Conditions: Neuroborreliosis, Borrelia Burgdorferi
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
Comparison of Doxycycline 200 mg once daily for six weeks versus Doxycycline 200 mg once daily for two weeks + placebo for four weeks. Primary objective is to answer the question "is two weeks doxycycline treatment (currently suggested treatment) at least as effective as six weeks doxycycline treatment in Lyme Neuroborreliosis?".Key secondary objectives are to provide a better understanding of the pathogenesis and long-term complaints, and to search for new biomarkers in Lyme Neuroborreliosis (LNB) by collecting clinical data, blood, and cerebrospinal fluid (CSF) in a biobank for future research

Endpoints:

Primary endpoint: Improvement on a composite clinical score from inclusion to six months after ended treatment defined as clinical score at inclusion minus clinical score at six months.

Secondary endpoints: Improvement on a composite clinical score 12 months after ended treatment. Fatigue Severity Scale (FSS),Patient Health Questionnaire (PHQ-15), Short Form 36 (SF-36) and blood and CSF findings at inclusion, after 6 and 12 months.

The study design is a multicenter, non-inferiority, randomized, penta-blind, placebo-controlled trial. 120 patients will be included from approximately 8 Norwegian hospitals.

Main inclusion criteria are neurological symptoms suggestive of LNB without other obvious reasons, one or both of a) Cerebrospinal fluid pleocytosis (\>5 leukocytes/mm3) b) intrathecal Bb antibody Production and signed informed consent. Safety assessments during the trial: Comparison of clinical outcome six months after end of treatment between the two treatment groups. Subjective experiences and blood tests including hematology and biochemistry for four weeks after ended treatment.

Detailed description:

Arms:
arm 1: Doxycycline 200 mg once daily for six weeks arm 2: Doxycycline 200 mg once daily for two weeks + placebo for four weeks.

Interventions: intervention 1: Doxycycline intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
BorrSci WP2 Version no.3– July 2017 
 
 
 
Lyme borreliosis; a scientific approach to reduce diagnostic and therapeutic uncertainties 
(BorrSci) 
 
WP2; SIX VERSUS TWO WEEKS TREATMENT WITH DOXYCYCLINE IN LYME 
NEUROBORRELIOSIS; A MULTICENTER, NON-INFERIORITY, PENTA-BLIND, 
RANDOMIZED TRIAL 
 
 
Protocol Identification Number:   BorrSciWP2 
EudraCT Number:   2015-001481-25 
 
SPONSOR: 
Frode Gallefoss 
Research department, Sørlandet Hospital HF, 
Servicebox 416, 4604 Kristansand, Norway  
Tel : +47 38 07 30 00 
E-mail: frode.gallefoss@sshf.no 
 
 
COORDINATING 
INVESTIGATORS : 
Åse Mygland and Unn Ljøstad 
Department of Neurology, Sørlandet Hospital 
HF, Servicebox 416, 4604 Kristansand, Norway 
Tel : +47 38 07 39 10 
E-mail:  
aase.mygland@sshf.no  
unn.ljostad@sshf.no  
 
 
 
 
PROTOCOL VERSION NO. 4 -  July  2017 
 
 
 


BorrSci WP2 Version no.3– July 2017 
CONTACT DETAILS  
Sponsor: 
Frode Gallefoss,  
MD, Professor, PhD, leader of research department  
Sørlandet Hospital HF,  
Servicebox 416,  
4604 Kristiansand 
Tel : +47 38 07 30 00 
E-mail: frode.gallefoss@sshf.no 
 
Coordinating Investigators 
Unn Ljøstad, MD, Professor, PhD 
Department of Neurology, Sørlandet Hospital HF, 
Servicebox 416,  
4604 Kristansand 
Tel : +47 38 07 39 10 
E-mail: unn.ljostad@sshf.no 
 
Åse Mygland, MD, Professor PhD 
Department of Neurology, Sørlandet Hospital HF,  
Servicebox 416,  
4604 Kristansand 
Tel : +47 38 07 39 10 
E-mail: aase.mygland@sshf.no  
 
Principal investigator (at each participating 
site or if single site study): 
Name and title 
Address 
Tel :  
E-mail: 
Participating Departments: 
Name and title 
Address 
Tel :  
E-mail:  
 
 
  
Participating Departments: 
Name and title 
Address 
Tel :  
E-mail: 
Monitor: 
Department of Clinical Research Support, Marta Colban 
Oslo University Hospital, 
Postbox 4956 Nydalen 
0424 Oslo 
E-mail: Marcol@ous-hf.no 


BorrSci WP2 Version no.3– July 2017 
SIGNATURE PAGE 
 
Title 
Lyme borreliosis; a scientific approach to reduce diagnostic and therapeutic uncertainties (BorrSci) 
WP2; six versus two weeks treatment with doxycycline in Lyme Neuroborreliosis; a multicenter, 
non-inferiority, penta-blind, randomized trial 
 
Protocol ID no: 
BorrSciWP2  
EudraCT no: 
2015-001481-25 
 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the applicable 
regulatory requirements: 
Name 
Title 
Role 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 4 of 25 
PROTOCOL SYNOPSIS 
 
Protocol title 
 
 
Six versus two weeks treatment with doxycycline in Lyme Neuroborreliosis; a 
multicenter, non-inferiority, penta-blind, randomized trial 
Sponsor 
 
Sørlandet Hospital HF 
Phase and study type 
Phase III, interventional 
Investigational Medical 
Product (IMP) (including 
active comparator and 
placebo) :    
Doxycycline 200 mg once daily for six weeks  
versus  
Doxycycline 200 mg once daily for two weeks + placebo for four weeks 
Centers: 
Sørlandet Hospital + 5-10 other Norwegian hospitals 
Study Period: 
 
Estimated date of first patient enrolled: 01.10.15 
Anticipated recruitment period: 01.10.15- 31.12.19 
Estimated date of last patient completed: 31.12.20 
Treatment Duration: 
Six weeks 
Follow-up: 
13 months  
Objectives  
Primary objective 
To answer the question “is two weeks doxycycline treatment (currently suggested 
treatment) at least as effective as six weeks doxycycline treatment in Lyme 
Neuroborreliosis?”   
Key secondary objectives  
To provide a better understanding of the pathogenesis and long‐term complaints, and 
to search for new biomarkers in LNB 
To collect clinical data, blood, and CSF in a biobank for future research 
Endpoints: 
 
Primary endpoint:  
Improvement in composite clinical score defined as clinical score at inclusion minus 
clinical score at 6 months. 
Secondary endpoints:  
Fatigue Severity Scale (FSS)  
Patient Health Questionnaire (PHQ-15)  
Short Form 36 (SF-36)  
Blood and CSF findings  
MRI, and neuropsychological assessments in a subset of patients  
Adverse events 
 
Study Design: 
Multicenter, non-inferiority, randomized, penta-blind, placebo-controlled trial 
Main Inclusion Criteria:    
1. Neurological symptoms suggestive of LNB without other obvious reasons and one 
or both of 
a. 
Cerebrospinal fluid pleocytosis (≥5 leukocytes/mm3) 
b. Intrathecal Bb antibody production 
2. Signed informed consent 
Main Exclusion Criteria 
 
Age less than 18 years 
 
Pregnancy, breast-feeding  
 
Adverse reaction to tetracyclines 
 
Treatment with cephalosporin, penicillin, or tetracycline the last 14 days 
 
Serious liver or kidney disease that contraindicates use of doxycyline 
 
Lactose intolerance 
 
Need to use medications contraindicated according to SmPC of the IMP 
 
Sample Size: 
120 patients 
Efficacy Assessments: 
 
Safety Assessments: 
Comparison of clinical outcome six months after end of treatment between the two 
treatment groups.  
Subjective experiences and blood tests including hematology and biochemistry for 
four weeks after ended treatment. 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 5 of 25 
 
TABLE OF CONTENTS 
 
CONTACT DETAILS ...................................................................................................................................................... 2 
SIGNATURE PAGE ........................................................................................................................................................ 3 
PROTOCOL SYNOPSIS ................................................................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................................ 8 
1 
INTRODUCTION .................................................................................................................................................... 9 
1.1 
Background – Lyme Neuroborreliosis (LNB)...................................................................................................... 9 
1.2 
Background - Therapeutic Information ................................................................................................................ 9 
1.3 
Pre-Clinical & Clinical Experience with Investigational Medicinal Product (IMP) ............................................ 9 
1.4 
Rationale for the Study and Purpose .................................................................................................................... 9 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS .................................................................................... 10 
2.1 
Primary Endpoint ............................................................................................................................................... 10 
2.2 
Secondary Endpoints .......................................................................................................................................... 11 
3 
OVERALL STUDY DESIGN ............................................................................................................................... 12 
4 
STUDY POPULATION ......................................................................................................................................... 12 
4.1 
Selection of Study Population ............................................................................................................................ 12 
4.2 
Number of Patients ............................................................................................................................................. 12 
4.3 
Inclusion Criteria................................................................................................................................................ 12 
4.4 
Exclusion Criteria .............................................................................................................................................. 13 
5 
TREATMENT ........................................................................................................................................................ 13 
5.1 
Drug Identity, Supply and Storage ..................................................................................................................... 13 
5.2 
Dosage and Drug Administration ....................................................................................................................... 13 
5.3 
Duration of Therapy ........................................................................................................................................... 13 
5.4 
Concomitant Medication .................................................................................................................................... 13 
5.5 
Subject Compliance ........................................................................................................................................... 14 
5.6 
Drug Accountability ........................................................................................................................................... 14 
5.7 
Drug Labeling .................................................................................................................................................... 14 
5.8 
Subject Numbering ............................................................................................................................................ 14 
6 
STUDY PROCEDURES ........................................................................................................................................ 14 
6.1 
Flow Chart ......................................................................................................................................................... 14 
6.2 
By Visit .............................................................................................................................................................. 15 
6.2.1 
Screening/Before Treatment Starts Visit ..................................................................................................... 15 
6.2.2 
During Treatment ......................................................................................................................................... 16 
6.2.3 
End of Treatment Visit (four weeks after ended treatment) ......................................................................... 16 
6.2.4 
Withdrawal Visit (desirable but voluntary) .................................................................................................. 16 
6.2.5 
Six months After End of Treatment (Follow-up) ......................................................................................... 16 
6.2.6 
Twelve months After End of Treatment (Follow-up) .................................................................................. 16 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 6 of 25 
6.3 
Criteria for Patient Discontinuation ................................................................................................................... 16 
6.4 
Procedures for Discontinuation .......................................................................................................................... 17 
6.4.1 
Patient Discontinuation ................................................................................................................................ 17 
6.4.2 
Trial Discontinuation ................................................................................................................................... 17 
6.5 
Laboratory Tests ................................................................................................................................................ 17 
7 
ASSESSMENTS ..................................................................................................................................................... 17 
7.1 
Assessment of Efficacy ...................................................................................................................................... 17 
7.2 
Safety and Tolerability Assessments .................................................................................................................. 17 
8 
SAFETY MONITORING AND REPORTING ................................................................................................... 18 
8.1 
Definitions .......................................................................................................................................................... 18 
8.1.1 
Adverse Event (AE) ..................................................................................................................................... 18 
8.1.2 
Serious Adverse Event (SAE) ...................................................................................................................... 18 
8.1.1 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ....................................................................... 18 
8.2 
Expected Adverse Events ................................................................................................................................... 18 
8.3 
Disease Progression ........................................................................................................................................... 18 
8.4 
Time Period for Reporting AE and SAE ............................................................................................................ 18 
8.5 
Recording of Adverse Events ............................................................................................................................. 19 
8.6 
Reporting Procedure .......................................................................................................................................... 19 
8.6.1 
AEs and SAEs .............................................................................................................................................. 19 
8.6.2 
SUSARs ....................................................................................................................................................... 19 
8.6.3 
Annual Safety Report ................................................................................................................................... 20 
8.6.4 
Clinical Study Report ................................................................................................................................... 20 
8.7 
Procedures in Case of Emergency ...................................................................................................................... 20 
9 
DATA MANAGEMENT AND MONITORING ................................................................................................. 20 
9.1 
Case Report Forms (CRFs) ................................................................................................................................ 20 
9.2 
Source Data ........................................................................................................................................................ 20 
9.3 
Study Monitoring ............................................................................................................................................... 20 
9.4 
Confidentiality ................................................................................................................................................... 21 
9.5 
Database management ........................................................................................................................................ 21 
10 
STATISTICAL METHODS AND DATA ANALYSIS ....................................................................................... 21 
10.1 
Determination of Sample Size ........................................................................................................................... 21 
10.2 
Randomization ................................................................................................................................................... 21 
10.2.1 Allocation- sequence generation .................................................................................................................. 21 
10.2.2 Blinding and emergency unblinding ............................................................................................................ 21 
10.3 
Population for Analysis ...................................................................................................................................... 21 
10.4 
Planned analyses ................................................................................................................................................ 21 
10.5 
Statistical Analysis ............................................................................................................................................. 21 
11 
STUDY MANAGEMENT ..................................................................................................................................... 22 
11.1 
Investigator Delegation Procedure ..................................................................................................................... 22 
11.2 
Protocol Adherence ............................................................................................................................................ 22 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 7 of 25 
11.3 
Study Amendments ............................................................................................................................................ 22 
11.4 
Audit and Inspections ......................................................................................................................................... 22 
12 
ETHICAL AND REGULATORY REQUIREMENTS ....................................................................................... 22 
12.1 
Ethics Committee Approval ............................................................................................................................... 22 
12.2 
Other Regulatory Approvals .............................................................................................................................. 22 
12.3 
Informed Consent Procedure .............................................................................................................................. 22 
12.4 
Subject Identification ......................................................................................................................................... 23 
13 
TRIAL SPONSORSHIP AND FINANCING ...................................................................................................... 23 
14 
TRIAL INSURANCE ............................................................................................................................................ 23 
15 
PUBLICATION POLICY ..................................................................................................................................... 23 
16 
REFERENCES ....................................................................................................................................................... 24 
17 
LIST OF APPENDICES ........................................................................................................................................ 25 
 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 8 of 25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or special term 
Explanation 
AE 
Adverse Event  
AR 
Adverse Reactions 
Bb 
Borrelia burgdorferi 
CIOMS  
Council for International Organizations of Medical Sciences 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form (electronic/paper) 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTU 
Clinical Trial Unit 
DAE 
Discontinuation due to Adverse Event 
DMC 
Disease Monitoring Commitee 
EC 
Ethics Committee  
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product (includes active comparator and placebo) 
ISF 
Investigator’s Study File 
ITT 
Intention to treat  
LNB 
Lyme Neuroborreliosis 
MRI 
Magnetic Resonance Imaging 
NMA 
Norwegian Medical Agency 
NTNU 
Norwegian University of Science and Technology  
OUS 
Oslo Universitetssykehus 
PHQ-15 
Patient Health Questionnaire 
PNS 
Peripheral Nervous System 
SAE 
Serious Adverse Event   
SDV 
Source document verification  
SF-36 
Short Form 36 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSHF 
Sørlandet Sykehus HF 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TMF 
Trial Master File 
WP 
Work Package 
 
 
 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 9 of 25 
1 
INTRODUCTION 
1.1 
Background – Lyme Neuroborreliosis (LNB) 
Lyme borreliosis is a multisystem infectious disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb), 
which frequently affects the nervous system. The most common clinical manifestations of European Lyme 
Neuroborreliosis (LNB) are painful radiculitis and cranial neuropathy (most often the facial nerve). Rarer 
manifestations are myelitis, encephalitis, and peripheral neuropathies. The diagnosis of LNB is based on a combination 
of clinical neurological findings, lymphocytic pleocytosis and intrathecal Bb antibody production (1).  
Most patients recover well within weeks to a few months after standard antibiotic treatment, but 25-50% of LNB 
patients report residual complaints often labelled post-Lyme syndrome (2-9). The most common remaining complaints 
are subjective symptoms as fatigue, pain, concentration and memory problems. Remaining objective findings as facial 
palsy and radiculopathy are rarer. 
The impact and prevalence of post-Lyme syndrome are debated, as similar symptoms are common in the general 
population. It is also questioned if the complaints are more common after LNB than after other infections in the nervous 
system. There are few controlled studies on the issue, but one previous study found more fatigue and lower mean scores 
on health related quality of life  among 50 well-characterized LNB patients 30 months after treatment for LNB than 
among 50 matched healthy controls (3).  
The underlying mechanism of post-Lyme syndrome is also debated and largely unresolved. Theories as ongoing chronic 
Bb infection (10), dysregulated immune responses (11, 12), genetic predisposition (13), co-infection with multiple tick-
borne pathogens (14), structural changes in the Central Nervous System (CNS) (15), and personal traits (16, 17), have 
been suggested.  
In the current trial, we will address the persistent infection hypothesis by assessing long-term prognosis after extended 
antibiotic treatment. Further, the trial is a part of the compound and large BorrSci study (Lyme borreliosis; a scientific 
approach to reduce diagnostic and therapeutic uncertainties) which also aims to address the other hypotheses mentioned 
above. These approaches are further described in the protocols for the other workpackages (WP) of BorrSci (Appendix 
A). The blood and cerebrospinal fluid (CSF) specimens along with comprehensive clinical information collected from 
the patients included in the current treatment trial is an important contribution to the biobank that will be established for 
these purposes. 
1.2 
Background - Therapeutic Information 
Standard treatment for Lyme Neuroborreliosis (LNB) is intravenous ceftriaxone or penicillin, or oral doxycycline for 
two to four weeks (1). Previous studies have shown that two weeks of oral doxycycline and intravenous ceftriaxone are 
equally effective for LNB with painful radiculitis or cranial neuritis (5, 18). However, evidence about the optimal 
duration of treatment is currently lacking. There are a few studies of prolonged antibiotic treatment in LNB, but they are 
hampered with poorly‐characterized patients, insufficient statistical power, lack of matched controls, and ambiguous 
results (19-23). A case series reported excellent or good response in 90% of patients with disseminated Lyme (including 
some with neuroborreliosis) after treatment with oral cefixime or IV ceftriaxone for 14 days followed by oral 
amoxicillin for 100 days (24). A controlled study of 152 patients with disseminated Lyme disease (including 62 with 
neuroborreliosis) (20), however, found similar outcome in patients treated with 3 weeks with IV ceftriaxone followed 
by oral amoxicillin for 100 days and patients treated with 3 weeks IV ceftriaxone followed by placebo for 100 days. An 
American openlabel randomized comparison of 14-days versus 28-days treatment with ceftriaxone for late Lyme 
borreliosis (143 patients, of whom a third with neurological symptoms), showed more treatment failures in the 14-day 
group than in the 28-day group, but did not have the power to determine if a clinical subset of patients may benefit from 
28 days of therapy. There were more discontinuations because of adverse events in the 28- days group (25). Another 
series of late LNB showed disappearance of symptoms in 87% after 100 days regimens with various antibiotics, 
whereas 14 days with ceftriaxone cured 31% (26). 
The possibility that a longer treatment with doxycycline, such as six weeks, is superior to the current standard treatment 
of two weeks in LNB has not been properly addressed in a randomized controlled trial. 
1.3 
Pre-Clinical & Clinical Experience with Investigational Medicinal Product (IMP)  
Doxycycline is a well-known drug with a good safety profile used for several infectious diseases worldwide.                           
1.4 
Rationale for the Study and Purpose 
The main purpose of the trial is to answer the “is two weeks doxycycline treatment (currently suggested treatment) at 
least as effective as six weeks doxycycline treatment in LNB?” The benefits of a positive answer to this question would 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 10 of 25 
be a reduced frequency of persisting complaints after treatment. The benefits of a negative answer would be avoidance of 
unnecessarily prolonged treatment with antibiotics and thereby reduced antibiotic resistance.  
Doxycycline 200 mg daily for 2 weeks is recommended for LNB, and half of the study patients will receive this standard 
treatment (and additional four weeks of placebo). The other half will receive doxycycline 200 mg daily for six weeks. 
Possible disadvantages for the trial participants are more adverse advents as nausea and diarrhea, disturbances in 
leukocyte and thrombocyte count, and skin reactions (mostly photosensitivity). Longer antibiotic treatment may also 
lead to higher prevalence of resistant bacteria in patients and the general society. We regard these possible 
disadvantages as minor as the patients’ subjective experiences and blood cell count will be closely monitored during the 
study, and both groups of patients will be discouraged sunbathing during treatment and up to two weeks after drug 
intake. In our opinion, the benefit of determination of preferred duration of treatment for the future eliminates the 
disadvantage of exposing. Besides this, several spin off effects strengthens the rationale for conducting the study. The 
collected clinical data and specimens (blood and CSF) from well-characterized LNB patients may enable us to address 
other hypotheses regarding long-term complaints as immune dysregulation, genetic predisposition, co-infections and 
structural changes in CNS, and it facilitates search for new biomarkers of LNB which could be used in diagnostics.  
 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
 
Objectives 
Endpoints 
Assessments 
Primary 
To answer the question “is two weeks 
doxycycline treatment (currently 
suggested treatment) at least as 
effective as six weeks doxycycline 
treatment in LNB?”   
 
Primary endpoint: Improvement of 
clinical score six months after ended 
treatment 
 
Secondary endpoints: Fatigue, 
subjective somatic symptoms, health 
related quality of life, cognitive 
function, safety, inflammation.  
- 
Composite clinical score.                
See section: 2.1 
 
- 
FSS, PHQ-15, SF-36, adverse 
events inflammatory 
parameters in CSF. See section 
2.2 
Secondary 
1. 
To provide a better understanding 
of the pathogenesis of LNB and 
long‐term complaints 
2. 
To search for new biomarkers in 
LNB 
 
Antibody and inflammatory profiles 
 
Genomic profiles 
 
Brain MRI 
 
Neuropsychological profiles 
Described in WP4 of BorrSci. 
See appendix A 
Exploratory 
To collect clinical data, blood, and CSF 
from well-characterized LNB patients 
in a biobank  
 
Further search for biomarkers, co-
infections and other factors involved 
in LNB 
 
Described in WP3 of BorrSci. 
See appendix A 
 
Table 1. Summary of objectives, endpoints, and assessments 
 
2.1 
Primary Endpoint  
The primary endpoint is improvement on a composite clinical score (Table 2) from inclusion to six months after ended 
treatment defined as clinical score at inclusion minus clinical score at six months.  


 
BorrSciWP2 Version no.3.  – November 2016 
Page 11 of 25 
 
Table 2. Composite clinical score.  
Each item is scored 0=none, 1=mild, without influence on daily life, or 2=severe, with influence on daily life.  
Maximum total score=64 (sum of subjective symptoms and objective findings) 
* Temporally and otherwise related to current LNB  
a Abnormal sensory findings  in a radicular pattern 
b Paresis in a radicular pattern 
c Abnormal sensory findings  in a non- radicular pattern (matching with peripheral nerve or plexus) 
d Paresis  in a non- radicular pattern (matching with peripheral nerve or plexus) 
e Central weakness and/or spasticity (central paresis, spasticity and/or impairment in pace or fine motor skills)  
2.2 
Secondary Endpoints 
Improvement of  composite clinical score from inclusion to 12 months after end of treatment defined as clinical score 
at inclusion minus clinical score at 12 months. (Table1) 
Fatigue Severity Scale (FSS) at six and 12 months after end of treatment. FSS is translated and validated for Norwegian 
purposes (12). It measures level of agreement (1– 7) with nine statements. The ﬁnal score represents the mean value of 
the nine items. Severe fatigue is defined as a score >5 in a Norwegian population. Reported mean score in 20 American 
Subjective symptoms 
Subjective symptoms related* by the patient to the current/recent LNB 
Score 
Malaise (sykdomsfølelse, redusert almentilstand) 
 
Fatigue (trøtthet, utmattelse) 
 
Headache (hodepine) 
 
Neck and/or back pain (nakke og/eller ryggsmerte) 
 
Abdominal and/or breast pain (smerter i bryst og/eller mageregion) 
 
Arm pain (smerter i armer) 
 
Leg pain (smerter i ben) 
 
Generalized pain located to joints and/or muscles (smerter i ”hele kroppen” (ledd og muskler)) 
 
Memory and/or concentration problems (hukommelse og/eller konsentrasjonsproblemer) 
 
Other (annet) 
 
Objective findings, PNS 
Findings related* to the current/recent LNB 
Score 
Facial palsy (facialisparese) 
 
Paresis of eye muscles (øyemuskelparese) 
 
Reduced hearing (redusert hørsel) 
 
Other cranial neuropathies (andre hjernenerveutfall) 
 
Cervical radicular sensory findingsa (cervikale radikulære sensoriske funn) 
 
Cervical radicular paresisb (cervikal radikulær parese) 
 
Thoracal radicular sensory findingsa (thoracale radikulære sensoriske funn) 
 
Lumbal radicular sensory findingsa (lumbale radikulære sensoriske funn) 
 
Lumbal radicular paresisb (lumbal radikulær parese) 
 
Non-radicular sensory findingsc (ikke-radikulære sensoriske funn) 
 
Non-radicular paresisd (ikke-radikulær nevropati med pareser) 
 
Other (annet) 
 
Objective findings, CNS 
Findings related* to the current/recent LNB 
Score 
Central findingse in one extremity (sentralnervøse funn i en ekstremitet)  
 
Central findingse in a hemi pattern (sentralnervøse funn i en kroppshalvdel) 
 
Central findingse in both legs (sentralnervøse funn i begge ben) 
 
Central findingse in all extremities (sentralnervøse funn i alle ekstremiteter)  
 
Gait ataxia (gangataksi, ustøhet) 
 
Dysphasi/aphasi (talevansker) 
 
Nystagmus (nystagmus) 
 
Involuntary movements including tremor (ufrivillige bevegelser inkl. skjelving) 
 
Cognitive impairment (kognitiv svikt/forvirring) 
 
Other (annet) 
 
Total score 
 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 12 of 25 
healthy adults is 2.3 (13), and reported mean score in 50 Norwegian patients treated for LNB is 3.5 versus 2.1 in the 
control group (3). 
Patient Health Questionnaire (PHQ-15) at six months. PHQ-15 is a brief, validated questionnaire, which consists of 13 
questions concerning severity of different subjective somatic symptoms the last 4 weeks, and 2 questions concerning 
sleep and tiredness. Each item is scored from 0 to 2, and sum score ranges from 0 to 30. Sum scores of 5, 10, and 15 
represent cutpoints for low, medium, and high symptom severity, respectively (27).  
Short Form-36 (SF-36): SF-36 is a valid and reliable questionnaire assessing health related quality of life. It consists of 
36 questions concerning general health perceptions, physical functioning, physical role functioning, emotional role 
functioning, social role functioning, bodily pain, vitality and mental health. A Norwegian normal material exist (28). 
CSF findings at six and 12 months: Cell count, IgG index, OCB’s, and Bb antibodies  
Other laboratory tests, MRI, and neuropsychological assessments: In a subset of patients at inclusion and six months 
after end of treatment (WP4 of BorrSci).  
Safety as measured by serious adverse events and less serious side effects of treatment (Table 3)  
 
Table 3. Safety measures 
 
Secondary and exploratory objectives and their endpoints and assessments are detailed in WP 3 and 4 (Appendix A) 
3 
OVERALL STUDY DESIGN 
The study is a phase Phase III, randomized, penta-blind, placebo-controlled, multicenter trial with a non-inferiority design. 
The trial will be conducted and reported according to the CONSORT statement (Consolidated Standards of Reporting 
Trials), the SPIRIT initiative (Standard Protocol Items: Recommendations for Interventional Trials), and Good Clinical 
Practice (GCP) standards, and registered in ClinicalTrials.gov 
Study Period 
 
Estimated date of first patient enrolled: 01.10.15 (startup at Sørlandet Hospital 2015, 
recruitment from other centres gradually during 2016) 
Anticipated recruitment period: 01.10.15 - 31.12.19 
Estimated date of last patient completed: 31.12.20 
Treatment Duration: 
Six weeks 
Follow-up: 
13 months 
 
4 
STUDY POPULATION 
4.1 
Selection of Study Population 
The study will be headed from Sørlandet Hospital HF (SSHF). Selected hospitals throughout Norway (5-10) will recruit 
consecutive patients diagnosed with LNB. A contact person, familiar with diagnosis and treatment of LNB, at each study 
site will be trained in the current study and in general GCP.  
4.2 
Number of Patients 
We plan to enroll 120 patients, 60 in each treatment arm.  
4.3 
Inclusion Criteria 
In everyday clinical practice, patients with suspected LNB are routinely examined neurologically and their CSF is 
analyzed regarding cell count, protein level, IgG index, oligoclonal bands (OCB’s) and Bb antibodies (including 
Treatmentweek 
0 
1 
2 
3 
4 
5 
6 
7-10 
Nausea  
 
x 
x 
x 
x 
x 
x 
x 
Vomiting  
 
x 
x 
x 
x 
x 
x 
x 
Diarrhea  
 
x 
x 
x 
x 
x 
x 
x 
Skin reactions 
 
x 
x 
x 
x 
x 
x 
x 
Vaginitis 
 
x 
x 
x 
x 
x 
x 
x 
Blodtests (Hb, Hb, white blood cell count with differential, platelet count, ASAT, ALAT, GT, ALP, 
Creatinine) 
x 
 
x 
 
x 
 
 
 
Other AE or complications  
 
x 
x 
x 
x 
x 
x 
x 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 13 of 25 
calculations whether there are intrathecal production of Bb antibodies). Diagnostics may be somewhat uncertain in 
subacute cases as antibiotic treatment is often initiated before Bb antibody results are available, and Bb antibody 
production may be absent in early phases of LNB. In this trial, we will therefore use the following inclusion criteria:  
1. Neurological symptoms suggestive of LNB without other obvious reasons, and one or both of 
a. CSF pleocytosis (leucocytes ≥5/mm3) 
b. Intrathecal Bb antibodyproduction 
2. Signed informed consent  
During the course of the disease, the patients will be classified as either definite or possible LNB according to European 
diagnostic criteria (Table 4) (1). 
 
Table 4. European diagnostic criteria 
 aIf criterion 3 is lacking after a duration of six weeks, there have to be found Bb-specific antibodies in serum. 
 
 
 
 
4.4 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
 
Age less than 18 years 
 
Pregnancy, breast-feeding and/or women of childbearing potential not using adequate contraception. 
Adequate contraception include oral, injected or implanted hormonal methods of contraception, placement of 
an intrauterine device or system, vasectomized partner, or sexual abstinence imposed during treatment. 
 
Adverse reaction to tetracyclines 
 
Treatment with cephalosporin, penicillin, or tetracycline macrolide during the last 14 days before start of 
doxycycline treatment * 
 
Serious liver or kidney disease that contraindicates use of doxycyline 
 
Lactose intolerance 
 
Need to use medications contraindicated according to SmPC of the IMP (Antacid drugs, Didanosin, 
Probenecide, Phenobarbital, Phenytoin, Carbamazepine, Rifamphicin) 
*If used for other conditions than LNB, or if the active LNB has been treated with antibiotic drugs or dosage deviating 
from the protocol   
5 
TREATMENT 
For this study, doxycycline and placebo are defined as Investigational Medicinal Product (IMP). 
Included patients will be randomized to two weeks treatment with oral doxycycline (200 mg once daily) followed by four 
weeks placebo or six weeks treatment with oral doxycycline (200 mg once daily). 
5.1 
Drug Identity, Supply and Storage 
IMPs (active drug and placebo) will be produced at Kragerø Tablettproduksjon. Production documentation is described 
in a separate document (Appendix B).  All included patients will receive active drug (doxycyline) for 14 days, thereafter 
half of them will receive placebo and the other half will receive active drug (doxycyline) for four weeks.  
5.2 
 Dosage and Drug Administration  
Both active drug and placebo will be admistered per os as capsules every 24 hours.  IMPs should be taken together with 
abundant water and a small meal. Iron tablets, calcium preparations youghurt, milk and food/ beverages that contain 
calcium may weaken the effect of doxycycline, and should not be taken less than three hours before or after intake of 
IMP. 
5.3 
Duration of Therapy 
The patients will be treated for six weeks unless disease progression (see section 8.3) or unacceptable toxicity. 
5.4 
Concomitant Medication 
The following medications are not allowed while the patient is in the treatment phase of the study: 
Definite LNB 
All three criteria fulfilled 
Possible LNBa 
Two criteria fulfilled 
                 1. Neurological symptoms suggestive of LNB without other obvious reasons 
                   2. Cerebrospinal fluid pleocytosis 
                   3. Intrathecal Bb antibody production 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 14 of 25 
 
Antacid drugs (single use) 
 
Didanosin (single use) 
 
Probenecide (chronic use) 
 
Phenobarbital (chronic use) 
 
Phenytoin (chronic use) 
 
Carbamazepine (chronic use) 
 
Rifamphicin (chronic use) 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) used by the patient 
will be recorded in the patient’s file and CRF.  
5.5 
Subject Compliance 
Pillcount and patients compliance diary will be used to determine adherence to treatment.  
5.6 
Drug Accountability 
The responsible site personnel will confirm receipt of study drug and will use the study drug only within the framework 
of this clinical study and in accordance with this protocol. Distribution and return of the study drug will be documented 
in the drug accountability log and in the CRFs.  
 
If patients are included in the study after already having started doxyxycline 200 mg per day, the responsible site personnel 
will ensure that the appropriate amount of capsules, depending on the number of days already treated, are removed from 
the study drug packaging before distribution to the patients. The amount of study drug delievered to the patients will be 
documented in the CRF.  
5.7 
Drug Labeling 
The IMPs will have a label permanently affixed to the outside and will be labeled according with GCP and national 
regulations (29, 30), stating that the material is for clinical trial/investigational use only and should be kept out of reach 
of children.The labeling will be prepared by Kragerø Tablettproduksjon. All text will be in Norwegian. Labeling details 
are described in separate document attatched (Appendix C). 
Labels will also include blank lines for:  
 
Patient’s initials 
 
Patient’s enrolment code 
 
Date dispensed 
 
Name of prescribing doctor 
5.8 
Subject Numbering 
Each subject is identified in the study by a unique subject number that is assigned when the subject is entered into the 
eCRF for the first time, after signing the Informed Consent Form. Once assigned the subject number cannot be reused for 
any other subject. The study treatment will be dispensed to the subject by authorized site personnel only.  
6 
STUDY PROCEDURES 
6.1 
Flow Chart 
 
Baseline  
 
Treatment and post-treatment Period 
Week 1-10 
Follow-up Period 
 
Time 
 
Before 
treatment 
 
Once 
weekly 
 
Week 
2 - 4 
Day 6-8 
after start 
of 
treatment  
 
End of 
week 10 
6 months 
after  
end of 
treatment 
12 months 
after  
end of 
treatment 
Enrollment and Infprmed 
consent 
x 
 
 
 
 
 
 
Basic demographics 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Concomitant medications 
x 
 
 
 
 
 
 
x 
 
x 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 15 of 25 
 
Baseline  
 
Treatment and post-treatment Period 
Week 1-10 
Follow-up Period 
 
Time 
 
Before 
treatment 
 
Once 
weekly 
 
Week 
2 - 4 
Day 6-8 
after start 
of 
treatment  
 
End of 
week 10 
6 months 
after  
end of 
treatment 
12 months 
after  
end of 
treatment 
Telephone to check for 
reasons to discontinue IMP 
(treatment failure, toxicity, 
and so on) 
 
 
 
 
x 
 
 
 
Composite clinical score 
(Table 2) 
x 
 
 
 
 
x 
x 
 
x 
FSS  
x 
 
 
 
x 
x 
x 
PHQ-15 
 
 
 
 
 
x 
x 
SF-36 
 
 
 
 
 
x 
 
CSF sampling 
X** 
 
 
 
 
x 
x 
Blood sampling 
X** 
 
 
 
 
x 
x 
IMP delivery 
x 
 
 
 
 
 
 
Patientregistration of 
compliance, concomitant 
medication, and adverse 
events  
(Table 3) 
 
 
x 
 
 
 
 
 
 
 
 
Bloodtests to check toxicity 
of treatment 
 
x 
 
 
xx 
 
 
 
 
Pill count and collection of 
patients diaries 
 
 
 
 
x 
 
 
Cerebral MRI* 
 
 
x 
 
 
x 
 
Neuropsychological 
screening tests* 
 
 
x 
 
 
 
 
 
Neuropsychological testing* 
 
 
 
 
 
x 
 
 
Table 5.  Trial flow chart  
*a subset of patients (WP4) 
** obtained by clinican before inclusion 
6.2 
By Visit 
Clinical data will be collected in a clinical research e-database at Department of clinical research support at Oslo 
University Hospital (OUS).   
 
Informed consent 
Informed consent must have been given voluntarily by each subject before any study specific procedures are initiated.  
6.2.1 
Screening Visit 
 
Evaluate patient eligibility based on symptoms, findings and CSF findings 
 
Demographic data: Age, sex, education, occupational status, civil status 
 
Medical history: Comorbidity, medication, tick bite (ever and last six months), Erythema Migrans (ever and last 
six months), earlier treatment for Lyme borreliosis 
 
Clinical picture: Symptom description, symptom duration 
 
Physical examination: General clinical and neurological examination including composite clinical score 
 
Concomitant medication: All concomitant medication (incl. vitamins, herbal preparation and other “over-the-
counter” drugs) used by the subject within 28 days of treatment start will be recorded in the CRF. 
 
Laboratory analysis from samples obtained before inclusion 
o 
Blood: Hb, white blood cell count with differential, platelet count, ASAT, ALAT, GT, ALP, 
Creatinine, CRP, electrophoresis, Bb antibodies, TBE antibodies. Pregnancy test should have been 
taken within the last 14 days before inclusion in fertile women.  
o 
CSF: Cellcount, protein level, Oligoclonal bands, Bb antibodies, PCR for Herpes Simplex Virus (HSV), 
Varicella Zoster Virus (VZV) and Enterovirus  
 
In addition aliquots of specimens will be transferred for biobank storage after inclusion 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 16 of 25 
 
FSS 
6.2.2 
During Treatment 
 
Adverse events: Diary (on paper or electronic - optional) every week until four weeks after ended treatment 
 
Registration of concomitant medications 
 
Blood analyses 2 and 4 weeks after treatment start (Hb, white blood cell count with differential, platelet count, 
ASAT, ALAT, GT, ALP, Creatinine) 
 
Talk (meeting or telephone, optional) 1 week after treatment start to uncover reasons for discontinuation of IMP 
(deterioration, progression or other - see 6.3)  
 
Non-scheduled visit in case of disease progression SAE or SUSAR 
 
Cerebral MRI and neuropsychological screening in a subset of patients (see APPENDIX A) 
6.2.3 
End of Treatment Visit (four weeks after ended treatment) 
 
Counting and relinquishment of remaining pills  
 
Collection of patients diary 
 
Registration of symptoms, concomitant medication, and adverse events 
 
Composite clinical score 
 
FSS 
6.2.4 
Withdrawal Visit (desirable but voluntary) 
 
Interview about medical history, symptom description, concomitant medication, reason for withdrawal, and 
adverse events 
 
Composite clinical score 
6.2.5 
Six months After End of Treatment (Follow-up) 
 
Interview about symptom description, concomitant medication, and sick leave attributable to LNB 
 
Composite clinical score 
 
FSS, PHQ-15, SF-36 
 
Laboratory analyses 
o 
Blood: Hb, white blood cell count with differential, platelet count, ASAT, ALAT, GT, ALP, Creatinine, 
CRP, electrophoresis, Bb antibodies, TBE antibodies 
o 
CSF: Cellcount, protein level, Oligoclonal bands, Bb antibodies,  
o 
In addition aliquots of specimens will be transferred for biobank storage  
 
Cerebral MRI and neuropsychological testing in a subset of patients (Appendix A) 
 
6.2.6 
Twelve months After End of Treatment (Follow-up) 
 
Interview about symptom description, concomitant medication, and sick leave attributable to LNB 
 
Composite clinical score 
 
FSS, PHQ-15 
 
Laboratory analyses 
o 
Blood: Hb, white blood cell count with differential, platelet count, ASAT, ALAT, GT, ALP, Creatinine, 
CRP, electrophoresis, Bb antibodies, TBE antibodies 
o 
CSF: Cellcount, protein level, Oligoclonal bands, Bb antibodies,  
o 
In addition aliquots of specimens will be transferred for biobank storage  
6.3 
Criteria for Patient Discontinuation  
Patients may be discontinued from study treatment and assessments at any time. Specific reasons for discontinuing a 
patient for this study are: 
 
Voluntary discontinuation by the patient who is at any time free to discontinue his/her participation in the study, 
without prejudice to further treatment. 
 
Safety reason as judged by the coordinating investigators 
 
Major protocol deviation 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 17 of 25 
 
Incorrect enrolment ie, the patient does not meet the required inclusion/exclusion criteria for the study 
 
Patient lost to follow-up 
 
A female patient becoming pregnant during treatment 
 
Disease progression  
 
Deterioration in the patient’s condition which in the opinion of the coordinatingl investigators warrants study 
medication discontinuation (to be recorded as an AE or under Investigator Discretion) 
 
Patient’s non-compliance to  study treatment and/or procedures 
6.4 
Procedures for Discontinuation 
6.4.1 
Patient Discontinuation 
Patients who withdraw or are withdrawn from the study, will either stop further treatment or receive another antibiotic 
therapy. If possible, a final assessment shall be made (withdrawal visit and/or follow-up visits). The reason for 
discontinuation will be recorded, and the investigator will follow up any significant adverse events until the outcome is 
either recovered or resolved. Patients who withdraw or are withdrawn from the study before start of treatment, will be 
replaced. 
6.4.2 
Trial Discontinuation 
The whole trial may be discontinued in the event of any of the following: 
 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
 
Medical or ethical reasons affecting the continued performance of the trial 
 
Difficulties in the recruitment of patients 
The coordinating investigators will inform all investigators, the relevant Competent Authorities and Ethics Committees 
of the termination of the trial along with the reasons for such action. If the study is terminated early on grounds of safety, 
the Competent Authorities and Ethics Committees will be informed within 15 days. 
6.5 
Laboratory Tests 
Blood and CSF samples will be analyzed at the local laboratories for registration of side effects of treatment and for 
diagnostic purposes according to existing routines. In addition, aliquots of specimens will be transferred for biobank 
storage and applied for genetic and immunologic purposes. Details regarding collection, handling, storage, packaging, 
shipment and destruction will be described in WP3 and WP4 in BorrSci (Appendix A). 
 
7 
ASSESSMENTS  
7.1 
Assessment of Efficacy  
The treatment efficacy will be assessed by measuring symptoms and signs six months after ended treatment and 
summarized on a composite clinical score which reports subjective symptoms and objective findings in a clinical 
neurological examination. . The primary endpoint is improvement in the composite clinical score. The score is a 
modified version of a score used in an earlier treatment trial in LNB (5). Even if the score is not validated it is, in our 
opinion, the best way to assess outcome after LNB as it addresses and grades the most commonly reported remaining 
symptoms and signs. Our experience with the previous score was that it worked well, but some points were not entirely 
clear or somewhat overlapping. We therefore find it appropriate and more accurate to simplify it to reduce interrater 
disagreement and scala biases. 
To support treatment effect assessment we have chosen several secondary endpoints; inflammatory findings in CSF as 
measured by cellcount, protein level and oligoclonal bands, fatigue as measured by FSS, burden of somatic symptoms as 
measured by PHQ-15, and health related quality of life as measured by SF-36. We will also apply proportion of patients 
with full recovery (score zero on the composite clinical score) as a secondary endpoint. In a subset of patients, MRI 
findings and neuropsychological profile will be a secondary endpoint. 
7.2 
Safety and Tolerability Assessments  
Significant findings that are present prior to the signing of informed consent will be included in the relevant medical 
history/ current medical condition page of the CRF. For the assessment of safety and tolerability, refer to Flow chart in 
Section 6 and Table 3.  


 
BorrSciWP2 Version no.3.  – November 2016 
Page 18 of 25 
8 
SAFETY MONITORING AND REPORTING 
The site invetigators and the coordinating investigators are responsible for the detection and documentation of events 
meeting the criteria and definition of an adverse event (AE) or serious adverse event (SAE). Each patient will be instructed 
to contact the site investigator immediately should they manifest any signs or symptoms they perceive as serious. 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. The term AE is used to include both serious and non-serious 
AEs. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability or incapacity 
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one 
of the outcomes listed above 
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical events may 
not be immediately life threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the listed outcomes in the definitions above. In such situations, or in doubtful cases, the 
case should be considered as serious. Hospitalization for administrative reason (for observation or social reasons) is 
allowed at the investigator’s discretion, and will not qualify as serious unless there is an associated adverse event 
warranting hospitalization. 
8.1.1 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
Adverse Reaction: all untoward and unintended responses to an investigational medicinal product related to any dose 
administered. 
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not consistent with the applicable 
product information. 
Suspected Unexpected Serious Adverse Reaction: SAE (see section 8.1.2) that is unexpected as defined in section 8.2 
and possibly related to the IMP. 
8.2 
Expected Adverse Events 
Nausea, vomiting, diarrhea, vaginitis, skin reactions, disturbancies in bloodtests are all expected AE. The manufactorers 
SmPC will be used as reference document. All AE will be recorded in the CRF.  
8.3 
Disease Progression 
Disease progression in this trial is defined as worsening of the patient’s condition attributable to LNB despite treatment 
for 14 days with doxycycline, or serious progression of neurological signs from CNS (myelitis or encephalitis) during 
treatment. Events that are definitely due to disease progression will not be reported as an AE/SAE unless the investigator 
considers there is a causal relationship between treatment with IMP or protocol design/procedures and the disease 
progression/recurrence. Death due to progressive disease is to be recorded on a specific from in the CRF but not as an 
SAE. 
8.4 
Time Period for Reporting AE and SAE  
For each patient the standard time period for collecting and recording AE and SAEs will begin at start of study treatment 
and will continue for at least four weeks following the last dose of study treatment.for each patient.  
During the course of the study all AEs and SAEs will be proactively followed up for each patient; events should be 
followed up to resolution, unless the event is considered by the investigator to be unlikely to resolve due to the underlying 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 19 of 25 
disease. Every effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. 
8.5 
Recording of Adverse Events 
If the patient has experienced adverse event(s), the investigator will record the following information in the CRF: 
 
The nature of the event(s) will be described by the investigator in precise standard medical terminology (i.e. not 
necessarily the exact words used by the patient). 
 
The duration of the event will be described in terms of event onset date and event ended data. 
 
The intensity of the adverse event: Mild/Moderate/Severe according to Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE). 
 
The Causal relationship of the event to the study medication will be assessed as one of the following: 
Unrelated: 
There is not a temporal relationship to investigational product administration (too early, or late, or investigational 
product not taken), or there is a reasonable causal relationship between non-investigational product, concurrent 
disease, or circumstance and the AE. 
Unlikely:  
There is a temporal relationship to investigational product administration, but there is not a reasonable causal 
relationship between the investigational product and the AE. 
Possible:  
There is reasonable causal relationship between the investigational product and the AE. Dechallenge information 
is lacking or unclear. 
Probable:  
There is a reasonable causal relationship between the investigational product and the AE. The event responds to 
dechallenge. Rechallenge is not required. 
Definite:  
There is a reasonable causal relationship between the investigational product and the AE.  
 
Action taken 
 
The outcome of the adverse event – whether the event is resolved or still ongoing. 
8.6 
Reporting Procedure 
8.6.1 
AEs and SAEs 
All adverse events and serious adverse events that should be reported as defined in section 8.1.1 will be recorded in the 
patient's CRF. 
SAEs must be reported by the site investigator to the sponsor represented by the coordinating investigators within 24 
hours after the site has gained knowledge of the SAE. Every SAE must be documented by the investigator on the SAE 
pages (to be found as part of the CRF). The Serious Adverse Event Report Form must be completed and signed. The 
initial report shall promptly be followed by detailed, written reports if necessary. The initial and follow-up reports shall 
identify the trial subjects by unique code numbers assigned to the latter.  
The coordinating investigators keep detailed records of all SAEs reported and perform an evaluation with respect to 
seriousness, causality and expectedness. 
8.6.2 
SUSARs 
SUSARs will be reportd to the Competent Authority according to national regulation. The following timelines should be 
followed: 
On suspicion of SUSAR the site investigator report to the sponsor represented by the coordinating investigators. If the 
coordinating investigators consider the event as a SUSAR they report it to the Department of clinical research support. 
Personell at the department of clinical research support, not otherwise involved in the trial, will unblind the treatment and 
ensure that all relevant information about SUSARs that are fatal or life-threatening is recorded and reported unblinded as 
soon as possible to the Competent Authority, no later than seven days after knowledge of such a case, and that relevant 
follow-up information is subsequently communicated within an additional eight days. 
All other SUSARs will be reported to the Competent Authority concerned and to the Ethics Committee concerned as soon 
as possible but within a maximum of 15 days of first knowledge. 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 20 of 25 
SUSARs will be reported using the CIOMS form.  
8.6.3 
Annual Safety Report 
Once a year throughout the clinical trial, the sponsor will provide the Competent Authority with an annual safety report. 
The format will comply with national requirements.  
8.6.4 
Clinical Study Report 
The adverse events and serious adverse events occurring during the study will be discussed in the safety evaluation part 
of the Clinical Study Report. 
8.7 
Procedures in Case of Emergency 
The site investigators are responsible for assuring that there are procedures and expertise available to cope with 
emergencies during the study. Code break may be relevant in case of toxicity and other events were knowledge of 
treatmentarm matters for further management of the patient. Envelopes with randomization codes are available in such 
cases. 
9 
DATA MANAGEMENT AND MONITORING   
9.1 
Case Report Forms (CRFs) 
The designated investigator staff will enter the data required by the protocol into an electronic Case Report Form (CRF). 
The site investigators are responsible for assuring that data entered into the CRF is complete, accurate, and that entry is 
performed in a timely manner. The signature of the investigator will attest the accuracy of the data on each CRF. If any 
assessments are omitted, the reason for such omissions will be noted on the CRFs. Corrections, with the reason for the 
corrections will also be recorded.  
9.2 
Source Data  
The medical records for each patient should contain information which is important for the patient’s safety and continued 
care, and to fulfill the requirement that critical study data should be verifiable.  
To achieve this, the medical records of each patient should clearly describe: 
 
That the patient is participating in the study, e.g. by including the enrollment number and the study code or other 
study identification; 
 
Date when Informed Consent was obtained from the patient and statement that patient received a copy of the signed 
and dated Informed Consent; 
 
Results of all assessments confirming a patient’s eligibility for the study; 
 
Diseases (past and current; both the disease studied and others, as relevant); 
 
Treatments withdrawn/withheld due to participation in the study; 
 
Results of assessments performed during the study; 
 
Treatments given, changes in treatments during the study and the time points for the changes;  
 
Visits to the clinic / telephone contacts during the study, including those for study purposes only; 
 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments;  
 
Date of, and reason for, discontinuation from study treatment;  
 
Date of, and reason for, withdrawal from study; 
 
Date of death and cause of death, if available; 
 
Additional information according to local regulations and practice. 
9.3 
Study Monitoring  
We plan a strategic monitoring with focus on the most critical data, such as primary endpoint data and key safety data, 
including adverse events and a higher source document verification (SDV) coverage on the first one or two subjects 
enrolled at each site in order to establish an early data quality “yardstick” for each site. A risk-based monitoring plan 
will be made. 
Monitors, and/or competent authorities will be allowed access to source data for SDV in which case a review of those 
parts of the hospital records relevant to the study may be required.  


 
BorrSciWP2 Version no.3.  – November 2016 
Page 21 of 25 
9.4 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. Patient files shall be 
kept for the maximum period of time permitted by each hospital. The study documentation (CRFs, Site File etc) shall be 
retained and stored during the study and for 15 years after study closure. All information concerning the study will be 
stored in a safe place inaccessible to unauthorized personnel. 
9.5 
Database management 
The Department of clinical research support, OUS, will perform data management in accordance with ICH guidelines, 
CRS SOPs, and described in the trial specific Data Handling Plan. The plan will describe the processes and documentation 
related to data capture and data quality control.  The data will be captured in an electronic CRF (eCRF). The eCRF will 
ensure security (to prevent unauthorized access to, or loss of data) and storage during trial. After database lock, the trial 
will be archived by sponsor and removed from the eCRF.  
10 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1 
Determination of Sample Size ** Manuela? 
In a previous trial on well-characterized LNB patients, 102 patients were treated with either oral doxycyline or IV 
cephtriaxone for two weeks. From this trial we have available outcome scores at 12 months from 93 patients, measured 
on a slightly different composite clinical scale, but with the same max score of 64. We consider the scales as so similar 
that the results from the former trial can be used in power analyses in the current planned trial. The mean score in the 
former trial was 1.7 with a standard deviation (SD) of 2.6.  
10.2 
Randomization  
10.2.1 
Allocation- sequence generation 
Computerized allocation to two or six weeks doxycycline (1:1) will be performed at Department of clinical research 
support, OUS by an internet based solution.  Automatic e-mails with the result of the randomization will be sent to the 
involved hospitals.  
10.2.2 
Blinding and emergency unblinding 
To achieve maximum objective performance and reporting of the study we will use the “penta blind” approach. First, we 
use the traditional double blind design with blinding of participants and investigators (first and second blinding). The staff 
evaluating end-points and adverse effects is blinded to all other study information (third blinding). Then the content of all 
tables and figures are fixed before any study data are available (fourth blinding) and then the statistical procedures are 
performed with treatment groups marked as group A and B. First, when all the tables and figures are filled out, the 
randomization code is broken. Unblinding for the investigator will be done when all patients have completed the six 
month visit (primary and several secondary end-points answered), and for the patients after the 12 month registration.  
Emergency unblinding is permissible as described in section 8.7. Unblindingprocedure in case of SUSAR is described in 
section 8.6.2. 
10.3 
Population for Analysis 
 The following populations will be considered for the analyses:  
- 
Intention to treat (ITT) population: All randomized participant, regardless of protocol adherence.   
- 
Per-protocol population (PP): Includes all without significant protocol deviation 
- 
Safety population: Includes all subjects who have received at least one dose of study medication. Subjects who 
withdraw from the study will be included in the safety analysis. A list of withdrawn subjects, preferably with the 
reasons for withdrawal, will be made. 
10.4 
Planned analyses 
The main statistical analysis is planned when all patients have completed the six months visit. Deviation from the original 
statistical plan will be described and justified in the Clinical Study Report. Amendments to plan can be done until day of 
database lock. 
10.5 
Statistical Analysis **Manuela? 
Results will be reported as mean scores with standard deviation or proportions as appropriate. 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 22 of 25 
To compare the two groups on the primary outcome, we will use a general linear model with treatment group was factor 
and adjust for duration of symptoms, gender and age. The analysis will be conducted according to the intention to treat 
principle.   
For other analysis, comparison between groups will be done with e.g. independent samples t-test, nonparametric Mann-
Whitney-U test or Pearsons chi-square test for crosstabs as appropritate.  
P-values <0.05 are considered statistically significant. 
 
11 
STUDY MANAGEMENT 
11.1 
Investigator Delegation Procedure 
The coordinating investigators are responsible for making and updating a “delegation of tasks” listing all the involved co-
workers and their role in the project. They will ensure that appropriate training relevant to the study is given to all of these 
staff, and that any new information of relevance to the performance of this study is forwarded to the staff involved. 
11.2 
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
11.3 
Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol 
(Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics Committee according 
national regulations. 
11.4 
Audit and Inspections 
Authorized representatives of a Competent Authority and Ethics Committee may visit the centre to perform inspections, 
including source data verification. Likewise the representatives from sponsor may visit the center to perform an audit. 
The purpose of an audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, and any applicable regulatory requirements. The principal investigators will ensure 
that the inspectors and auditors will be provided with access to source data/documents. 
12 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration of patient data will 
be carried out in accordance with national personal data laws. 
12.1 
Ethics Committee Approval 
The study protocol, including the patient information and informed consent form to be used, must be approved by the 
regional ethics committee before enrolment of any patients into the study. 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse events and/or 
major amendments to the protocol as per national requirements. 
12.2 
Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before commencement of the study. 
The protocol will also be registered in www.clinicaltrials.gov before inclusion of the first patient. 
12.3 
Informed Consent Procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about the nature, 
purpose, possible risk and benefit of the study. They will be informed as to the strict confidentiality of their patient data, 
but that their medical records may be reviewed for trial purposes by authorized individuals other than their treating 
physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in 
the protocol whenever she/he wants. This will not prejudice the patient’s subsequent care. Documented informed consent 
must be obtained for all patients included in the study before they are registered in the study. This will be done in 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 23 of 25 
accordance with the national and local regulatory requirements. The investigator is responsible for obtaining signed 
informed consent. 
A copy of the patient information and consent will be given to the patients. The signed and dated patient consent forms 
will be filed in the Investigator Site File binder and also scanned to be part of the patient’s electronic medical record at 
the hospital. 
12.4 
Subject Identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment or undergone any 
study specific procedure) including patient’s date of birth and personal number, full names and last known addresses.  
The patients will be identified in the CRFs by patient number, initials and date of birth. 
13 
TRIAL SPONSORSHIP AND FINANCING 
The study is sponsored by HELSEFORSK funds from the Research Counsil of Norway administered by Sørlandet 
Hospital HF. The funds are assigned the composite project BorrSci. 
14 
TRIAL INSURANCE 
The coordinating investigators will obtain insurance coverage through membership of the Drug Liability Association.  
15 
PUBLICATION POLICY 
Upon study completion, the results of this study will be submitted for publication. The results of this study will also be 
submitted to the Competent Authority and the Ethics Committee according to national regulations. All personnel who 
have contributed significantly with the planning and performance of the study (Vancouver convention 1988) may be 
included in the list of authors. 
 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 24 of 25 
 
16 
REFERENCES 
1. 
Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I. EFNS guidelines on the diagnosis 
and management of European Lyme neuroborreliosis. European journal of neurology : the official journal of the 
European Federation of Neurological Societies. 2010;17(1):8-16, e1-4. 
2. 
Ljostad U, Mygland A. Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; 
frequency, pattern and risk factors. European journal of neurology : the official journal of the European Federation of 
Neurological Societies. 2010;17(1):118-23. 
3. 
Eikeland R, Mygland A, Herlofson K, Ljostad U. European neuroborreliosis: quality of life 30 months after 
treatment. Acta neurologica Scandinavica. 2011;124(5):349-54. 
4. 
Eikeland R, Ljostad U, Mygland A, Herlofson K, Lohaugen GC. European neuroborreliosis: 
neuropsychological findings 30 months post-treatment. European journal of neurology : the official journal of the 
European Federation of Neurological Societies. 2012;19(3):480-7. 
5. 
Ljostad U, Skogvoll E, Eikeland R, Midgard R, Skarpaas T, Berg A, et al. Oral doxycycline versus intravenous 
ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. The 
Lancet Neurology. 2008;7(8):690-5. 
6. 
Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y Follow-up study of patients with 
neuroborreliosis. Scandinavian journal of infectious diseases. 2002;34(6):421-5. 
7. 
Karkkonen K, Stiernstedt SH, Karlsson M. Follow-up of patients treated with oral doxycycline for Lyme 
neuroborreliosis. Scandinavian journal of infectious diseases. 2001;33(4):259-62. 
8. 
Vrethem M, Hellblom L, Widlund M, Ahl M, Danielsson O, Ernerudh J, et al. Chronic symptoms are common 
in patients with neuroborreliosis -- a questionnaire follow-up study. Acta neurologica Scandinavica. 2002;106(4):205-8. 
9. 
Treib J, Fernandez A, Haass A, Grauer MT, Holzer G, Woessner R. Clinical and serologic follow-up in 
patients with neuroborreliosis. Neurology. 1998;51(5):1489-91. 
10. 
Cameron DJ. Proof that chronic lyme disease exists. Interdisciplinary perspectives on infectious diseases. 
2010;2010:876450. 
11. 
Strle K, Stupica D, Drouin EE, Steere AC, Strle F. Elevated levels of IL-23 in a subset of patients with post-
lyme disease symptoms following erythema migrans. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America. 2014;58(3):372-80. 
12. 
Soloski MJ, Crowder LA, Lahey LJ, Wagner CA, Robinson WH, Aucott JN. Serum inflammatory mediators as 
markers of human Lyme disease activity. PloS one. 2014;9(4):e93243. 
13. 
Steere AC, Klitz W, Drouin EE, Falk BA, Kwok WW, Nepom GT, et al. Antibiotic-refractory Lyme arthritis is 
associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. The Journal of experimental medicine. 
2006;203(4):961-71. 
14. 
Belongia EA. Epidemiology and impact of coinfections acquired from Ixodes ticks. Vector borne and zoonotic 
diseases (Larchmont, NY). 2002;2(4):265-73. 
15. 
Aalto A, Sjowall J, Davidsson L, Forsberg P, Smedby O. Brain magnetic resonance imaging does not 
contribute to the diagnosis of chronic neuroborreliosis. Acta radiologica (Stockholm, Sweden : 1987). 2007;48(7):755-
62. 
16. 
Djukic M, Schmidt-Samoa C, Nau R, von Steinbuchel N, Eiffert H, Schmidt H. The diagnostic spectrum in 
patients with suspected chronic Lyme neuroborreliosis--the experience from one year of a university hospital's Lyme 
neuroborreliosis outpatients clinic. European journal of neurology : the official journal of the European Federation of 
Neurological Societies. 2011;18(4):547-55. 
17. 
Ljostad U, Mygland A. The phenomenon of 'chronic Lyme'; an observational study. European journal of 
neurology : the official journal of the European Federation of Neurological Societies. 2012;19(8):1128-35. 
18. 
Bremell D, Dotevall L. Oral doxycycline for Lyme neuroborreliosis with symptoms of encephalitis, myelitis, 
vasculitis or intracranial hypertension. Eur J Neurol. 2014. 
19. 
Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, et al. Study and treatment of post Lyme 
disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60(12):1923-30. 
20. 
Oksi J, Nikoskelainen J, Hiekkanen H, Lauhio A, Peltomaa M, Pitkaranta A, et al. Duration of antibiotic 
treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. 
European journal of clinical microbiology & infectious diseases : official publication of the European Society of 
Clinical Microbiology. 2007;26(8):571-81. 
21. 
Sjowall J, Ledel A, Ernerudh J, Ekerfelt C, Forsberg P. Doxycycline-mediated effects on persistent symptoms 
and systemic cytokine responses post-neuroborreliosis: a randomized, prospective, cross-over study. BMC infectious 
diseases. 2012;12:186. 
22. 
Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, et al. Two controlled trials of antibiotic 
treatment in patients with persistent symptoms and a history of Lyme disease. The New England journal of medicine. 
2001;345(2):85-92. 


 
BorrSciWP2 Version no.3.  – November 2016 
Page 25 of 25 
23. 
Delong AK, Blossom B, Maloney EL, Phillips SE. Antibiotic retreatment of Lyme disease in patients with 
persistent symptoms: a biostatistical review of randomized, placebo-controlled, clinical trials. Contemporary clinical 
trials. 2012;33(6):1132-42. 
24. 
Oksi J, Nikoskelainen J, Viljanen MK. Comparison of oral cefixime and intravenous ceftriaxone followed by 
oral amoxicillin in disseminated Lyme borreliosis. European journal of clinical microbiology & infectious diseases : 
official publication of the European Society of Clinical Microbiology. 1998;17(10):715-9. 
25. 
Dattwyler RJ, Wormser GP, Rush TJ, Finkel MF, Schoen RT, Grunwaldt E, et al. A comparison of two 
treatment regimens of ceftriaxone in late Lyme disease. Wiener klinische Wochenschrift. 2005;117(11-12):393-7. 
26. 
Wahlberg P, Granlund H, Nyman D, Panelius J, Seppala I. Treatment of late Lyme borreliosis. The Journal of 
infection. 1994;29(3):255-61. 
27. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for evaluating the severity of 
somatic symptoms. Psychosomatic medicine. 2002;64(2):258-66. 
28. 
Loge JH, Kaasa S. Short form 36 (SF-36) health survey: normative data from the general Norwegian 
population. Scandinavian journal of social medicine. 1998;26(4):250-8. 
29. 
Helse-og omsorgsdepartementet. Merking av utprøvepreparater 2009. Available from: 
https://lovdata.no/dokument/SF/forskrift/2009-10-30-1321. 
30. 
Norwegian Medicines Agency. Veiledning ved klinisk forskning med legemidler på mennesker. Available 
from: http://www.legemiddelverket.no/Godkjenning_og_regelverk/Klinisk-
utproving/Veiledning_klinisk_forskning/Sider/default.aspx. 
 
17 
LIST OF APPENDICES 
 
A  Protocoll for work packages 3, 4, and 5 in BorrSci 
B  Chemical and pharmacological documentation of IMPs 
C     Details of labeling of IMPs 
D     Informed consent