
SCHEDULE OF EVENTS ............................................................................................................... 16 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................... 16 
9.1 
SUBJECT INCLUSION CRITERIA.................................................................................................... 16 
9.2 
SUBJECT EXCLUSION CRITERIA ................................................................................................... 17 
9.3 
WITHDRAWAL OF SUBJECTS ....................................................................................................... 18 
9.4 
SUBJECT LOG AND SCREENING OF SUBJECTS .............................................................................. 19 
10 
TREATMENT OF SUBJECTS ............................................................................................. 19 
10.1 
TREATMENT ADMINISTRATION ............................................................................................. 19 
10.2 
DESCRIPTION OF INVESTIGATIONAL PRODUCTS .................................................................... 20 
10.3 
PACKAGING AND LABELLING OF INVESTIGATIONAL PRODUCTS ............................................ 20 
10.4 
STORAGE AND HANDLING .................................................................................................... 21 
10.5 
RANDOMIZATION AND BLINDING ......................................................................................... 21 
10.6 
CONCOMITANT THERAPY ...................................................................................................... 21 
10.7 
COMPLIANCE WITH THE TREATMENT ................................................................................... 22 
10.8 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCTS ............................................................. 22 
10.9 
CONTINUATION OF TREATMENT ........................................................................................... 22 
11 
ASSESSMENT OF EFFICACY ............................................................................................ 22 
11.1 
INVESTIGATOR’S ASSESSMENTS ................................................................................................... 22 
11.2 
SUBJECT´S ASSESSMENTS ........................................................................................................... 23 
12 
ASSESSMENT OF SAFETY ................................................................................................. 23 
12.1 
DEFINITION OF ADVERSE EVENTS......................................................................................... 23 
12.2 
METHODS FOR ELICITING, RECORDING AND FOLLOW-UP OF ADVERSE EVENTS .................... 23 
12.3 
ASSESSMENT OF INTENSITY ................................................................................................... 24 

  
 
 
 
 
 
 
 
 
 
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12.4 
ASSESSMENT OF CAUSALITY .................................................................................................. 24 
12.5 
DEFINITION OF SERIOUS ADVERSE EVENTS ........................................................................... 24 
12.6 
REPORTING OF SAES, SUSARS AND DSUR ........................................................................... 25 
12.7 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ....................................... 26 
12.8 
PROCEDURES IN CASE OF MEDICAL EMERGENCY .................................................................. 26 
12.9 
LABORATORY ASSESSMENTS .................................................................................................. 27 
13 
STATISTICS AND DATA MANAGEMENT ....................................................................... 28 
13.1 
DATA MANAGEMENT ............................................................................................................ 28 
13.2 
STATISTICAL ANALYSIS .......................................................................................................... 28 
13.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................ 29 
14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................... 29 
15 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 30 
15.1 
SOURCE DATA .......................................................................................................................... 30 
15.2 
MONITORING ........................................................................................................................... 30 
15.3 
DATA SAFETY MONITORING BOARD ............................................................................................. 31 
16 
ETHICS REVIEW BOARD .................................................................................................. 31 
16.1 
ETHICAL CONDUCT OF THE STUDY ................................................................................................ 32 
16.2 
RISK - BENEFITS ....................................................................................................................... 32 
16.3 
PATIENT INFORMATION AND INFORMED CONSENT ........................................................................... 33 
17 
DATA HANDLING AND RECORD KEEPING ................................................................ 34 
17.1 
CASE REPORT FORMS ................................................................................................................. 34 
17.2 
RECORD KEEPING ...................................................................................................................... 34 
18 
INSURANCE ........................................................................................................................ 35 
19 
PUBLICATION POLICY ..................................................................................................... 35 
20 
SUPPLEMENTS ................................................................................................................... 35 
20.1 
CHANGES OF THE STUDY PROTOCOL ..................................................................................... 35 
20.2 
APPLICATION TO REGULATORY AUTHORITIES ....................................................................... 35 
20.3 
STAFF INFORMATION ............................................................................................................ 36 
20.4 
CRITERIA FOR TERMINATION OF THE STUDY ......................................................................... 36 
21 
REFERENCES ..................................................................................................................... 37 
22 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .................................................. 39 
23 
APPENDICES ....................................................................................................................... 40 
23.1 
DECLARATION OF HELSINKI ................................................................................................ 40 
23.2 
RATING SCALES OR DIARIES FOR ASSESSMENT OF EFFICACY OR SAFETY ................................ 40 
23.3 
LABELING OF INVESTIGATIONAL PRODUCTS ..................................................................... 40 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
AE 
Adverse Event 
CIOMS 
Council for International Organisation 
of Medical Sciences 
CKF 
Center for Clinical Research, Dalarna 
CRF 
Case Report Form 
CV 
Curriculum vitae 
DSMB 
Data safety monitoring board 
DSUR 
Development Safety Update Report 
ENT 
Ear Nose and Throat 
ERB 
Ethical Review Board 
FACE 
Facial nerve palsy and cortisone 
evaluation in children study 
FaCE-scale 
Facial Clinimetric Evaluation Scale 
FDI 
Facial Disability Index 
GCP  
Good Clinical Practice 
ICF 
Informed Consent Form 
LSLV 
Last subject last visit 
MPA 
Medical Products Agency 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event 
SAQ 
Synkinesis Assesment Questionnaire 
SUSAR 
Suspected Unexpected Serious Adverse 
Reaction 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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3 
GENERAL INFORMATION/STUDY ADMINISTRATIVE 
STRUCTURE 
 
 
 
 
  
Coordinating Investigator 
 
Barbro Hedin Skogman, MD, PhD  
Center for Clinical Research (CKF) Dalarna 
Nissers väg 3 
S-791 82 Falun 
Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile: +46 (0)70 309 11 01 
E-mail address: 
barbro.hedinskogman@regiondalarna.se 
 
Co-Investigator 
 
Sofia Karlsson, MD, PhD-student  
Center for Clinical Research (CKF) Dalarna 
Nissers väg 3 
S-791 82 Falun 
Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile: +46 (0)70 351 92 82 
E-mail address: 
sofia.a.karlsson@regiondalarna.se 
 
Statistician, UCR 
Nermin Hadziosmanovic 
Uppsala Science Park 
Dag Hammarskjöldsv 14 B 
751 83 UPPSALA 
Sweden 
Mobile: +46 (0)18 611 95 21 
E-mail address: 
nermin.hadziosmanovic@ucr.uu.se 
 
Also, see the form for the Regional Ethics Review 
Board in Uppsala, Bilaga 1and 9 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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4 
SIGNATURE PAGES 
SPONSOR 
 
 
 
 
 
Sponsor  
Dalarnas county council (Region Dalarna) 
Vasagatan 27 
S-791 37 Falun 
Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile +46 (0)70 551 88 50 
E-mail address:  
bjorn.ang@regiondalarna.se 
 
 
 
 
 
 
 
Signature and date:  
 
 
_______________________________________ 
  Björn Äng, Research manager 
  Dalarnas county council (Region Dalarna) 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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COORDINATING INVESTIGATOR 
I, the undersigned, have read and understand the protocol and agree that it contains all 
necessary information for conducting the study.  
I agree to conduct the study according to this protocol and according to the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent 
with Good Clinical Practice and the applicable national laws and regulations. 
 
 
 
 
Co-ordinating Investigator 
Barbro Hedin Skogman, MD, PhD  
Center for Clinical Research Dalarna (CKF) 
Nissers väg 3 
S-791 82 Falun 
Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile +46 (0)70 309 11 01 
E-mail address: 
barbro.hedinskogman@regiondalarna.se 
 
 
Signature and date:  
 
 
_______________________________________ 
 
 

  
 
 
 
 
 
 
 
 
 
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5 
BACKGROUND INFORMATION 
The annual incidence of acute facial nerve palsy in European pediatric populations 
are about 5-21/100 000 children (1,2). The facial nerve palsy is often idiopathic, but 
may be caused by a Borrelia infection in the nervous system (2,3). The physiological 
reason for impairment of the facial nerve is an anatomically tight passage through 
the bone of the scull and when the nerve becomes swollen, for some reason, the 
nerve function is impaired and the facial muscles on the ipsilateral side are affected.  
 
In children, Borrelia associated facial nerve palsy occurs more often (65%) than 
idiopathic facial nerve palsy (35%) (2). Borrelia associated facial nerve palsy is 
treated with antibiotics according to European guidelines (4,5).  
 
An acute facial nerve palsy, regardless of etiology, may lead to a permanent 
dysfunction in 20-30 % of the patients, involving problems with tear secretion, 
drooling and pronunciation in addition to cosmetic and social problems (6-8).  
 
Adult patients with idiopathic acute facial nerve palsy (Bell’s palsy) are 
recommended cortisone treatment in order to improve the recovery rate (9). This 
recommendation is based on several randomized clinical trials (RCTs) (9,10). Studies 
on pediatric patients with acute facial nerve palsy and cortisone treatment are 
scarce and no RCT has been performed (11,12).  
 
There are a few uncontrolled treatment studies on cortisone to children with acute 
idiopathic facial nerve palsy showing a total recovery rate up to 80-90% (13-16). 
Prednisolone in a dosage of 1-2 mg/kg daily in 7-14 days has been used in pediatric 
patients without reported adverse events (15,17).  
 
One protocol has recently been published from New Zealand about a RCT study 
using prednisolone 1 mg/kg daily in 10 days (with a reduced dose day 7-10) for 
treatment of children with facial nerve palsy (18). We have in the FACE study chosen 
prednisolone in a dosage of 1 mg/kg daily in 10 days without taper in order to give a 
treatment that is easy to follow (compliance) and effective enough to regain function 
of the facial nerve (efficacy). 
 
5.1 
STUDY RATIONALE 
Since no RCT has previously been performed on cortisone treatment in children with 
acute facial nerve palsy, there is a lack of evidence-based guidelines.                         

  
 
 
 
 
 
 
 
 
 
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The aim of the FACE study is to evaluate the efficacy and safety of cortisone 
treatment given to children with acute facial nerve palsy in a randomized placebo-
controlled trial.  
If the cortisone treatment is shown to be beneficial for recovery in children with 
facial nerve palsy, cortisone treatment will be introduced in clinical practice and 
international evidence-based guidelines will be published. 
5.2 
STUDY TIME TABLE  
Study planning 2017-2018. 
Patient inclusion 2019-2023 with follow-up until 2024 
Results and publishing 2025-2026 
 
6 
STUDY OBJECTIVES 
6.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the efficacy of cortisone versus 
placebo treatment in children with acute facial nerve palsy.  
 
6.2 
SECONDARY OBJECTIVES 
The secondary objectives are: 
 
 to evaluate the total recovery rate at 1 month as compared to the total 
recovery rate at 12 months, in order to evaluate if prediction of recovery at 1 
month is feasible and/or useful in children with acute facial nerve palsy 
 
 to evaluate subjective symptoms and influence in daily life in children with 
acute facial nerve palsy 
 
 to evaluate the safety profile for cortisone in children with acute facial nerve 
palsy 
 

  
 
 
 
 
 
 
 
 
 
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7 
ENDPOINTS 
7.1 
PRIMARY ENDPOINT 
The primary endpoint is the total recovery rate at 12 months follow-up in the two 
treatment groups measured with the House-Brackmann scale (19). 
 
The House-Brackmann scale (1 is normal function and 6 is total loss of function) is 
chosen as primary outcome measure since it is a validated, objective instrument, 
easy to perform and most frequently used in previous studies (13,14,19). The time 
point 12 months for evaluation of total recovery is chosen as no further 
improvement of the facial nerve function is expected after 12 months (14). 
 
7.2 
SECONDARY ENDPOINTS 
 
Secondary endpoints are: 
 
 the total recovery rate at 12 months follow-up in the two treatment groups 
measured with the Sunnybrook scale (20, 21). 
 
The Sunnybrook scale (100 is normal function and 0 is total loss of function) is 
another objective scale for grading the facial nerve function. It will be used as 
secondary outcome measure. It is validated for children, easy to perform and 
has been used in previous studies (20, 21). It correlates well to the House-
Brackmann scale and has been shown to be useful for prediction of recovery 
in adult patients (21). 
 
 the total recovery rate at 1 month follow-up as compared to the total 
recovery rate at 12 months follow-up, measured with Sunnybrook and 
House-Brackmann scale (prediction) (20, 21). 
 
 quality of daily life at 1 and 12 months follow-up measured with the Facial 
Clinimetric Evaluation (FaCE) scale and the Facial Disability Index (FDI) and at 
the 12 months measured with the Synkinesis Assessment Questionnaire 
(SAQ) (22, 23). 
 
 number of Adverse Events possibly or probably related to the study drug 
during the 12 months follow-up. 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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8 
STUDY DESIGN 
8.1 
STUDY OUTLINE 
The FACE study is a randomized double-blind, placebo-controlled, multicenter trial. 
 
Efficacy of cortisone versus placebo treatment in children with acute facial nerve 
palsy will be measured by comparing the total recovery rate measured with the 
House-Brackmann scale at 12 months follow-up. 
 
End of the study is defined as the 12 months follow-up visit for the last patient.  
 
 
8.2 
STUDY ASSESSMENTS AND PROCEDURES 
 
A Principal Investigator (a pediatrician) at each study center will be responsible for 
clinical care of the patients.   
 
The Principal Investigator (a pediatrician) or a co-Investigator (an Ear-Nose-Throat 
specialist) will be responsible for performing the objective evaluation of the facial 
nerve function on admission (or one day after) and at the follow-up visits 1 month 
and 12-months.  
 
The Principal- and co-Investigators at each study center will be thoroughly informed 
how to assess the House-Brackmann and Sunnybrook scales in order to minimize 
inter-rater differences. 
 
Study nurses will take care of parts of the study work, such as performing the one 
and two weeks telephone calls, collecting questionnaires from the 
child/parents/guardians, collecting and entering data in the CRFs and being the main 
contact person for the monitor. 
 
Screening/Baseline visit 
 
Children and their parents/guardians visiting the hospital for the child´s acute facial 
nerve palsy will be informed about the study and eligibility criteria will be checked. If 
the child and the parents/guardians accept to participate in the study, an informed 
consent (ICF) will be signed by both parents/guardians. If only one parent/guardian is 
present at the visit, the other parent/guardian will be contacted by telephone, 
informed about the study, given the chance to ask questions and sent an ICF by e-
mail. The signed ICF will then be sent back by e-mail, or as a photocopy on the 

  
 
 
 
 
 
 
 
 
 
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mobile phone, to the investigator and saved in the Investigators file until the original 
ICF is returned.  
 
Data about demographics, medical history, concomitant medication, physical 
examination including blood pressure will be collected. Blood sample for white and 
red blood cell count, CRP, electrolytes and glucose as well as investigation of the 
spinal fluid will be performed as part of normal clinical routine. The NeBoP score (a 
clinical neuroborreliosis prediction test), as used in routine, will be assessed on all 
children for early prediction of diagnosis associated to Borrelia infection (24). 
 
Grading of the facial nerve palsy by using the House-Brackmann and Sunnybrook 
scales will be performed either by a pediatrician or an ear-nose-throat specialist (the 
principal or co-investigator). 
 
The study medication including instructions about route of administration and 
dosage for the specific child will be distributed at the baseline visit. CRFs will be 
completed by the investigator or study nurse. 
 
One week ±3 days telephone call and two weeks ±3 days telephone call 
 
After one and two weeks, the study nurse will call the child and/or 
parents/guardians to follow up that study medication is taken according to 
instructions and to check whether any AEs have occurred. Bottles with remaining 
study medication will be returned after end of treatment for accountability check.  
Safety is followed-up by asking for AEs. CRFs will be completed by the study nurse.  
 
One month ± 5 days and 12 months ±2 weeks follow-up visits  
 
After 1 month and 12 months, the child with parents/guardians come to a follow-up 
at the pediatric or ENT-clinic. Grading of the facial nerve palsy with House-
Brackmann and Sunnybrook will be performed. Safety followed-up by asking for 
adverse events. Also concomitant medications will be updated, if applicable. CRF’s 
will be completed at 1 month and at 12 months by the investigator or study nurse. 
 
The child and the parents/guardians will complete the Facial Clinimetric Evaluation 
(FaCE) scale, the Facial Disability Index (FDI) at 1 and 12 months follow-up and the 
Synkinesis Assessment Questionnaire (SAQ) at the 12 months follow-up. 
 
Complementary treatment (for example physical therapy or massage) is asked for at 
the 12 months follow-up. If the patient has a moderate – severe persistent facial 
nerve palsy, a visit at an ENT-specialist will be arranged for further evaluation. 
 

  
 
 
 
 
 
 
 
 
 
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End of the study is defined as completed at the 12-months follow-up visit for the last 
included patient (LSLV). An end-of-the-study CRF for each participant will be 
completed by the Principal Investigator. The Medical Products Agency and the 
Regional Ethical Review Board will be informed within 90 days from the date of LSLV.  
 
 
8.3 
SCHEDULE OF EVENTS 
 
 
 
 
Screening/ 
Baseline 
 
 
Telephone 
call  1 week     
± 3 days 
 
Telephone 
call  2 
weeks  
 ± 3 days 
 
 
Visit        
1 month 
± 5 days 
 
Visit         
12 months  
± 2 weeks 
 
Informed consent 
X 
 
 
 
 
Inclusion /Exclusion criteria 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Weight/length/BMI 
X 
 
 
 
 
Physical examination 
X 
 
 
 
 
NeBoP score 
X 
 
 
 
 
House-Brackmann scale 
X 
 
 
X 
X 
Sunnybrook scale 
X 
 
 
X 
X 
Concomitant medication 
X 
 
 
X 
X 
Distribution of study medication 
X 
 
 
 
 
Compliance of study medication 
 
X 
X 
 
 
Reporting of Adverse Events 
 
X 
X 
X 
X 
Return of unused tablets 
 
 
 
X 
 
Facial disability index  
 
 
 
X 
X 
Facial Clinimetric Evaluation Scale  
 
 
 
X 
X 
Synkinesis Assessment Questionnaire 
 
 
 
 
X 
 
 
 
 
 
 
 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 
SUBJECT INCLUSION CRITERIA 
1. 1-17 years of age 
2. Acute peripheral unilateral facial nerve palsy 
3. Less than 72 hours since debut of symptoms 
4. Signed informed consent  
 
 

  
 
 
 
 
 
 
 
 
 
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9.2 
SUBJECT EXCLUSION CRITERIA 
 
1. Head trauma < 1 month 
2. Central or bilateral facial nerve palsy 
3. Malformations in head and neck 
4. Conditions not compatible with cortisone treatment (arterial 
hypertension, diabetes mellitus, psychiatric disorder, active or latent 
tuberculosis, intolerance of lactose)* 
5. Current or past oncological diagnosis 
6. Other serious medical conditions (meningitis, encephalitis, stroke) 
7. Acute otitis media  
8. Signs of herpes simplex or varicella zoster infection (vesicles in the ear 
region)  
9. Pregnancy or breastfeeding 
10. Use of any systemic or inhaled steroids within 2 weeks prior onset of 
symptoms 
11. Immunization with live vaccine 1 month prior onset of symptoms 
12. Requirement of live vaccine within 2 months from start of experimental 
treatment (prednisolone or placebo) 
13. Evaluation of primary endpoint at 12 months not feasible for any 
reason 
14. Previously included into the FACE study 
 
*clarifications about some exclusion criterias: 
 
Latent or active tuberculosis: 
The Swedish children/adolescent population is at very low risk for TB. 
However, immigrants, children to immigrants and adopted children may be of higher 
risk and these groups are in Sweden routinely tested at the health check-up, 
including PPD (and if possible PPD, a Quantiferon test and lung X-ray) in order to find 
children in risk of having latent or active TB. Children diagnosed with latent or active 
TB are treated according to Swedish guidelines and will be excluded for participation 
in the study. If negative Quantiferon test, the TB diagnosis is excluded and the child 
can participate in the study.    
 
Arterial hypertension:  
All children diagnosed with arterial hypertension (with or without treatment) will be 
excluded. All other eligible children will be checked for blood pressure according to 
normal procedures at pediatric emergency wards or pediatric out-patients clinics 
before inclusion in the study. If the blood pressure (measured after relaxation in 5-
10 minutes, in the right arm with the correct size of the cuff and with a mean value 
of three measurements) is above the 90th percentile (for age, sex and length) the 
child will be excluded for participation (27).  

  
 
 
 
 
 
 
 
 
 
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Children not being eligible for enrolment will be registered on the screening list for 
gender, age and reason for exclusion. 
 
 
9.3 
WITHDRAWAL OF SUBJECTS 
Participants can leave the study at any time without giving any specific reason but will 
be followed-up for safety reasons.  
The Investigator can decide to withdraw a participants from a study treatment. If this 
decision is made because of a serious adverse event (SAE) related to the study 
medication, the treatment is discontinued and appropriate measures are taken. The 
participants will continue follow-up according to the protocol. 
In case of written withdrawal of consent for follow-up visits and unless otherwise 
stated by the participants, the Investigator will be encouraged to follow the medical 
status of the patients.  
The Sponsor should be notified immediately (within 24 hrs) about participants 
withdrawals due to Serious Adverse Events. The reason for the study discontinuation 
will be recorded in the CRF. 
Specific criteria for withdrawal are: 
- 
AE that precludes further continuation of treatment 
- 
No compliance with study procedures 
- 
The patient becomes pregnant  
- 
Other medical reason according to the Investigator 
- 
Patient’s decision 
Participants, who are withdrawn from the study will receive medical care according to 
local practice. In case of withdrawal due to an AE, participants will be closely 
monitored until resolution or stabilization of this AE. This may mean that follow-up 
will continue due to safety reasons. 
Participants, who are not eligible for the study because in hindsight they were not 
eligible for the study, will continue to follow the study schedule.  
For participants considered lost to follow-up, the CRF must be completed up to the 
last visit performed. 
 
 

  
 
 
 
 
 
 
 
 
 
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9.4 
SUBJECT LOG AND SCREENING OF SUBJECTS 
Participants will receive a consecutive screening number when signing the informed 
consent and are thereafter considered to be enrolled in the study. 
It is the responsibility of the Investigator that all participants that have signed 
Informed Consent are listed on the “Screening and enrolment log”. The reason for 
rejecting a participants before first treatment should be specified in the comment field 
of the log.  
If the participant is eligible, he/she will receive a randomization number and the study 
drug bottle with the same randomization number will be distributed to the patient 
and the parents/guardians. It is the responsibility of the investigator to keep a patient 
identification log, identifying the individual behind each randomization number. 
 
The Subject Enrolment and Identification log contains information to enable 
identification of each participant. It is included in the Investigator´s File and shall be 
kept by the Principal Investigator in a safe place.  
The participants will have the same randomization number through the study and this 
number will not be reused in case the participant is withdrawn from the study. 
 
 
10 
TREATMENT OF SUBJECTS 
10.1 
TREATMENT ADMINISTRATION 
The intervention is treatment with either prednisolone (capsule Prednisolone 5 mg),           
1 mg/kg once daily in 10 days or control treatment (capsule placebo) once daily in 10 
days. The number of capsules is based on the child’s weight pre-calculated in table 2.  
The dosage choice is based on results from earlier studies on prednisolone 
treatment, and a clear schedule (same dosage once daily in 10 days) will make a 
good compliance possible.  
 
The specific child’s dosage will be given to parents/guardians and noted in CRF. If the 
child has problems to swallow the capsules, they may be opened and the content 
can be mixed with a small amount (about one tablespoon) of something tasty in 
order to facilitate per oral administration and to ascertain the intake of the child’s 
dosage of the study medication.   
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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Table 2. Dosage of prednisolone/placebo. Treatment period is 10 days, maximum 
dosage is 50 mg per day. 
 
Child´s weight /kg 
Number of capsules/day 
Total number of capsules 
5 - 9.9  
2 
20 
10 - 14,9  
3 
30 
15 - 19.9  
4 
40 
20 - 24.9  
5 
50 
25 - 29.9  
6 
60 
30 - 34.9  
7 
70 
35 -  39.9  
8 
80 
40 - 44.9 
9 
90 
>45 
10 
100 
 
 
10.2 
 DESCRIPTION OF INVESTIGATIONAL PRODUCTS 
 
Capsule Prednisolon 5 mg (APL), dosage 1 mg/kg (max 50 mg) once daily for 10 days 
according to pre-calculated weight table (Table 2). All bottles include 100 capsules.  
 
Capsule Placebo (APL), dosage once daily equivalent to 1 mg/kg (max 10 capsules) 
for 10 days according to pre-calculated weight table (Table 2). All bottles include 100 
capsules.  
 
See separate product information and pharmacological documents from APL for 
prednisolone and placebo.  
 
10.3 
PACKAGING AND LABELING OF INVESTIGATIONAL 
PRODUCTS 
 
The study medication (prednisolone and placebo capsules) will be put in bottles and 
labelled with a unique study code according to randomization list (prepared by the 
statistician at UCR) at APL, and then sent to Tamro AB for distribution to study 
centers. 
 
 

  
 
 
 
 
 
 
 
 
 
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The bottles of study medication will be given to the patients/guardians at the 
screening/baseline visit after informed consent has been signed and eligibility for 
participation is confirmed by the Investigator. 
 
 
10.4 
STORAGE AND HANDLING 
 
The study medication can be stored in room temperature. The medication can be 
placed at the local pharmacy or in a locked cabinet or room for medical products at 
the clinic. 
 
10.5 
RANDOMIZATION AND BLINDING 
 
Randomization is repared by the study statistician at UCR. A randomization list using 
variable block sizes will be used and applied when undertaking blinding, coding and 
labeling the study medication (prednisolone or placebo).  
 
The study drugs (prednisolone or placebo) will be labeled with the randomization 
code at APL, and then sent to Tamro AB for further distribution to the different study 
centers.  
  
The code envelopes for unblinding will be kept at each study center. In case the code 
has to be broken due to an emergency situation, the Coordinating Investigator 
(Barbro Hedin Skogman) will be contacted, see also details in section 12.8. 
 
 
10.6 
CONCOMITANT THERAPY 
 
Children with Borrelia associated acute facial nerve palsy will receive antibiotic 
treatment according to national guidelines, i.e. ceftriaxone 50-100 mg/kg x 1 in 10-
14 days (1-7 years of age), or doxycycline 4 mg/kg x 1 in 10-14 days, or 200 mg x 1 
first day and then 100 mg x 1 in 10-14 days (5).  
 
If other concomitant medications permitted in the study are taken, they will be listed 
in the CRF. Data registered are generic/trade name, dosage, start and end date of 
the medication, and indication.  
 
 

  
 
 
 
 
 
 
 
 
 
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Use of any systemic or inhaled steroids within 2 weeks prior to onset of symptoms is 
not permitted. No live vaccines are permitted during the period one month prior to 
onset until 2 months after study treatment.  For more information about medical 
conditions not permitted in the study, see Subject Exclusion Criteria, section 9.2. 
 
10.7 
COMPLIANCE WITH THE TREATMENT 
 
The study nurse will inform the child/parents on how to administer the study 
medication (capsules with prednisolone or placebo). If it is not possible for the child 
to swallow the capsules, there is a possibility to open the capsules and mix the 
content with something tasteful in order to facilitate compliance.  
 
Telephone calls 1 and 2 weeks after baseline are planned to support the families and 
the compliance of the study medication and to follow-up if Adverse Events have 
occurred. 
 
Parents/guardians will be instructed to return the bottles with the remaining study 
medication for drug accountability check. 
 
10.8 
ACCOUNTABILITY OF INVESTIGATIONAL PRODUCTS 
 
Accountability will be measured by counting remaining capsules in the bottles, which 
should be returned to the study nurse at the pediatric clinic after usage, at the latest 
at the 1 month follow-up visit.  
 
10.9 
CONTINUATION OF TREATMENT 
 
After 10 days treatment stops. No further treatment will replace the study 
medication. 
 
Concomitant therapy (e.g. antibiotics 10-14 days, se 10.6) will be finished as 
prescribed by the responsible pediatrician.  
 
 
11 
ASSESSMENT OF EFFICACY 
11.1 
INVESTIGATOR’S ASSESSMENTS 
 

  
 
 
 
 
 
 
 
 
 
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The Investigators will perform evaluation using the House-Brackmann and 
Sunnybrook grading scales for facial nerve palsy at the three study visits 
(screening/baseline, 1 month, 12 months). Education for the study, including written 
instructions on how to perform the evaluation will be given to the investigators 
before study start.  
 
11.2 
SUBJECT´S ASSESSMENTS 
The child and/or parents/guardians will complete the Facial Disability Index (FDI), the 
Facial Clinimetric Evaluation Scale (FaCE scale) at 1 month and 12 months follow-up 
and the Synkinesis Assessment Questionnaire (SAQ) at the 12 months follow-up to 
evaluate their personal subjective experience of the facial nerve palsy. 
 
These questionnaires will be completed by the child/adolescent alone or together 
with the parents/guardians, which will be optional and documented at the end of 
each questionnaire.  
 
12 
ASSESSMENT OF SAFETY 
Safety will be evaluated by recording of routine laboratory tests (white and red blood 
cells, CRP, electrolytes and glucose), physical examinations, blood pressure and vital 
signs measurements. Adverse Events (AEs) or Serious Adverse Events (SAEs), will be 
reported if occurring during the study period (12 months).  
 
Any clinically relevant changes and actions taken, for instance occurrence of an 
adverse event or administration of concomitant medication, will be recorded in the 
CRF and hence in the database. 
12.1 
DEFINITION OF ADVERSE EVENTS 
An AE is any untoward medical occurrence that does not necessarily have to have a 
causal relationship with the investigational product. An AE can be any unfavourable, 
unintended clinical sign, symptom, medical complaint or clinically relevant change in 
laboratory variables or clinical tests. Accidents, operations not pre-planned, changes 
in medication or deterioration in concurrent illness are also considered as AEs. 
 
12.2 
METHODS FOR ELICITING, RECORDING AND FOLLOW-UP OF 
ADVERSE EVENTS 
Information regarding AEs is to be obtained by questioning or examining the subject 
after having signed the ICF. At each visit all new complaints and symptoms (i.e., those 
not existing prior to signing of informed consent) must be recorded on the AE CRF. 

  
 
 
 
 
 
 
 
 
 
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Pre-existing complaints or symptoms that increase in intensity or frequency after 
having signed the ICF must also be reported as an AE. 
 
All AEs must be characterized in terms of their start and stop dates, maximum 
intensity, action taken on the study medication, relationship to study medication, 
subject outcome and whether or not the AE led to a SAE. Any clinically relevant 
increase or decrease to the intensity or frequency of a reported AE requires a separate 
entry on the AE form. 
 
12.3 
ASSESSMENT OF INTENSITY 
The Investigator should rate the intensity of any AE as follows: 
Mild: 
The AE does not interfere with the subject’s usual function. 
Moderate: The AE interferes to some extent with the subject’s usual function. 
Severe: 
The AE interferes significantly with the subject’s usual function. 
 
12.4 
ASSESSMENT OF CAUSALITY 
The Investigator shall judge whether or not, in his/her opinion, the AE is associated 
with the study medication. When stating the causality, the following nomenclature 
should be used: 
 
Unrelated: There is little or no chance that the study medication caused the AE. 
Possibly related: The association of the AE with the study medication is unknown, 
however, the AE is not clearly due to another condition. 
Probably related: A reasonable temporal association exists between the AE and the 
study medication. Based on the Investigator’s clinical experience, the association of 
the AE with the study treatment seems likely. 
12.5 
DEFINITION OF SERIOUS ADVERSE EVENTS  
A serious AE is any untoward medical occurrence that at any dose: 
- 
Results in death. 
- 
If life threatening at the time of the event. 
- 
Requires inpatient hospitalisation 
- 
Requires prolongation of existing hospitalisation. 
- 
Results in persistent or significant disability/incapacity. 
- 
Is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization, but may 
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outcomes listed in the definition above. These also should usually be considered 
serious. 
 
Also serious events which could be associated with the study procedures (rather than 
with the study medication) will be reported as SAEs, even if occurring outside the 
treatment period.  
 
Under this protocol, the following events will not be considered as an SAE and should 
not be entered on the SAE form: 
 
Elective hospital admission 
Pre-planned hospitalizations for diagnostic, therapeutic, or surgical procedures for a 
pre-existing condition that did not worsen during the course of a clinical study.  These 
pre-planned hospitalizations and the underlying conditions must be entered on the 
medical history form. 
 
12.6 
REPORTING OF SAEs, SUSARs and DSUR 
The reporting by the Investigator to the Sponsor shall cover all SAEs (whether or not 
considered as related to the study treatment), including their intensity and cause. The 
initial report should be sent within 24 h after becoming aware of the occurrence of 
the event, using a Serious Adverse Event Report Form. The SAE report forms must be 
sent via e-mail to the Sponsor (see contact details below). If additional information is 
required, a follow-up report should be sent as soon as possible within another 4 days. 
 
Sponsor: Barbro Hedin Skogman 
E-mail:barbro.hedinskogman@ltdalarna.se 
  
If the initial SAE report is incomplete it should as far as possible be supplemented by 
detailed information on diagnosis/symptoms, the relationship with the start of 
treatment and the latest dose taken and any further relevant data.  
 
The Investigator should also inform the Sponsor about other safety problems such 
as: 
- 
Increased incidence and/or severity of AEs possibly or probably related to the 
study medication  
 
If a participant discontinued the study because of an in-treatment SAE, this should be 
noted: 
- 
On the SAE form by marking “dosing stopped” under “action taken” 
- 
On the last visit CRF by marking “(serious) adverse event” as the reason for 
discontinuation 
 

  
 
 
 
 
 
 
 
 
 
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Suspected, Unexpected Serious Adverse Reactions (SUSARs) that are fatal or life 
threatening shall be reported to the MPA and the ERB as soon as possible and at the 
latest within 7 calendar days from the first knowledge by the Sponsor. The report 
shall as far as possible be supplemented by additional information, but at the latest 
within a further 8 calendar days. It is the responsibility by the sponsor to report 
SUSAR to the MPA and ERB.  
 
The reporting of other SUSARs to the MPA ad ERB shall be done as soon as possible, 
but not later than 15 calendar days after the first knowledge by the sponsor.  
 
CIOMS forms will be used for submission to MPA, who will be responsible for the 
electronic reporting into EudraVigilance. 
 
Sponsor should once a year during the study report safety issues including SAEs to 
the MPA and ERB by a Development Safety Update Report (DSUR). 
 
12.7 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
All (S)AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a specialist. 
 
12.8 
PROCEDURES IN CASE OF MEDICAL EMERGENCY 
The Investigator should ensure that there are procedures and expertise available at 
the study center to cope with emergencies during the study. The Coordinating 
Investigator must be informed when a code has been broken. Code envelopes will be 
distributed to the centers in conjunction with distribution of the study drug. The 
envelopes will be stored at the clinic in case codes need to be broken for safety 
reasons. 
There is also a possibility to contact the coordinating center where the complete 
code list will be stored. The persons listed have access to the code list, only one of 
them needs to be contacted: 
Barbro Hedin Skogman, MD, PhD (co-ordinating Investigator)  
Center for Clinical Research (CKF) Dalarna  
Nissers väg 3 
S-791 82 Falun, Sweden 
Telephone number: +46 (0)23 49 20 00 
Mobile: +46 (0)70 309 11 01 
E-mail: barbro.hedinskogman@ltdalarna.se 

  
 
 
 
 
 
 
 
 
 
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or 
 
 
Sofia Karlsson, MD, PhD-student (co-investigator)  
Center for Clinical Research (CKF) Dalarna 
Nissers väg 3 
S-791 82 Falun, Sweden 
Telephone number +46 (0)23 49 20 00 
Mobile: +46 (0)70 351 92 82 
E-mail address: sofia.a.karlsson@regiondalarna.se 
 
or 
 
Karin Björling (administrative staff) 
Center for Clinical Research (CKF) Dalarna 
Nissers väg 3 
S-791 82 Falun, Sweden 
Telephone number: +46 (0)72 083 59 21 
E-mail: karin.bjorling@regiondalarna.se 
 
or 
 
Isabell Boväng Östman (administrative staff) 
Center for Clinical Research (CKF) Dalarna 
Nissers väg 3 
S-791 82 Falun, Sweden 
Telephone number: +46 (0)72-083 38 35 
E-mail: isabell.bovangostman@regiondalarna.se 
 
At least one of these persons will always be available during the whole study period.  
 
12.9 
LABORATORY ASSESSMENTS 
Safety laboratory assessments (white and red blood cells, CRP, electrolytes and 
glucose) will be performed at admission according to clinical practice. However, no 
laboratory data will be collected in the study. 
 

  
 
 
 
 
 
 
 
 
 
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13 
STATISTICS AND DATA MANAGEMENT 
13.1 
DATA MANAGEMENT 
All data collected in this study will be recorded in CRFs. Data will be entered by the 
Investigators and/or their delegated staff. Data captured via the CRF will be entered 
into a database at Center for Clinical Research Dalarna. A copy of each CRF will be 
retained at the study centre for at least 10 years following completion of the study 
depending on the applicable regulations. 
 
Prior to the start of the clinical study the Investigator will complete a Signature and 
Delegation Log showing the names of persons who are authorized to enter or change 
data in the CRFs.  
 
Signing end of the study is considered to be the final authorization of the CRF; it must 
be signed and dated by one of the Investigators. The signature is a guarantee that 
(s)he has reviewed the CRF and certifies them to be complete and accurate. 
 
Monitoring by a Sponsor’s representative will be performed to ensure the safety of 
the human subjects, the quality of data, its scientific integrity and compliance with the 
applicable guidelines and regulations. Both representatives of the Sponsor and 
relevant authorities must have access to all study data and documents at the clinic at 
any time. 
 
The Sponsor will not collect data of subjects who are not randomised into the study  
(i.e. screening failures). All subjects asked to participate will be listed on a screening 
list, which will be filed in the Investigator Study File, and if a subject is not randomized, 
the reason for that has to be registered on the list. A copy of the screening list will be 
collected by the Sponsor. 
 
Children not being eligible for enrolment will be registered on the screening list for 
gender, age and reason for exclusion. 
 
13.2 
STATISTICAL ANALYSIS 
The statistical methods will be described in detail in a statistical analysis plan (SAP) 
that will be finalized and approved before data base lock is performed. Statistical 
testing may be undertaken for hypothesis generating purposes, using two-sided tests 
and 5% alpha level, unless otherwise stated. 
 
Data will be presented by treatment group (prednisolone/placebo). Graphical 
methods may be used wherever it is regarded as appropriate. 
 
The last pre-administration observation will be used as the baseline value for 
calculating post-administration changes from baseline. All data obtained on the CRF 

  
 
 
 
 
 
 
 
 
 
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and entered into the database will be provided in separate data listings showing 
individual subject values. Tabulations of summary statistics, graphical presentations, 
and listings will be performed by the UCR statistician. All statistical calculations will be 
performed using SAS® version 9.4 or later (SAS Institute Inc., Cary, NC, USA) or SPSS 
statistics, version 21 (IBM Corporation, USA). 
 
Intention-to-treat will be applied when analyzing results from the primary outcome. 
Comparisons between groups for dichotomous endpoints (recovery/no recovery) 
will be performed using Fisher’s exact test and for categorical endpoints (scale) using 
Mann-Whitney U-test. For correlations between scales, Pearson’s correlation test, or 
Cohen's kappa if appropriate, will be used. When predicting recovery at 1 month to 
12 months, diagnostic performance will be calculated on recovery defined as House-
Brackmann grade 1. Analysis of early predictors will be performed to understand 
variance of subgroups. Furthermore, logistic regression analysis will be used to 
evaluate recovery in relation to baseline data. 
 
Study patients that have been screened but not received any study medication, will 
be considered as screen failures and will not be included in the study database. 
 
 
13.3 
DETERMINATION OF SAMPLE SIZE 
 
Power for the FACE study is calculated on the primary end-point (number of patients 
with total recovery from the facial nerve palsy in each intervention group, measured 
by House-Brackmann grade 1 at 12 months follow-up). A difference of 10% of the 
total recovery rate between groups (90% versus 80%) is estimated from earlier non-
RCT treatment studies (3, 15) and used for calculations of sample size.  A p-value less 
than 0.05, a power of 0.80 and a calculated portion of patients not taking part of the 
study follow-up is included in the analysis.  
A sample size of 500 patients need to be included in the FACE study according to this 
power analysis. No minimum number of included patients at one single site is 
determined. 
 
14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigators/institutions will permit study-related monitoring, audits, review 
and regulatory inspections, providing access to source data/hospital records. 
Sponsor verifies that each patient has consented in writing to direct access to the 
original source data/hospital records by the use of written patient information and 
signed Informed Consent.  

  
 
 
 
 
 
 
 
 
 
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15 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
SOURCE DATA 
The following minimum amount of information should be recorded in the hospital 
records: 
 
Study  
 Study title 
 Aim of the study 
 Randomization number 
 Subject identification 
 Date when signed Informed Consent was obtained 
 Diagnosis 
 Fulfillment of eligibility criteria 
 Visit dates 
 Concomitant medications 
 Any AEs 
 Specification of the subject’s cessation in the study 
 Specification of the subject’s outcome in the study 
 Specification of study treatment (after code break at study end) 
 
Gradings by House-Brackmann and Sunnybrook, as well as information about Facial 
Clinimetric Evaluation Scale, Facial Disability Index and Synkinesis Assessment 
Questionnaire will be reported directly in the CRF as source data. 
 
15.2 
MONITORING 
 
In accordance with the principles of Good Clinical Practice (GCP), monitoring of the 
study will be arranged by the Sponsor. During the study, the Monitor will have 
regular contacts with the study centers, including visits to ensure that the study is 
conducted and documented properly in compliance with the protocol, GCP and 
applicable regulatory requirements.  
The study nurse will that ensure that accountability of study medication is performed 
and documented in an accountability log. The monitor will review source documents 
for verification of consistency with the data recorded in the CRFs. The Monitor will 

  
 
 
 
 
 
 
 
 
 
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also provide information and support to the Investigator(s). The monitoring work is 
described in a monitoring plan. 
 
The study center may also be subject to quality assurance audit by the Sponsor as 
well as inspection by the MPA. The Investigator and other responsible personnel 
must be available during the monitoring visits, audits and inspections and should 
devote sufficient time to these processes.  
The Investigator and study staff should provide a curriculum vitae (CV) or equivalent 
documentation of suitability to be responsible for the study. All Investigators and 
other responsible personnel should be listed together with their function in the 
study on the signature and delegation list.  
 
15.3 
DATA SAFETY MONITORING BOARD 
An independent data safety monitoring board (DSMB) will be engaged, including 2-3 
members. These member(s) will be chosen from having appropriate scientific 
knowledge in the field.  
 
The DSMB will evaluate safety data after the first 50 patients have completed the 
study. The next safety evaluations will occur when 200 and 400 patients have been 
included. There is always a possibility to have more safety evaluations if found 
needed. A DSMB charter will be written for the members to outline the working 
procedures and their duties. 
 
16 
ETHICS REVIEW BOARD 
It is the responsibility of the Sponsor to obtain approval of the study 
protocol/protocol amendments, the patient information and the Informed Consent 
from the ERB before enrolment of any subject into the study.  
The study medication will not be delivered to the study centers until approval from 
the ERB has been obtained.  
The Sponsor shall report all SUSARs also to the ERB, unless otherwise agreed. If a study 
stops prematurely at a study center for any reason, the ERB must be informed. At the 
end of the study, the Sponsor should notify the ERB. The Sponsor should file all 
correspondence with the ERB.  
 

  
 
 
 
 
 
 
 
 
 
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16.1 
ETHICAL CONDUCT OF THE STUDY 
 
The study will be conducted in accordance with the protocol, applicable regulatory 
requirements, GCP and the ethical principles of the Declaration of Helsinki as 
adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964 and 
subsequent versions (Appendix 23.1). 
 
16.2 
RISK - BENEFITS  
A risk analysis for this study has been made. These risks together with the actions to 
minimize these risks are compiled below: 
 
 Anticipated risk 
Action 
1 Side effects such as minor behavior 
problems (mood changes), sleep 
disturbances, nausea or vomiting  
Reported as Adverse Events and follow 
up until recovered. A Development 
Safety Update Report (DSUR) will be 
presented yearly to MPA 
2 Trauma for the child to take medicine 
Capsules may be opened and the 
content can be mixed with something 
tasty. The study nurse will instruct the 
parents/guardians when study 
medication is distributed and will also 
follow up how it works by telephone 
calls one and two weeks after Baseline 
3 No effect on the recovery rate 
There is no alternative treatment, why 
there is no risk that the patient looses 
an effective treatment by participating 
in the study 
 
  
A short-course oral treatment with corticosteroids (defined as 1-2 mg/kg once daily 
in 7-14 days) is not associated with major side effects, such as risk of growth 
retardation, osteoporosis or diabetes mellitus in children, but may be associated 
with minor side effects, such as behavioral problems (mood changes), sleeping 
disturbances, nauseas or vomiting in 4,3 – 5,4 % of cases (17,25,26). 
 
The risk of minor side effects will be reduced with the dose 1 mg/kg x 1 (17), as we 
plan on using in the present study.  

  
 
 
 
 
 
 
 
 
 
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Increased susceptibility to infection (<1%) is the most frequent (S)AEs associated 
with short courses of corticosteroids (25,26). In five large RCTs on short-course 
corticosteroid treatment, three children with varicella infection needed intensive 
care due to complications (25).  
 
Parents/guardians will be informed before start of treatment in the current study 
about the importance to attend health care if fever or signs of infection occur during 
the study period.      
 
In summary, the benefits, i.e. possibly improved recovery of the facial nerve palsy 
are anticipated being higher than the risks.  
 
16.3 
PATIENT INFORMATION AND INFORMED CONSENT 
It is the responsibility of the Investigator to provide each participant with full and 
adequate verbal and written information about the objectives, procedures and 
possible risks and benefits of the study. All participant will be given the opportunity 
to ask questions about the study and will be given sufficient time to decide whether 
or not to participate in the study. All information about the study will be age-
adjusted in order to obtain good adherence for both younger and older children and 
adolescents. 
The written patient information must not be changed without being approved by the 
Ethics Review Board. 
The participant will be notified of their voluntary participation and of their freedom 
to withdraw from the study at any time and without giving any particular reason. 
participant must also be informed that withdrawing from the study will not affect 
their future medical care, treatment or benefits to which the participant is otherwise 
entitled.  
Parents/guardians will sign the informed consent for children 1-17 years of age. 
The Investigator is responsible for obtaining written Informed Consent from all 
parents/guardians prior to enrolment in the study. If only one parent/guardian is 
present at the visit, the other parent/guardian will be contacted by telephone, 
informed about the study, given the chance to ask questions and sent an ICF by e-
mail. The signed ICF will then be sent back by e-mail, or as a photocopy on the 
mobile phone, to the Investigator and saved in the Investigator’s file until the 
original ICF is returned. 
 

  
 
 
 
 
 
 
 
 
 
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The parents/guardians will consent to: 
- 
Participating in the study. 
- 
Personnel from the sponsor or the regulatory authorities to gain full access to 
hospital records to check the quality of data collected in the study.  
- 
Recording, collection and processing of data and storing of data in a database. 
- 
Possible transfer of information from the study to countries outside the 
European Union (EU).  
 
It should be clearly stated that the data will not identify any participant taking part in 
the study, in accordance with the European General Data Protection Regulation 
(GDPR) (2016/679/EU). 
A copy of the patient information and the ICF will be given to the parents/guardians. 
The Investigator (or a co-Investigator) who gave the verbal and written information 
to the participant will sign the ICF. The Investigator will file the signed ICFs in the 
Investigator’s File.  
 
17 
DATA HANDLING AND RECORD KEEPING 
 
17.1 
CASE REPORT FORMS 
CRFs are required and should be completed for each included participant. The child’s 
identity must always remain confidential.  
 
Paper CRFs will be used and study data will be entered in a database at the Sponsor 
(Center for Clinical Research Dalarna). The completed study database is the sole 
property of the Sponsor and will not be made available in any form to third parties 
(except for authorized representatives of appropriate regulatory authorities) without 
written permission from the Sponsor.  
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility 
and timeliness of the data recorded in the CRF. Corrections to the CRF must be 
signed by the Investigator or a designated representative.  
 
17.2 
RECORD KEEPING 
To enable audits and inspections by regulatory authorities, the Investigators will 
keep records (essential documents) of the study for at least 10 years. This includes 
any original source data related to the study, the subjects identification list (with 
subject numbers, full names and personal numbers), the original signed ICFs, copies 
of all CRFs and detailed records of study medication disposition.  

  
 
 
 
 
 
 
 
 
 
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The Sponsor is also, as per GCP-requirements, responsible for archiving their part of 
the study documentation. 
 
18 
INSURANCE 
Patients participating in this study are covered by the Swedish Patient Insurance 
(Patientskadeförsäkringen LÖF-Landstingens Ömsesidiga Försäkringsbolag) and the 
Swedish Pharmaceutical Insurance (Läkemedelsförsäkringen). 
 
19 
PUBLICATION POLICY 
All information not previously published concerning the clinical study is considered 
as confidential and will remain the sole property of the Sponsor. The Investigator 
agrees to use this information only in connection with this study and will not use it 
for other purposes without written permission from the Sponsor.  
After completion of the study, the statistical analyses will be performed and the 
results will be presented to the Investigators. Based on these data, the Sponsor, in 
cooperation with the Investigators, will prepare a clinical study report. The report 
will be submitted to the MPA and may form the basis for a manuscript intended for 
publication in a medical/scientific journal.  
 
20 
SUPPLEMENTS 
20.1 
CHANGES OF THE STUDY PROTOCOL 
No change in the study procedures will be effected without the mutual agreement of 
the Investigators and the Sponsor (except where necessary to eliminate an 
immediate hazard to subjects). All changes of the final study protocol must be 
documented by signed protocol amendments. If substantial changes to the design of 
the study are made, the MPA and the ERB will be notified for review and approval.  
 
20.2 
APPLICATION TO REGULATORY AUTHORITIES 
Prior to initiating the clinical study, the Sponsor will submit an application for 
authorization to conduct the study, including all required documents, to the MPA. 
Additional documentation may be demanded for investigational products with 
special characteristics. 

  
 
 
 
 
 
 
 
 
 
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One complete application will be submitted. For each planned study center, the 
address and the name and position of the Investigator will be indicated on the 
application.  
20.3 
STAFF INFORMATION 
It is the responsibility of the Investigator to ensure that all personnel involved in the 
study are fully informed of all relevant aspects of the study, including detailed 
knowledge of and training in all procedures to be followed.  
20.4 
CRITERIA FOR TERMINATION OF THE STUDY 
The Sponsor reserves the right to discontinue the study prior to inclusion of the 
intended number of subjects, but intends to exercise this right only for valid 
scientific or administrative reasons. After such a decision, all delivered unused 
investigational products and other study-related materials must be collected and all 
CRFs must be completed as far as possible. 
The study can be prematurely discontinued in the following cases (examples): 
- 
Unexpectedly high proportion of adverse events, possibly or probably related to 
the study medication. 
- 
New findings about the investigational product(s) that changes the benefit/risk 
ratio. 
- 
Study protocol is difficult to cope with. 
- 
Recruitment of eligible subjects is far too low. 
- 
Problems with manufacturing or stability of the investigational product(s). 
- 
Unacceptable low Investigator, Sponsor or subject compliance. 
- 
Critical change in personnel, administrative or scientific standards at the Sponsor 
or at the study centers. 
- 
No significant result will be obtained as anticipated. 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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21 
REFERENCES  
1. Tveitnes D, Oymar K, Natas O. Acute facial nerve palsy in children: how often 
is it lyme borreliosis? Scand J Infect Dis. 2007;39(5):425-31. 
2. Christen HJ, Hanfeld F, Eiffert H, Thomssen R. Epidemiology and clinical 
manifestations of Lyme borrelios in childhood, Acta Paediatr Suppl; 2003; 
386, 1-76. 
3. Peltomaa M, Saxen H, Seppala I, Viljanen M, Pyykko I, Paediatric facial palsy 
caused by Lyme borrelios: aa prospective and retrospective analysis, Scand J 
Ing Dis; 1998; 30; 269-275.  
4. Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schutzhard E, Steiner I. EFNS 
guidelines on the diagnosis and management of European Lyme 
neuroborriosis. Eur J Neurol; 2010; 17 (1): 8-16.  
5. Läkemedelsverket. Läkemedelsbehandling av Borreliainfektion - ny 
rekommendation. 2009 [updated 2013-12-03; cited 2016-05-24]. 
6. Skogman BH, Croner S, Odkvist L. Acute facial palsy in children--a 2-year 
follow-up study with focus on Lyme neuroborreliosis. Int J Pediatr 
Otorhinolaryngol. 2003;67(6):597-602. 
7. Skogman BH, Glimaker K, Nordwall M, Vrethem M, Odkvist L, Forsberg P. 
Long-term clinical outcome after Lyme neuroborreliosis in childhood. 
Pediatrics. 2012;130(2):262-9. 
8. Bagger-Sjoback D, Remahl S, Ericsson M. Long-term outcome of facial palsy in 
neuroborreliosis. Otol Neurotol. 2005;26(4):790-5. 
9. Engstrom M, Berg T, Stjernquist-Desatnik A, Axelsson S, Pitkaranta A, 
Hultcrantz M, et al. Prednisolone and valaciclovir in Bell's palsy: a 
randomised, double-blind, placebo-controlled, multicentre trial. Lancet 
Neurol. 2008;7(11):993-1000. 
10. Sullivan FM, Swan IR, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al. 
Early treatment with prednisolone or acyclovir in Bell's palsy. N Engl J Med. 
2007;357(16):1598-607. 
11. Salman MS, MacGregor DL. Should children with Bell's palsy be treated with 
corticosteroids? A systematic review. Journal of child neurology. 
2001;16(8):565-8. 
12. Dhiravibulya K. Outcome of Bell's palsy in children. Journal of the Medical 
Association of Thailand = Chotmaihet thangphaet. 2002;85(3):334-9. 
13. Pitaro J, Waissbluth S, Daniel SJ. Do children with Bell's palsy benefit from 
steroid treatment? A systematic review. Int J Pediatr Otorhinolaryngol. 
2012;76(7):921-6. 
14. Shih WH, Tseng FY, Yeh TH, Hsu CJ, Chen YS. Outcomes of facial palsy in 
children. Acta Otolaryngol. 2009;129(8):915-20. 
15. Prescott CA. Idiopathic facial nerve palsy in children and the effect of 
treatment with steroids. Int J Pediatr Otorhinolaryngol. 1987;13(3):257-64. 

  
 
 
 
 
 
 
 
 
 
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16. Unuvar E, Oguz F, Sidal M, Kilic A. Corticosteroid treatment of childhood Bell's 
palsy. Pediatr Neurol. 1999;21(5):814-6. 
17. Arican P, Dundar NO, Gencpinar P, Cavusoglu D. Efficacy of Low-Dose 
Corticosteroid Therapy Versus High-Dose Corticosteroid Therapy in Bell's 
Palsy in Children. Journal of child neurology. 2017;32(1):72-5. 
18. Babl FE, Mackay MT, Borland ML, Herd DW, Kochar A, Hort J, et al. Bell's Palsy 
in Children (BellPIC): protocol for a multicentre, placebo-controlled 
randomized trial. BMC Pediatr. 2017;17(1):53. 
19. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head 
Neck Surg. 1985;93(2):146-7. 
20. Berg T, Jonsson L, Engstrom M. Agreement between the Sunnybrook, House-
Brackmann, and Yanagihara facial nerve grading systems in Bell's palsy. Otol 
Neurotol. 2004;25(6):1020-6. 
21. Marsk E, Bylund N, Jonsson L, Hammarstedt L, Engstrom M, Hadziosmanovic 
N, et al. Prediction of nonrecovery in Bell's palsy using Sunnybrook grading. 
The Laryngoscope. 2012;122(4):901-6. 
22. Marsk E, Hammarstedt-Nordenvall L, Engstrom M, Jonsson L, Hultcrantz M. 
Validation of a Swedish version of the Facial Disability Index (FDI) and the 
Facial Clinimetric Evaluation (FaCE)scale.Acta Otolaryngol. 2013;133(6):662-9. 
23. Mehta RP, Mackay MT, Borland ML, Hers DW, Kochar A et al. Validation of 
the synkinesis assessmen questionnaire. Laryngoscope. 2007; 117(5):923-6. 
24. Skogman, B.H., J. Sjowall, and P.E. Lindgren: The NeBoP score - a clinical 
prediction test for evaluation of children with Lyme Neuroborreliosis in 
Europe. BMC Pediatr, 2015. 15: p. 214 
25. Aljebab F et al. Systemic review of the toxicity of short-course oral 
corticosteroids in children. Arch Dis Child. 2016; 0:1-6. 
26. Liu D et al. A practical guide to the monitoring and management of the 
complications of systemic corticosteroid therapy. Allergy & Clinical 
Immunology. 2013;9:1-25                                                                                    
27. Lurbe E et al. European Society of Hypertension guidelines for the 
management of high blood pressure in children and adolescents. Journal of 
Hypertension. 2016. 34 (10): 1887-1920 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
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22 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
To be signed per study centre.  
 
 
EudraCT number: 2017-004187-35 
 
Title of the study: 
The Facial nerve palsy And Cortisone Evaluation (FACE) study in children:               
A randomized double-blind, placebo-controlled, multicenter trial 
 
 
 
I, the undersigned, have read and understand the protocol specified above and agree on 
the contents. The study protocol, the Clinical Study Agreement and the additional 
information given about the study medication will serve as a basis for co-operation in 
this study.  
I agree to conduct the study according to this protocol and according to the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent 
with Good Clinical Practice and the applicable national laws and regulations. 
 
PRINCIPAL INVESTIGATOR  
 
Principal Investigator 
 
Address to participating clinic 
Signature and date:  
_______________________________________ 
 
 
 

  
 
 
 
 
 
 
 
 
 
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23 
APPENDICES 
 
23.1 
DECLARATION OF HELSINKI 
23.2 
RATING SCALES OR DIARIES FOR ASSESSMENT OF EFFICACY 
OR SAFETY 
23.3 
LABELING OF INVESTIGATIONAL PRODUCTS