Burden of Herpes Zoster and Post-herpetic Neuralgia Among People ≥ 50 Years Old in France: the POSTHER Study
Conditions: Herpes Zoster
Sponsor: GlaxoSmithKline

 
 
   
  
  
  
  
  
  
  
  
  
  
  
 
  
POSTHER  
Burden of herpes zoster and postherpetic neuralgia  
among people ≥ 50 years old in France  
  
EPI-ZOSTER-020 BOD FR (201926)  
 
  
  
  
Protocol V2 
17 October 2014  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
 
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Nukléus  
55 rue Bobillot – 751013 Paris  
 
Tél :    PPD 
- Fax : PPD 
 – PPD 
POSTHER protocol / GSK EPI-ZOSTER-020 BOD FR (201926)   
  
Version 2, 17th October 2014  
  
TABLE OF CONTENTS  
 
Table of contents  
2
 
    
 
List of abbreviations  
3
 
    
 
Key personnel  
4
 
    
 
Signature  
5
 
    
 
Synopsis  
6
 
    
 
Amendments and update  
10
 
    
1 
Rational and background  11 
    
2 
Objectives  
12 
    
2.1 
Primary objective  
12 
    
2.2 
Secondary objectives  
12 
    
3 
Endpoints  
12 
    
4 
Study design  
12 
   5 
    
Study population  14 
    
5.1 
Physicians  
14 
    
5.2 
Patients  
14 
    
5.2.1 
    
HZ cohort inclusion and exclusion criteria  
14 
   5.2.2 
    
PHN cohort inclusion and 
exclusion criterion  
15 
    
6 
Data collection  15 
    
6.1 
Signed patient agreement  
15 
    
6.2 
HZ cohort  
15 
    
6.3 
Patient self-administered questionnaire at inclusion  16 
    
6.4 
Patient phone interview during the follow-up:  
16 
    
7 
Study size  
16 
    
7.1 
Patient sample size  
16 
    
7.2 
Physician sample size  
17 
    
8 
Data-management  
17 
   9 
    Data analysis  
17 
    
9.1 
Study population  
18 
    
9.2 
Physicians  
18 
    
9.3 
Patients included  
18 
    

 
 
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9.4 
Outcome  
18 
    
9.5 
Statistical methods  
18 
    
10 
Quality control  19 
    
11 
Limitations of the research methods  
19 
    
12 
Protection of human subjects  
19 
   12.1.1     Ethic Committee (CPP)  
19 
    
12.1.2 
    
National Council of Physicians (CNOM)  
19 
   12.1.3     
Data privacy (CNIL) 
 
20 
    
13 
Management and reporting of adverse events/adverse reactions  
20 
    
14 
Plan for disseminating and communicating study results  
20 
    
15 
References  
20 
    
  
  
POSTHER protocol / GSK EPI-ZOSTER-020 BOD FR (201926)  
 
  
  
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LIST OF ABBREVIATIONS  
CNIL  
French data privacy council (Commission Nationale de l’Informatique et des 
Libertés)  
CNOM  
National Council of Physicians (Conseil National de l’Ordre des Médecins)  
CCP  
French ethic committee (Comité de Protection des Personnes)  
DMP  
Data Management Plan  
DRESS  
Department for Evaluation and statistics of the French Health Ministry
(Direction de la Recherche, des Etudes, de l'Evaluation et des Statistiques)  
EQ-5D 5L  
Health-related quality of life questionnaire  
GPS  
General Practitioners  
HZ  
Herpes Zoster  
PHN  
PostHerpetic Neuralgia  
SAP  
Statistical Analysis Plan  
VHZ  
Varicella Zoster Virus  
ZBPI  
Zoster Brief Pain Inventory (ZBPI)  
  
  
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KEY PERSONNEL  
 
PPD 
  
 
 
Pharmacoepidemiologist consultant   
Département de Pharmacologie  
 
  
Université de Bordeaux  
33000 Bordeaux  
 
  
SPONSOR  
GlaxoSmithKline (GSK)  
100 route de Versailles  
78163 Marly-le-Roi Cedex  
Director of Pharmacoepidemiologyand Health    
 
EPI & HO project leader  
   
PPD 
   
PPD 
  
SCIENTIFIC BOARD  
 
  
Hôpital de la Croix Rousse  
PPD 
PPD 
PPD 
PPD 
C OORDINATING CENTRE  
Nukl é us  
  
rue Bobillot  
55 
– 751013 Paris  
  
   
Fax  
  
  
Director  
  
  
  
  
   
Project Manager  
  
  
  
  
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
Outcome  unit  
 
  
PPD 
PPD 

 
 
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Infectiologist  
Service des Maladies Infectieuses  
103 Grand Rue de la Croix Rousse 
69004 LYON  
 
 
  
ESSEC  
 
Health Economist  Avenue Bernard Hirsch  
95021 CERGY PONTOISE Cedex  
 
  
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SIGNATURE  
  
  
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
 
PPD 
  
PPD 

 
 
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PPD 

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SYNOPSIS  
  
 
TITLE Burden of herpes zoster and postherpetic neuralgia among people ≥ 50 years old in France: 
the POSTHER Study  
 
RATIONAL AND  
Herpes zoster (HZ) is a painful disease resulting from the reactivation of the  
BACKGROUND  
latent varicella zoster virus from dorsal root or cranial nerve ganglia. The  
annual incidence of HZ was estimated to 3.8‰ in France with a linear increase 
with age, and a lifetime risk of HZ to 26.5%.  
Some people develop complications after an initial acute episode of HZ, such 
as encephalitis, peripheral nerve palsies, myelitis, herpes ophthalmicus and 
postherpetic neuralgia (PHN), the most frequent complication. PHN remains 
long after the HZ lesions have healed, and often persists for months or years. 
PHN was estimated to occur in 8% to 32% of people with HZ.  
The burden of HZ and PHN is not well characterized in France. A prospective 
cohort of incident cases of HZ, diagnosed by community first line practitioners 
concerned by HZ diagnosis, represents a suitable approach to describe the 
burden of herpes zoster and postherpetic neuralgia among people ≥ 50 years old 
in France.  
RESEARCH 
QUESTIONS AND 
OBJECTIVES  
Research question: To assess the burden of HZ and PHN among people ≥ 50 
years old in France, in terms of healthcare resources used, medical direct and 
indirect costs, as well as pain severity and impact on quality of life.  
Primary objective  
• To evaluate HZ-related and PHN-related direct medical costs and indirect 
costs during a 9-month period (overall, by gender and age-classes).  
Secondary objectives  
• To describe HZ and PHN pain severity during a 9-month period (overall, by 
gender and age-classes),  
• To evaluate impact of HZ and PHN on the quality of life of patients during a 
9-month period (overall, by gender and age-classes).  

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STUDY DESIGN  An observational, prospective cohort study of patients ≥ 50 years old with a HZ 
diagnosis, carried out by a national random sample of community first line 
practitioners concerned by HZ diagnosis: general practitioners (GPs), 
dermatologists and ophthalmologists.   
Inclusion   
• HZ cohort: All patients ≥ 50 years old with a HZ diagnosis (as the primary 
diagnosis and without history of previous HZ) during approximately 6 
months inclusion period will be included in the HZ cohort, until total study 
target is achieved (competitive inclusion),  
• PHN cohort: All patients of the HZ cohort presenting PHN (defined as ZBPI 
pain ≥3) 3 months after HZ rash onset symptoms will be included 
secondarily in the PHN cohort.  
Follow-up  
 
• HZ cohort: Patients of the HZ cohort will be followed-up for 3 months using 
phone interviews with a nurse 1 and 3 months after HZ rash onset (M1 ± 3 
days, M3 ± 1 week).   
• PHN cohort: Patients of the PHN cohort will be followed-up for another 6 
months using phone interviews with a nurse 6 and 9 months after HZ rash 
onset (M6 ± 1 week, M9 ± 1 week).  
The overall design of the study is presented in the following figure:  
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Inclusion   
(6 months)  
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M1  
M3  
M6  
M9  
M0  

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POPULATION  
Study carried out by a random sample of community first line practitioners 
concerned by HZ diagnosis: GPs, dermatologists and ophthalmologists.  
HZ cohort inclusion-exclusion criteria   
• Patient with a first visit for a diagnosis of HZ and who attend the clinic within 
two week of the HZ start of symptoms (defined as unilateral pain 
accompanied by a unilateral rash without alternative diagnosis),  
• Patient ≥ 50 years old without history of previous HZ,  
• Patient who agree to participate and signed informed consent,   
• Patient able to understand the study, to complete self-administered 
questionnaires (alone or with the help of a relative) and to answer to phone 
interviews.  
PHN cohort inclusion-exclusion criterion   
• Patient of the HZ cohort presenting PHN 3 months after onset of the HZ rash 
onset (defined as the presence of HZ-associated severe “worst” pain: pain ≥ 
3 from ZBPI item “worst pain”)  
VARIABLES  
Index date: date of HZ rash onset.  
PHN: “worst pain” item ≥ 3 from the Zoster Brief Pain Inventory (ZBPI) 
questionnaire ≥ 3 months after index date.  
Outcomes:  
• Direct medical cost: medical visits, emergency room (≤ 24h), hospitalisation 
(≥ 24h), drugs prescribed, procedures performed or  
 
prescribed in relation with HZ or PHN.  
• Indirect cost: patient sick leave.  
• HZ and PHN severity: three categories for last 24h worst pain from ZBPI 
questionnaire: mild pain (0<pain<3), moderate pain (3 ≤ pain < 7) and 
severe pain (7 ≤ pain).  
• Quality of life and utilities: EQ-5D 5L heath state.  
Patients’ and disease characteristics at inclusion.  

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DATA  
COLLECTION  
Inclusion  
From participating physicians   
 Inclusion-exclusion criteria,  
 Date of visit,  
 Patient’s characteristics (gender, date of birth, current occupational status),   
 HZ characteristics (date of rash onset, prodromal symptoms, rash 
localization, complications, contributing factors, immunosuppressant drugs), 
 Drugs used and prescribed for HZ with dosage and duration,  
 Sick leave prescription and duration,  
 Patient referred to a specialist or hospital and reason(s).  
Signed patient informed consent with contact details to send booklets and to 
realize phone interviews.  
Patient self-administered questionnaire at inclusion 
 ZBPI questionnaire,  EQ-5D 5L health state.  
Follow-up  
Patient phone interview at: M1, M3, M6 in case of PHN declared at M3 and 
M9 in case of PHN declared at M6.   
Phone interview will be realized with the help of a patient booklet given to 
the patient to report week by week HZ and PHN-related healthcare resources 
used during the past three months (between M1 and M3, M3 and M6, M6 and M9):  
 Date of the interview , or reason if it can’t be done,  
 Drug used with dosage and number of boxes,  
 Sick leave prescription and duration,  
 Number of GP visits, specialist visits, emergency room (≤ 24h) and reasons, 
 Hospitalization (≥ 24h), reason and duration.  ZBPI questionnaire,  
 EQ-5D 5L health state.  
STUDY SIZE  
• 250 cases of HZ and 40 cases of PHN expected (hypothesis of 16% of PHN 
at M3).  
• Approximately 170 GPs, 20 dermatologists and 20 ophthalmologists with the 
hypotheses of a mean of 1 patient ≥ 50 years old with HZ diagnosis per GPs 
and 2 per specialist over a 6-month inclusion period.  
• Assuming 2/3 of active participation, approximately 210 GPs, 30 
dermatologists and 30 ophthalmologists will be recruited.  
STATISTICAL 
ANALYSIS  
• Flowchart of physician recruitment and cohort inclusion (HZ and PHN). • 
Primary objective: description of healthcare resources used with  

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valorisation to estimate direct medical and indirect cost per episode (overall, 
by gender and age-classes) from a payer and societal perspective:  
 For the HZ cohort during the study period (M0, M1 and M3);  
 For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
• HZ and PHN severity: Description using ZBPI questionnaire with three 
categories for last 24h worst pain: mild pain (0<pain<3), moderate pain (3 ≤ 
pain < 7) and severe pain (7 ≤ pain).  
 For the HZ cohort during the study period (M0, M1 and M3);  
 For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
• Quality of life and utilities: description of EQ-5D 5L and associated utility 
score:  
 For the HZ cohort during the study period (M0, M1 and M3);  
 For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
• The EQ-5D 5L health state will be used to estimate utility and to estimate 
loss in quality of life associated with HZ and PHN. The EQ-5D 5L will be 
converted into a single summary index showing the utility function over time. 
The comparison of these utility scores with existing reference value set 
derived for EQ-5D in France will provide the average loss in quality of life 
(so-called QALY weights) associated with HZ and PHN.  
• Statistical correlations between HZ and PHN severity (three categories 
defined above) and cost on the one hand and severity and utility scores on 
the other hand will be derived.  
• Description of the patients’ and disease characteristics at inclusion.  
PROJECTED 
MILESTONES  
Protocol and CRF  
Administrative phase  
Oct. 2014 
Oct. 2014 – Feb 2015 
Physician recruitment  
Mar-Apr 2015 
Inclusion period (6 months)  
Apr-Sept 2015 
End of follow-up (9 months)  
Jun 2016 
Data management and analysis   
Jul 2016-Sept 2016 
Scientific Board  
Oct 2016 
First Version of study report   
Nov 2016 
  
  
AMENDMENTS AND UPDATE  
Number  
Date  
Section of 
study protocol  
Amendment or 
update  
Reason  
  
  
  
  
  

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1  RATIONAL AND BACKGROUND  
Herpes zoster (HZ) is a painfull disease resulting from the reactivation of the varicella zoster virus 
(VHZ). Upon primary infection VHZ becomes latent in the dorsal root or cranial nerve ganglia. 
Following a variable period of latency time, VHZ can reactivate to produce an infectious virus. 
This virus can travel to the skin and re-infect it causing a vesicular rash accompanied by acute pain 
in the region of the affected dermatome (Arvin 2000, Kennedy 2002, Dworkin 2007).  
The incidence of HZ in the United States and Western Europe varies from 1.4 to 4.8 per 1 000 
person-years with 20% to 30% of people affected by HZ in their lifetime (MacDonald 2000, 
Chidiac 2001, Insing 2005, Dworkin 2007, Yawn 2007, Gonzales 2010, Mick 2010, Pinchinat 
2013). Older age and immunodeficiency states (cancer, autoimmune disease, HIV infection, 
immunosuppressive drug…) are associated with an increased risk of HZ (Pope 2004, Insinga 2005, 
Sharvadze 2006).  
In France, the General Practitioners’ (GPs) sentinel electronic surveillance network estimated the 
lifetime risk of HZ to 26.5% and the annual incidence of HZ to 3,8‰ between 2005 and 2008, 
with a linear increase with age (Gonzales 2010). In a retrospective study using medical files of a 
random sample of GPs, dermatologists, neurologists and departments of pain management the 
2005 annual incidence of HZ was estimated to 9.0‰ of patients aged 50 years and above (Mick 
2010), which is concordant with the results of older population of the GPs sentinel network study.  
Some people who experience an initial acute episode of HZ develop complications (Dworkin 
2007). These include encephalitis, peripheral nerve palsies (both rare complications), myelitis, 
herpes ophthalmicus and postherpetic neuralgia (PHN), the most frequent complication. PHN is a 
debilitating condition in which neuropathic pain remains long after the HZ lesions have healed, 
and often persists for months or years. The classic definition is chronic pain persisting 3 months 
after rash onset. As with other HZ complications, the elderly and patients with immunodeficiency 
are at a higher risk for the development of PHN (Insinga 2005).  
PHN is estimated to occur in 8% to 32% of people with HZ overall  (Di Luzio 1999, Helgason 
2000, Oxman 2005, Scott 2006, Insinga 2007, Gauthie, 2009; Mick 2010, Bouhassira 2012), 
depending on the PHN definition, time since the onset of the acute phase, age of the study 
population and probably the study methods. In the French retrospective study cited above, the 
proportion of patients aged 50 years and above presenting PHN at 3 and 6 months was 32.1% and 
17.6% respectively (Mick 2010); while a large prospective study with French GPs estimated the 
prevalence of PHN among patients aged over 50 years to 11.6%, 8.5%, 7.4% and 6.0% at 3, 6, 9 
and 12 months respectively, with higher prevalence in patients ≥ 70 years old (Bouhassira 2012).  
Several studies have shown that HZ has a negative impact on quality of life and this negative 
impact was more important for patients with PHN (Johnson 2010). In England, HZ would be 
responsible for a lost 2000 quality adjusted life years (QALYS) and 87% of it in relation with PHN 
(Insinga 2007). The cost of the disease was studied in many countries (Edmunds 2001, Kennedy 
2002, Pope 2004, Yawn 2007, White, 2009). The 2005 annual cost of HZ management and PHN 
in France was estimated to about 170 millions Euros of which 36% were covered by the national 
health insurance (Mick, 2010).  
The burden of HZ and PHN is not well characterized in France. A prospective cohort of incident 
cases of HZ, diagnosed by community first line practitioners concerned by HZ diagnosis, 

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represents a suitable approach to describe the burden of HZ and PHN among people ≥ 50 years 
old in France.  
  
  
2  OBJECTIVES  
2.1 PRIMARY OBJECTIVE  
The primary objective is to evaluate HZ-related and PHN-related direct medical costs and indirect 
costs during a 9-month period (overall, by gender and age-classes).  
2.2 SECONDARY OBJECTIVES Secondary 
objectives are:  
- To describe HZ and PHN pain severity during a 9-month period (overall, by gender and 
ageclasses),  
- To evaluate impact of HZ and PHN on the quality of life of patients during a 9-month period 
(overall, by gender and age-classes).  
   
3  ENDPOINTS  
The primary endpoint is HZ-related and PHN-related direct medical costs and indirect costs, 
estimated with the valorisation of the HZ and PHN healthcare resources used (medical visits, 
emergency room (≤ 24h), hospitalisation (≥ 24h), drugs prescribed, procedures performed or 
prescribed in relation with HZ or PHN, as well as patient sick leave).  
Secondary endpoints are:  
- HZ and PHN severity using three categories for last 24h worst pain from ZBPI questionnaire: 
mild pain (0<pain<3), moderate pain (3 ≤ pain < 7) and severe pain (7 ≤ pain). - Quality of 
life and utilities using EQ-5D 5L.  
The index date is defined as the date of HZ rash onset.  
PHN is defined as “worst pain” item ≥ 3 from the Zoster Brief Pain Inventory (ZBPI) questionnaire 
≥ 3 months after index date.   
  
4  STUDY DESIGN  
An observational, prospective cohort study of patients ≥ 50 years old with a HZ diagnosis, carried 
out by a national random sample of community first line practitioners concerned by HZ diagnosis: 
general practitioners (GPs), dermatologists and ophthalmologists.   
Inclusion  
All patients ≥ 50 years old with a HZ diagnosis (as the primary diagnoses and no earlier case of 
HZ) during approximately 6 months inclusion period will be included in the HZ cohort, until total 
study target is achieved (competitive inclusion).  
All patients of the HZ cohort presenting PHN 3 months after HZ rash onset symptoms will be 
included secondarily in the PHN cohort.  

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Follow-up  
- HZ cohort: Patients of the HZ cohort will be followed-up for 3 months using phone interviews 
with a nurse 1 and 3 months after HZ rash onset (M1 ± 3 days, M3 ± 1 week).  
- PHN cohort: Patients of the PHN cohort will be followed-up for another 6 months using phone 
interviews with a nurse 6 and 9 months after HZ rash onset (M6 ± 1 week, M9 ± 1 week).   
- A postal mail or email will be sent 8-12 days before the phone interview with the ZBPI and 
EQ-5D 5L for the interview.  
  
The list of procedures is presented in table 1 and the overall design of the study is presented in the 
following figure 1: Table 1: list of procedures  
  
HZ COHORT  
PHN COHORT  
  
Inclusion  
M1  
± 3 days  
M3  
± 5 week  
M6  
± 1 week  
M9  
± 1 week  
Initiation activities that will be managed by the site  
Aggregated demographic data  
X  
  
  
  
  
Signed patient agreement  
X  
  
  
  
  
Eligibility criteria  
X  
  
  
  
  
Medical history  
X  
  
  
  
  
Clinical Diagnosis of HZ   
Procedure performed or prescribed  
X  
  
  
  
  
HZ characteristics and co-morbidity 
HZ severity  
X  
  
  
  
  
Healthcare resources prescribed 
Direct and indirect cost  
X  
  
  
  
  
Patient booklet   
Report week by week HZ-related 
healthcare resources used between 
Inclusion and M1  
X  
  
  
  
  
ZBPI Self-administered questionnaire  
X  
  
  
  
  
EQ-5D 5L Health State 
Selfadministered questionnaire  
X  
  
  
  
  
Follow up activities that will be managed during the phone interviews  
ZBPI questionnaire   
  
X  
X  
X  
X  
EQ-5D 5L Health State   
  
X  
X  
X  
X  
Healthcare resources used 
Direct and indirect cost  
  
X  
X  
X  
X  

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Sent reminder to patient for phone 
interview  
8-12 days before phone date  
  
X  
X  
X  
X  
Sent the patient booklet Report week 
by week HZ-related healthcare 
resources used during the next three 
months  
  
  
X  
X  
X  
  
  
  
  
  
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Figure 1: study design  
  
5  STUDY POPULATION  
5.1 PHYSICIANS  
The study will be carried out by a random sample of approximately 210 community first line 
practitioners concerned by HZ diagnosis: 210 GPs, 30 dermatologists and 30 ophthalmologists 
with the hypothesis that 2/3 of them will be active (≥ 1 patient included), i.e. about 170 GPs, 20 
dermatologists and 20 ophthalmologists (cf. 7.2 Physician sample size).  
5.2 PATIENTS  
The study has been designed to include 250 patients ≥ 50 years old with a first visit for a diagnosis 
of HZ during a 6-month inclusion period (HZ cohort) and 40 expected PHN 3 months after HZ 
rash onset (cf. 7.1 Patient sample size).  
Inclusion   
(6 months)  
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M1  
M3  
M6  
M9  
M0  

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5.2.1 HZ cohort inclusion and exclusion criteria  
To be included in the HZ cohort, patients have to fulfill all the following criteria:  
- Patient with a first visit for a diagnosis of HZ and who attend the clinic within two week of the 
HZ start of symptoms (defined as unilateral pain accompanied by a unilateral rash without 
alternative diagnosis),  
- Without history of previous HZ,  
- ≥ 50 years old,  
- Who agree to participate and signed informed consent,   
- Able to understand the study, to complete self-administered questionnaires (alone or with the 
help of a relative) and to answer phone interviews.  
5.2.2 PHN cohort inclusion and exclusion criterion  
All Patients of the HZ cohort presenting PHN 3 months after onset of the HZ rash onset will be 
included in the PHN cohort. PHN will be defined as the presence of HZ-associated severe pains: 
≥ 3 of the ZBPI item “worst pain”.   
  
6  DATA COLLECTION  
6.1 SIGNED PATIENT AGREEMENT  
All patients included in the HZ cohort will have to sign a patient informed consent, including 
contact details to send booklets and to realize phone interviews:  - First name, surname, postal 
and email address, phone number(s),  - Preferred time to be contacted for a phone interview.  
All patients included in the HZ cohort will receive a  patient booklet at inclusion, to report weekby-
week HZ-related healthcare resources used during the next three months. The following patient 
booklet (for the next three month period) will be sent by courier.  
6.2 HZ COHORT  
For all patients included in the HZ cohort, physicians will have to complete a medical questionnaire 
with the following information:  
- Inclusion-exclusion criteria   
- Date of visit,  
- Gender, date of birth, current occupational status,   
- HZ characteristics: date of HZ rash onset, prodromal symptoms, rash localization, pain 
evaluation (ZBPI questionnaire), complications (cutaneous, neurological, ocular, HZ oticus, 
visceral, other),  
- Pre-existing contributing factors:  
 
▪  Emotional problem, stress, depression,  
 
▪  Alcoholism  
 
▪  Tabagism  
 
▪  Diabetes, renal failure or dialysis, liver disease,  
 
▪  Hepatitis C under active therapy in the 12 months before HZ diagnosis,  
▪ HIV infection with low CD4 count (≤ 350 CD4/µl) or history of opportunistic disease or 
other AIDS related conditions any time before HZ diagnosis,  

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▪ Solid malignancy: active chemotherapy or widespread radiation therapy, or statement of 
metastatic or active disease in the 6 months before the diagnosis of HZ,  
▪ Blood malignancy: active chemotherapy or widespread radiation therapy, or statement of 
metastatic or active disease in the 6 months before the diagnosis of HZ,  
▪ Solid organ transplantation in the 12 months before HZ diagnosis or longer but continues on 
anti rejection treatment.  
▪ Hematopoetic cell/ bone marrow transplantation in the 12 months before HZ diagnosis or 
longer but continues on anti rejection treatment.  
▪ Autoimmune disease active and under therapy: both a confirmed diagnosis of the condition 
and immunosuppressive therapy (5mg/d or more of oral corticosteroids or other 
immunosuppressive therapy) required in the 12 months before HZ diagnosis (e.g. 
Rhumatoid arthritis, systemic Lupus Erythematosus, inflammatory Bowel Disease,  
Ankylosing Spondylitis, Psoriasis and other to be specified),  
▪  Immunosuppressive medications: Oral or parenteral corticosteroids, Cytostatics/ 
Chemotherapy treatment, Monoclonal and polyclonal antibodies, post transplantation anti 
rejection treatment / Drugs acting on immunophilins (Cyclosporin, tacrolimus, sirolimus), 
or other drugs to be specified.  
 
▪  Other drugs,   
- Drug used and prescribed (name, dosage and number of boxes) for HZ,  
- Patient sick leave prescription and duration,  
- Patient referred to a specialist or hospital and reason(s).  
6.3 PATIENT SELF-ADMINISTERED QUESTIONNAIRE AT INCLUSION  
All patients included in the HZ cohort will have to complete the 2 following self-administered 
questionnaires:  
- ZBPI questionnaire,  
- EQ-5D 5L health state.  
6.4 PATIENT PHONE INTERVIEW DURING THE FOLLOW-UP:   
A patient phone interview will be organized with a nurse by the Coordinating Center at M1 and 
M3 for all patients included in the HZ cohort, and at M6 and M9 for all patients included in the 
PHN cohort. The following information will be completed during the phone interview, using a 
patient booklet (to report weekly HZ-related healthcare resources used during the last three 
months):  
- Date of interview or the reason why the interview could not be done: patient agreement 
withdrawal, lost to follow-up, death and other to be specified.  
- Healthcare resources in relation with HZ or PHN since the last contact (inclusion or followup 
phone interview):  
 
▪  Drug used with dosage and number of boxes,   
 
▪  Sick leave prescription and duration  
▪  Number of GP visits, specialist visits, emergency room (≤ 24h) and reasons,  
▪  
Hospitalization (≥ 24h), reason and duration. - ZBPI questionnaire, - EQ-
5D 5L health state.  

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A postal mail or email will be sent 8-12 days before the planned interview to propose a date and 
time for the interview with the opportunity to plan another appointment, and to provide 
selfadministered questionnaires (ZBPI and EQ-5D 5L) for the interview, as well as the patient 
booklet for the next three months.  
A patient will be declared “lost to follow-up” if he cannot be reached after 5 call attempts 
distributed over one week, and if he does not ask for another appointment for the interview. In 
such a case, the physician will be contacted to try to document the reason.  
  
7  STUDY SIZE  
7.1 PATIENT SAMPLE SIZE  
The study has been designed to include 250 cases of HZ with 40 cases of PHN expected 
(hypothesis of 16% of PHN at M3). For quantitative variables, such as costs and utilities, the 
precision will be a function of the variability of the variable. Table 1 shows that a sample of 250 
cases, the precision will be between ± 3.1% and 24.8 % for a standard deviation between 1/4 and 
2 times the mean, and 40 cases a precision of the mean of between ± 7.7% and 62.0 % for a 
deviation standard between 1/4 and 2 time the mean.  
  
Table 1: Precision of a 95% confidence interval for a continuous variable, taking into account the 
standard deviation and sample size, according to the normal distribution for the mean (n ≥ 30)*  
Sample 
size (n)  
Standard Deviation (SD as % of the mean)  
1/4  
2/4  
3/4  
1  
1,5  
2  
250  
3,1%  
6,2%  
9,3%  
12,4%  
18,6%  
24,8%  
40  
7,7%  
15,5%  
23,2%  
31,0%  
46,5%  
62,0%  
* ±1.96 * SD/√n, with SD the Standard deviation and n the sample size.  
  
Table 2 : Precision of a 95% confidence interval for a continuous variable, taking into account the  
250 
    
3,10 
   € 
    
6,20
 
   € 
    
 
    
247,92
 
   € 
    
495,85 
   € 
    
40 
    
7,75 
   € 
    
15,50
 
   € 
    
154,95 
   € 
   
 
619,81 
   € 
    
 
    
 
 * ±1.96 * SD/√n, with SD the Standard deviation and n the sample size.  
 
    
 
    
    
Sample    Size    
(n) 
    
 
 
standard 
   deviation 
  
(SD) 
    
 
25 
  
50 
  
500 
  
2000 
  
4000 
  

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7.2 PHYSICIAN SAMPLE SIZE  
In the study of the General Practitioners’ (GPs) sentinel electronic surveillance network, the 
average yearly number of cases reported by each GP was 3.31 (95% CI 2.82–3.80) (Gonzales 
2010). For this study, we assume that GPs and specialists will include at least mean number of 1 
and 2 cases respectively, for a 6-month inclusion period. With this hypothesis, a random sample 
170 GPs, 20 dermatologists and 20 ophthalmologists could include 250 cases of HZ.   
In such studies, some participating physicians are not active, especially with scarce patients such 
as HZ cases. Assuming 2/3 of active participation, 210 GPs, 30 dermatologists and 30 
ophthalmologists will be recruited.  
  
8  DATA-MANAGEMENT  
A Data Management Plan (DMP) will define the database characteristics (item names and formats, 
dataset structure), as well as edit checks to ensure validity of database with a focus on missing, 
implausible or inconsistent data. The DMP will be approved prior to initiating data entry.   
A double data entry will be performed for the medical questionnaires, while phone interviews will 
use a direct single data entry during the interview. Data entry, database management and edit 
checks will be performed continuously during the study.  
  
9  DATA ANALYSIS  
Statistical analysis will be performed using SAS® software (SAS Institute, last version, North 
Carolina, USA). A Statistical Analysis Plan (SAP) will be developed and validated by the 
Scientific Committee before the analysis. The following statistical analysis will be performed.  
9.1 STUDY POPULATION  
A flowchart will summarize physician recruitment (contacted, refusing to participate and reasons, 
agreeing to participate, active), patient inclusion (in HZ and PHN cohorts) and withdrawn from 
the study and reasons.   
9.2 PHYSICIANS  
Physician characteristics (gender, age) will be compared to the National statistics of GPs, 
dermatologists and ophthalmologists from the Department for Evaluation and statistics of the 
French Health Ministry (DRESS: Direction de la recherche, des études, de l’évaluation et des 
statistiques).  
9.3 PATIENTS INCLUDED  
Patient and disease characteristics at inclusion will be described for patients included in the HZ 
cohort and in the PHN cohort.  
9.4 OUTCOME  
- Primary objective: Healthcare resources used will be described with estimation of the direct 
medical and indirect cost per episode (overall, by gender and age-classes) from a payer and 
societal perspective:  
 
▪  For the HZ cohort during the study period (M0, M1 and M3);  

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▪  For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
- HZ and PHN severity will be described with three categories for last 24h worst pain: mild 
pain (0<pain<3), moderate pain (3 ≤ pain < 7) and severe pain (7 ≤ pain):  
 
▪  For the HZ cohort during the study period (M0, M1 and M3);  
 
▪  For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
- Quality of life and utilities will be described using EQ-5D 5L and derived utility score:  
 
▪  For the HZ cohort during the study period (M0, M1 and M3);  
 
▪  For the PHN cohort during the study period (M0, M1, M3, M6 and M9).  
- Statistical correlations will be estimated between HZ and PHN severity (three categories 
defined above) and cost on the one hand, and severity and utility scores on the other hand will 
be derived.  
9.5 STATISTICAL METHODS   
- Qualitative variables (dichotomous or categorical) will be described in terms of number and 
frequency, as well 95% confidence interval (95%CI) for main variables, estimated using 
normal approximation distribution.  
- Quantitative variables will be described in terms of mean, standard deviation, geometrical 
mean, median, first and third quartiles, minimum and maximum as well 95% confidence 
interval (95%CI) for main variables.  
- The EQ-5D 5L health state will be used to estimate utility and to estimate loss in quality of life 
associated with HZ and PHN. The EQ-5D 5L health states will be converted into a single 
summary index showing the utility function over time. The comparison of these utility scores 
with existing reference value set derived for EQ-5D in France will provide the average loss in 
quality of life (so-called QALY weights) associated with HZ and PHN  
  
10 QUALITY CONTROL  
A quality control will be performed for a random sample of 10% of active physicians with:  
- On-site, face-to-face with participating physician to check adherence to the protocol, that all 
eligible patients were included, and collected data (major clinically-relevant data),  
- Verification of consistency between entered data and physician-completed inclusion paper 
CRF for corresponding patients.   
  
11 LIMITATIONS OF THE RESEARCH METHODS  
Selection bias:   
The study will be carried out with a national random sample of community first line practitioners 
concerned by HZ diagnosis, in order to identify a representative sample of patients with HZ first 
visit. However, active physicians are not necessarily representative for the others. The 
representativeness of active physicians will be evaluated by comparing their general characteristics 
to the national data from the Ministry of Health (Direction de la Recherche, des Etudes, de 
l'Evaluation et des Statistiques / DREES).  

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Moreover, the study does not concern primary severe cases that should be hospitalized without a 
first visit with a first line practitioner, or patients yet hospitalized for another cause. However, this 
situation has been considered to concern very few patients.  
In order to avoid a patient selection bias by physician, all patients ≥ 50 years old with a first visit 
for HZ will be included in the study. Patients lost to follow-up are the main source of attrition bias 
in cohort studies. In this study, the risk of loss of follow-up has been minimized using direct patient 
contact with phone interview.   
Information bias:   
Data collected by physicians at inclusion are usual in HZ diagnosis and no suspected information 
bias has been identified, nor frequent missing value risk. In order to avoid missing values during 
follow-up phone interviews with patients, self-administered questionnaires (ZBPI and EQ-5D 5L) 
will be sent by mail before the phone interview, and an  patient booklet, to report week by week 
HZ-related healthcare resources used, given at inclusion and then sent by mail for the M1, M6 and 
M9 visit.  
  
12 PROTECTION OF HUMAN SUBJECTS  
12.1.1 Ethic Committee (CPP)  
According to the French law (n°2004-806 of the 9/08/2004, article 88,), this study is an 
observational research, without specific drug evaluation, and with only small risks and constraints 
for the patients (follow-up visits and phone interview). The protocol will be submitted to a French 
Ethics Committee (Comité de Protection des Personnes / CPP).  
12.1.2 National Council of Physicians (CNOM)  
According to the French Public Health Code (article L.4113-6), the study protocol and the research 
agreements for investigators and members of the Scientific Committee will be submitted to the 
National Council of Physicians (Conseil National de l’Ordre des Médecins / CNOM).  
12.1.3 Data privacy (CNIL)  
The use of patient ID number and initial is justified in order to link patient documents (inclusion 
medical questionnaire and phone interview during follow-up), as well as edit checks and quality 
control on site. The use of nominative data (title, first names, surname, phone number, home and 
email address,) is justified to contact the patient for phone interviews during the follow-up. In 
order to keep medical confidentiality, two independent networks and servers will be used, one for 
nominative data and the other for medical information. An information letter related to data 
collection and data privacy will be given to the patient prior to entering the study and a patient 
agreement will be dated and signed by the patient.  
According to the chapter IX of French Data Privacy Law (n° 78-17 of the 6/01/1978, n° 94-548 of 
the 1/07/1994 et n°2004-801 of the 6/08/2004) the protocol and CRF will be submitted first of all 
to the French independent review board for data privacy in health research (Comité Consultatif sur 
le Traitement de l’Information en matière de Recherche sur la Santé / CCTIRS) and then to the 
French Data Privacy Commission (Commission National de l’Informatique et des Libertés / CNIL) 
for authorization.  

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13 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS  
It is an observational epidemiologic study without specific drug evaluation. According to the 
article R.5121.170 of Public Health Code, physicians, dentists, or midwives having noticed an 
adverse event suspected to be related to a medicinal product or to a product referred to in article 
R.121-150, whether they are or not the prescriber, have to make the immediate declaration to the 
Regional Centre of Pharmacovigilance (CRPV).  
  
14 PLAN FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS  
Study methods and results will be discussed with the scientific meetings and submitted for 
presentation in scientific meetings and publication in international scientific journals.  The report 
and publications will be used to support market authorizations of a HZ vaccination to prevent 
PHN.  
  
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 MacDonald BK, Cockerell OC, Sander JW et al. The incidence and lifetime prevalence of 
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 Mick G, Gallais JL, Simon F, Pinchinat S, Bloch K, Beillat M, Serradell L, Derrough T. 
Évaluation de l’incidence du zona, de la proportion des douleurs post-zostériennes, et des coûts 
associés dans la population française de 50 ans ou plus. Rev Epidemiol Sante Publique. 2010 
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 Oxman MN, Levin MJ, Johnson GR et al. A vaccine to prevent herpes zoster and postherpetic 
neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84.  
 Pinchinat S, Cebrián-Cuenca AM, Bricout H, Johnson RW. Similar herpes zoster incidence 
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10;13:170.  
 Pope JE, Krizova A, Ouimet JM et al. Close association of herpes zoster reactivation and 
systemic lupus erythematosus (SLE) diagnosis: case-control study of patients with SLE or 
noninflammatory musculoskeletal disorders. Journal of Rheumatology. 2004;31:274-79.  
 Scott FT, Johnson RW, Leedham-Green M et al. The burden of Herpes Zoster: a prospective 
population based study. Vaccine. 2006;24(9):1308-14.  
 Sharvadze L, Tsertsvadze T, Gochitashvili N et al. Peculiarities of herpes zoster in 
immunocomptent and immunocompromised hosts. Georgian Medical News. 2006:50-53.  
 Yawn BP, Saddier P, Wollan PC et al. A population-based study of the incidence and 
complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007; 
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 White RR, Lenhart G, Singhal PK et al. Incremental 1-year medical resource utilization and 
costs for patients with herpes zoster from a set of US health plans. Pharmacoeconomics. 2009; 
27: 781-792.