Randomized, Double-blind, Placebo-controlled Study to Measure 2L®ALERG (Homeopathic Drug) Efficacy on Symptoms of Allergic Rhinitis and Allergic Rhinoconjunctivitis in Patients With a Seasonal Allergy to Grass Pollen
Phase: PHASE4
Conditions: Seasonal Allergy
Sponsor: Labo'Life

 
Version 1.0, 04 February 2016, Page 1 
 
 
 
 
 
Clinical Study Protocol 
 
 
Randomized, double-blind, placebo-controlled study to measure 2L®ALERG 
(homeopathic drug) efficacy on symptoms of allergic rhinitis and allergic 
rhinoconjunctivitis in patients with a seasonal allergy to grass pollen 
 
 
Sponsor:  
Labo'Life Belgium 
Parc scientifique CREALYS 
Rue Camille Hubert, 11 
5032 Gembloux 
BELGIUM 
Phone: +32 81 40 87 81 - belgium@labolife.com 
 
EudraCT number : 2016-000097-38 
Study acronym: LLB-2016-01 
  
 
 
 
 

 
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PROTOCOL INVESTIGATOR AGREEMENT 
I agree: 
• 
To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, and with any other study 
conduct procedures and/or study conduct documents provided by Sponsor. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about the 
Sponsor’ investigational product(s) and other study-related duties and functions as 
described in the protocol. 
• 
To perform no other biological assays on the clinical samples except those described in 
the protocol or its amendment(s).  
• 
To co-operate with a representative of Sponsor’s designed Contract Research 
Organization (CRO) in the monitoring process of the study and in resolution of queries 
about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational product, and more generally about his/her financial 
ties with the sponsor. Sponsor will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
• 
To provide Sponsor with an updated Curriculum Vitae and other documents required by 
regulatory agencies for this study. 
 
Study Title 
Randomized, double-blind, placebo-controlled study to measure 
2L®ALERG (homeopathic drug) efficacy on symptoms of 
allergic rhinitis and allergic rhinoconjunctivitis in patients with a 
seasonal allergy to grass pollen 
EudraCT number 
2016-000097-38 
Date of protocol 
22 December 2015 
Study Acronym 
LLB-2016-01 
Investigator name 
 
Signature 
 
Date 
 
 
 
 

 
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SPONSOR INFORMATION SHEET 
Study Title 
Randomized, double-blind, placebo-controlled study to 
measure 2L®ALERG (homeopathic drug) efficacy on 
symptoms of allergic rhinitis and allergic rhinoconjunctivitis 
in patients with a seasonal allergy to grass pollen 
Study Acronym 
LLB-2016-01 
EudraCT number 
2016-000097-38 
1. Medical Advisor 
Dr. Xavier Van der Brempt, Pneumo-allergologie, 7, Rue du Petit-Bois, 6900 Waha, 
Belgium 
2. Principal Investigator 
Dr. Stéphane Heijmans, ResearchLink sprl, 78, Rue de la Station, 1630 Linkebeek, 
Belgium 
3. Project Manager (Sponsor) 
Béatrice Lejeune, Ind. Pharm. 
4. Project Manager of the Contract Research Organization (CRO) 
Isabelle Coupienne, BSc., ECSOR, 7, Rue Tienne Galop, 1450 Blanmont, Belgium 
5. Medical writing (Sponsor) 
Jacqueline Lafon, BSc., Labo’Life France 
6. Medical Writing, Data Management and Biostatistics (CRO) 
Jacques Bruhwyler, PhD 
7. Clinical Monitoring (CRO) 
Marie Verbeeren, Graduated Nurse 
8. Pharmacovigilance (CRO) 
Dr. Paul Willems, Semaphar, 31, Rue Francourt, 1370 Lathuy (Jodoigne), Belgium 
 
 

 
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SYNOPSIS 
Study Title 
Randomized double-blind, placebo-controlled study to measure 
2L®ALERG  (homeopathic drug) efficacy on symptoms of allergic rhinitis 
and allergic rhinoconjunctivitis in patients with seasonal allergy to grass 
pollen 
Objectives 
Primary objective: To demonstrate the superiority of 2L®ALERG over 
placebo in terms of efficacy on the symptoms of allergic rhinitis and 
allergic rhinoconjunctivitis in patients with seasonal allergy to grass pollen, 
corrected according to rescue medication intake 
Secondary objectives: To compare the allergy symptoms, the rescue 
medication intake, the quality of life and the safety in patients treated with 
2L®ALERG or with a placebo  
Study design 
Multicentre, randomized, double-blind, two-parallel group, interventional 
placebo-controlled study 
Phase IV - notified homeopathic medication, marketed since 2002 
Number of centres planned 20 General Practitioners (GPs) 
Study Therapy 
Micro-Immunotherapy medication 
 Planning study 
Total study duration: maximum 9 months 
Recruitment period: 1 month 
Duration of patient treatment: 6 months 
Duration of patient follow-up : up to 8 months 
Patient Population 
50 patients per group to achieve 40 cases completed per group, i.e., a total 
of 100 patients included for 80 cases completed. 
Duration of Study Follow-
Up 
Screening  before the peak of pollination 
Treatment set up two months before traditional pollen peak, then visits at 3 
months and 6 months, or end of the peak. 
Inclusion criteria 
- Age ≥18 years, male and female 
- Woman of childbearing age using effective contraceptive means 
- Patient having the faculties to understand and respect the constraints of 
the study  
- Symptomatic since at least two seasons and confirmed by positive skin 
test and/or the presence of IgE for grasses (prick test defined as positive 
if higher than or equal to half the negative control; IgE positive if at least 
class 3 (≥ 3.5 kU / L); these tests must have been performed at the latest 
at the first screening visit 
- Signature of the Informed Consent Form 
Exclusion criteria 
- Pregnant woman or woman wishing to become pregnant 
- Breastfeeding woman 
- Patient with an acute exacerbation of allergic rhinitis 
- Patient with uncontrolled asthma 
- Immunotherapy received within the last two years 
- Patient with a known lactose intolerance 
- Patient who participated in a clinical study in the previous three months 
- Patient who is not sufficiently motivated to engage on a follow-up period 
of 6 months or more, unable to complete the patient diary, or likely to 

 
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travel or to move before the end of the study, 
- Patient taking nasal or bronchial inhaled corticosteroids on a long term 
basis (intermittent consumption during the season is permitted provided 
it is mentioned in the patient’s records) 
Primary endpoint 
Area under the curve [AUC](total score of symptoms taking into account 
the Total 5 Symptom Score (T5SS) and consumption of rescue medications 
(RM) on the Y-axis, and time on X axis) during the entire follow-up period. 
Secondary endpoints 
- Total score on the T5SS scale and individual symptoms scores 
- Frequency of daily RM consumption 
- Evaluation of the quality of life: AUC (total score of 3 questions of 
quality of life included in the diary card on the Y-axis, and time on X 
axis) during the entire follow-up period  
- Safety: adverse events (AEs) and serious adverse events (SAEs) 
Sample size 
A sample size of 32 patients in each group will have 90% power to detect a 
difference in means of 25 (the difference between a placebo group mean, 
μ1, of 80 and a 2L®ALERG group mean, μ2, of 55) assuming that the 
common standard deviation is 30 using a two group t-test with a 0.05 two-
sided significance level. 
With a sample size of 43 patients in each group, the same assumptions are 
valid with a common standard deviation of 35. 
The final recommendation will be to include 50 patients per group in order 
to achieve at least 40 evaluable patients per group taking into account a 
potential drop-out rate of 20%. 
Study cohorts 
Two cohorts will be defined: 
- Intention-to-treat (ITT) cohort including all patients having been exposed 
to at least one dose of the investigational product and in whom at least 
one efficacy or safety information has been collected after V0. 
- Per protocol (PP) cohort including of the ITT having strictly adhered to 
the protocol and having a compliance between 80% and 120%. 
The primary cohort for the statistical analyses will be the ITT cohort. 
The patients who will prematurely stop the study will not be replaced. 
Statistical analysis 
A Statistical Analysis Plan (SAP) will be written by the Biostatistician of 
the CRO in charge of the study. This document will constitute the reference 
document as far as statistical analyses and statistical methodologies are 
concerned. It will be approved and signed by the Sponsor and the Principal 
Investigator before the last patient last visit at the latest. 
The objective will be to demonstrate the superiority of 2L®ALERG over 
placebo. This will be demonstrated using an independent Student’s test 
comparing the over-time T5SS (corrected with RM) evolution (AUCs) of 
the two study groups, over the whole treatment period. A P value lower 
than 5% will be considered statistically significant. 
 

 
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ABBREVIATIONS 
AE  
Adverse Event 
AFMPS 
Agence Féderale des Médicaments et des Produits de Santé 
AUC 
Area Under the Curve 
CD  
Cluster Differentiation 
CH 
Centésimale Hahnemannienne 
CRA 
Clinical Research Associate 
CRF 
Case Report Form  
CRO 
Clinical Research Organization 
GCP 
Good Clinical Practice 
GM-SF 
Granulocyte-Macrophage-Stimulating Factor 
HLA 
Human Leukocyte Antigen 
ICF 
Inform Consent Form 
ICH 
International Conference on Harmonization  
IgE 
Immunoglobulin E 
IL   
Interleukin 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per Protocol 
RM  
Rescue mediation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SNA 
Specific Nucleic Acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T5 SS  
Total 5 Symptoms Score 
Th 
T helper 
TNF 
Tumour Necrosis Factor  
 
 
 

 
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Table of Contents 
1. 
BACKGROUND AND STUDY RATIONALE ............................................................................ 9 
1.1. 
BACKGROUND ................................................................................................................................ 9 
1.2. 
STUDY RATIONALE ........................................................................................................................ 9 
1.3. 
BENEFITS AND RISKS FOR PEOPLE INVOLVED IN THE STUDY ....................................................... 14 
1.4. 
DESCRIPTION AND JUSTIFICATION OF THE THERAPEUTIC SCHEMA .............................................. 14 
2. 
OBJECTIVES AND ENDPOINTS .............................................................................................. 15 
2.1. 
PRIMARY OBJECTIVE AND PRIMARY ENDPOINT ........................................................................... 15 
2.2. 
SECONDARY OBJECTIVES AND SECONDARY ENDPOINTS .............................................................. 15 
3. 
STUDY DESIGN ........................................................................................................................... 16 
3.1. 
METHODOLOGY ........................................................................................................................... 16 
3.2. 
STUDY DESIGN ............................................................................................................................. 16 
4. 
STUDY POPULATION ................................................................................................................ 17 
4.1. 
DESCRIPTION OF THE POPULATION .............................................................................................. 17 
4.2. 
INCLUSION CRITERIA ................................................................................................................... 17 
4.3. 
EXCLUSION CRITERIA .................................................................................................................. 17 
5. 
STUDY DRUGS AND CONCOMITANT MEDICATIONS .................................................... 18 
5.1. 
DESCRIPTION OF THE STUDY DRUGS AND MANUFACTURING PROCESS ........................................ 18 
5.2. 
ADMINISTRATION OF STUDY DRUGS ............................................................................................ 19 
5.3. 
PERMITTED AND PROHIBITED DRUGS AND TREATMENTS ............................................................. 20 
5.4. 
RANDOMIZATION AND BLINDING ................................................................................................. 20 
5.5. 
MONITORING OF COMPLIANCE ..................................................................................................... 20 
5.6. 
LABELLING AND PACKAGING OF INVESTIGATIONAL MEDICINAL PRODUCTS ............................... 21 
6. 
CONDUCT OF THE STUDY ...................................................................................................... 22 
6.1. 
STUDY PROCEDURES .................................................................................................................... 22 
6.2. 
STUDY SCHEDULE ........................................................................................................................ 23 
6.3. 
IDENTIFICATION OF ALL THE DATA SOURCES THAT ARE NOT IN THE MEDICAL FILE .................... 24 
6.4. 
RULES FOR STUDY DISCONTINUATION ......................................................................................... 24 
7. 
DATA MANAGEMENT AND STATISTICS ............................................................................ 25 
7.1. 
DATA COLLECTION AND HANDLING OF STUDY DATA .................................................................. 25 

 
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7.2. 
BIOSTATISTICS ............................................................................................................................. 25 
8. 
PHARMACOVIGILANCE AND MANAGEMENT OF ADVERSE EVENTS ..................... 28 
8.1. 
DEFINITIONS ................................................................................................................................ 28 
8.2. 
SAFETY ENDPOINTS ..................................................................................................................... 29 
8.3. 
LIST OF EXPECTED AES ............................................................................................................... 29 
8.4. 
MANAGEMENT OF ADVERSE EVENTS ........................................................................................... 29 
8.5. 
MODALITIES AND DURATION OF FOLLOW UP AFTER THE OCCURRENCE OF ADVERSE EVENTS .... 29 
9. 
ADMINISTRATIVE AND REGULATORY ASPECTS ........................................................... 30 
9.1. 
RIGHT OF ACCESS TO SOURCE DATA ............................................................................................ 30 
9.2. 
MONITORING ............................................................................................................................... 30 
9.3. 
INSPECTION / AUDIT .................................................................................................................... 30 
9.4. 
ETHICAL CONSIDERATIONS .......................................................................................................... 30 
9.5. 
DECLARATION TO THE COMPETENT AUTHORITIES ....................................................................... 31 
9.6. 
FINANCING AND INSURANCE ....................................................................................................... 31 
9.7. 
PUBLICATION RULES .................................................................................................................... 31 
REFERENCES ................................................................................................................................................. 32 
 
 
 

 
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1. Background and study rationale  
1.1. Background 
For over 30 years the incidence of allergic diseases has increased so much that these diseases 
(asthma, atopic dermatitis, rhinitis, seasonal and annual per) present real problems of Public 
Health (Respiratory allergies are at the forefront of chronic diseases of the child). 
The treatment of respiratory allergic diseases include the environment control, the allergen 
eviction (this is sometimes impossible), the use of anti-allergy medications (antihistamines, 
steroids, to counter the symptoms) and allergic immunotherapy (desensitization) that treats the 
cause. 
Micro-immunotherapy, with the 2L®ALERG, is an alternative therapeutic approach that takes 
into account the patient's overall immune dysfunction, and also treats the cause, by rebalancing 
and re-educating the immune system. 
Micro-immunotherapy medications are sequential treatments distributed in capsules, respecting 
the different stages of development and the evolution of the disease; they are administered 
sublingually, where the immunocompetent cells are concentrated (oral mucosa and neighbouring 
lymphoid relay), allowing a rapid transmission of the information to the lymphatic system, the 
meeting point and the mobilization of immune cells. 
 
2L®ALERG is manufactured by the Laboratory Labo'Life Belgium, marketed since 2002 and 
notified to the Belgian Federal Agency for Medicine and Health Products (AFMPS /FAGG) 
under the number 1507 CH 119 F1. 
 
It has been successfully used in various types of allergy, no side effects have been reported to 
date. 
 
1.2. Study rationale  
The aim of this study is to show the efficacy of 2L®ALERG on the symptoms of seasonal allergy 
to grass pollens, which gives allergic rhinitis and rhinoconjunctivitis. Asthma will not fit into the 
scope of this study. 
A first randomized placebo for 2L®ALERG was carried out in Belgium under the leadership of 
Dr. X. Van der Brempt, on a population of 44 patients allergic to grass pollen, who were treated 
between 1 and 2 months before the pollination peak, and throughout the duration of the peak. 
This study showed a significant decrease in the consumption of rescue medication and in the 
global drug-symptoms score; it was published in 2011 in Revue Française d’Allergologie [1]. 
This study builds on the previous one, in order to validate this new therapeutic approach in the 
treatment of grass pollen allergies. 
 
A good support to the patient is important because on the one hand, according to figures from the 
GA2LEN [2], in 2015, one European out of two suffer from some form of allergy, and on the 
other hand, the complications caused by the respiratory allergies are important and often 
underestimated. [3–5]. Among people with respiratory allergies, 15% to 20% suffer from a severe 
form [6-7]. The investigation of the OPERA observatory has shown that the persistent allergic 
rhinitis associated with moderate to severe symptoms were the most common allergic rhinitis in 
general practice [8]. 
 
 

 
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Symptoms may limit daily activity, impair sleep quality [9] (77% of patients suffer from sleep 
disorders), and result in a state of fatigue, a negative impact on cognitive function, work 
productivity, the welfare psycho-social or on performance during exams [10-11]. A study has 
shown that students with a history of allergic rhinitis with hay fever symptoms had twice more 
bad exam results [12]. 
Experts recommend early introduction of the most global possible treatment, to treat but also to 
prevent the onset and/or worsening of allergy and asthma [13-18]. 
   
The different therapeutic options, apart from the environmental control and allergen avoidance 
(which is sometimes impossible) are the anti-allergy medications (antihistamines, steroids, to 
counter the symptoms) and the allergic immunotherapy (desensitization) that treats the cause, 
and therefore the symptoms [19-22]. Allergen immunotherapy is specific to a definite allergen and 
is administered mainly by subcutaneous or sublingual route, rarely by nasal route [23–24], the 
average duration of treatment is 3 to 5 years and involves a rigorous monitoring of protocol, to 
be effective [25], making it constraining treatment, and sometimes not suitable. 
Micro-Immunotherapy [26], with 2L®ALERG, is an interesting alternative therapeutic approach 
for taking into account the patient's overall care, preventive as well as curative. 
 
Let's see how 2L®ALERG can solve the problem, first let's see what the actors of an allergic 
reaction are. 
 
The allergic reaction is the result of an inappropriate immune response of the body, following the 
meeting with a foreign substance, the allergen. Allergy can affect the eyes, skin and respiratory 
system, like the nose or bronchi. 
The most common mechanism, at the origin of rhinitis, conjunctivitis and allergic asthma, is 
immediate hypersensitivity. 
 
As in all hypersensitivity responses, there are two phases in immunological immediate 
hypersensitivity. A first phase of sensitization/immunization, during which the immune system 
identifies the substance as an allergen, leading to the synthesis of IgE. It is clinically silent. The 
second phase, called "revelation" or "effector", when the body again comes into contact with the 
allergen, it is clinically symptomatic, due to the immediate activation by allergen of cells bearing 
IgE on their surface (mainly mast cells and basophils). 
 
The tissue borders of the body (such as skin or the respiratory or digestive mucosa) are the 
interface between the environment and the immune system and have a dual function of defence 
against infection and maintenance of tolerance with respect to environmental antigens. 
Depending on the size or nature of the antigen, the tissue borders prevent the penetration of 
antigens, or, if penetration occurs (e.g., in the digestive tract), keep and maintain tolerance 
through different mechanisms. 
 
Dendritic cells, present in all tissue borders, permanently capture antigens that enter. Dendritic 
cells having internalized the antigens, migrate to loco-regional lymph nodes completing their 
maturation. They then induce a cellular immune response by interacting with T cells. B cells 
specific response is also set up with the help of T helper lymphocytes, which results in IgE 
production by plasma cells. 
  
This excessive IgE production is related to a particular cytokines environment: 
- Rich in IL-4, IL-5 and IL-13 (called hyperpolarization Th2) 
- With a relative deficiency in IL-10 and TGF (Tregs default) 
- Deficit in γ interferon (Th1 polarization default) 

 
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This particular profile of cytokine production (IL-4, IL-5, IL-13) is also responsible for an 
increase in the number of mast cells, basophils and eosinophils into the tissues or the blood. 
Produced IgE present themselves in the circulating blood and in tissues, free or attached to the 
surface of mast cells and basophils. 
IgE persist for several months at the cell surface but only a few days in free form in the 
peripheral blood. 
 
All of these processes correspond to the immunization phase or primary immune response, called 
sensitization in the case of allergy, resulting in IgE production against a particular antigen. The 
IgE production against a given protein is polyclonal. The sensitization phase can last from 
several weeks to several years. 
 
The effector phase of the IgE-dependent immediate hypersensitivity is mainly the preservation of 
mast cells. In some cases, basophils may also play this role. The most important function of mast 
cell in the pathology is the effector phase of the allergic response. 
 
After the sensitization described above, in case of a new contact with the allergen, the 
recognition of the same allergen, by IgE that are on the surface of mast cells or basophils, leads 
to the cascade activation of these cells. 
The secretory granules contain numerous preformed mediators of the immediate phase 
vasoactive: amines (histamine mainly), proteoglycans, polypeptides, lysosomal enzymes, 
cytokines and chemokines. 
 
A mast cell can release at once 100% of its content of secretory granules and can participate in 
multiple episodes of degranulation, with a regeneration time of the granulations of 72 hours. This 
explains the need to respect a delay between the occurrence of an allergic episode and 
achievement of in vivo tests (skin tests) or ex vivo (measurement of basophils activation) to 
determine the aetiology of this episode. 
 
During exocytosis of granular contents, histamine diffuse through the tissues to bind to its 
receptors and cause vasodilation and increased capillary permeability (clinical consequences: 
hives, deep tissue oedema, circulatory failure up to anaphylactic shock), bronchospasm 
(consequence: asthma), hypersecretion of bronchial mucus. The released proteases, such as 
tryptase, NO synthase and beta-hexosaminidase, initiate inflammation and local tissue 
degradation. Chemokines attract and activate leukocytes, supplemented by the effect of the 
preformed cytokines TNF-alpha and IL-4, which release directs from the beginning to a new 
local immune response towards Th2 arm. 
 
After this immediate phase of the effector phase, comes the second step: the mast cell activation 
through stimulation of FcɛRI receptor, which indeed leads not only to rapid exocytosis of 
granular contents, but also to the deferred production of neoformed mediators. A wide range of 
these mediators can be produced, but the secretion is adapted to the type of stimulus received by 
the mast cell and its environment. 
Among the cytokines and mast cell growth factors neosynthesized the most important we find 
pro-inflammatory agents (IL-1, TNF, IL-6), cytokines involved in the orientation of Th 
responses (IL-10, IL-4 , IL-13), IL-5 that promotes the recruitment and activation of 
eosinophils, the Stem Cell Factor, main mast cell growth factor, GM-CSF growth factor of 
myeloid cells. Together, these newly formed mediators, often on an autocrine mode, contribute 
to the installation of a chronic inflammatory reaction with tissue remodelling (e.g., airway 

 
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remodelling in asthma, remodelling of the nasal mucosa in chronic rhinitis). The resolution 
failure is common and leads to the occurrence of irreversible anatomical lesions, self-sustained. 
Beside the mast cells, many other cells are involved in the pathogenesis of immediate 
hypersensitivity. Eosinophils (containing many mediators within their granules), basophils and 
neutrophils attracted on the site of the reaction through soluble mediators, perpetuate the lesions. 
The role of basophils may be dominant in the orientation Th2 immune responses on contact with 
the allergen. 
Genetic factors are important, in fact, several susceptibility genes have been associated with 
allergic diseases: 
- HLA molecules (ensuring the presentation of allergens to CD4 lymphocytes) 
- Β chain for the high-affinity receptor for IgE (FcɛRIβ) 
- IL-4 
- Receiver beta - adrenergic 
- TNF 
- CD14 (co-receptor lipopolysaccharide) 
 
Genetic changes may explain the increase in allergies in recent decades, however, it is now 
recognized that gene transcription is modulated by the environment (defining "epigenetic"). 
 
Let's now see how the 2L®ALERG, Micro-Immunotherapy medication, can act: 
Micro-Immunotherapy is based on the use of endogenous molecules obtained by 
biotechnological synthesis and administered in very low doses sublingually. These physiological 
mediators aim to restore the balance Th1/Th2 [27] without focusing on the causative agent of the 
disease. 
 
Composition of 2LALERG®: 
Interleukin 1  
 
 
 
17 CH 
Interleukin 4  
 
 
 
17–27 CH 
Interleukin 5  
 
 
 
17 CH 
Interleukin 6  
 
 
 
17 CH 
Interleukin 10  
 
 
 
17 CH 
Interleukin 12  
 
 
 
9 CH 
Interleukin 13  
 
 
 
17 CH 
Tumor Necrosis Factor Alpha  
17 CH 
Transforming Growth Factor Beta    5 CH 
Pulmo histaminum   
 
15 CH 
SNA-HLA-II  
 
 
18 CH 
 
According to the law of Arndt-Schultz, high dilutions are used to obtain a braking effect, average 
dilutions, a modulating effect, and low dilutions, a stimulating effect. 
 
IL-1 is in high dilution to slow down the activity of B and T lymphocytes, protein production 
and the acute phase of inflammation, and IL6 production by Th2 [27-29]. 
IL-4 is in high dilution to reduce Th2 differentiation [30] and to brake IgE synthesis. 
IL-5 is high dilution to slow activation and proliferation of eosinophils and thus prevents the 
influx into the airways. 
IL-6 is in high dilution to slow the inflammatory Th2 response [31] under the influence of IL-1. 
IL-10 is in high dilution to reduce the stimulatory effects of IL-4 [32]. 

 
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IL-13 is in high dilution to decrease the expression of HLA class II molecules on macrophages 
and to brake the production of IgE [33], which reduces the allergic reaction. 
TNF-α in the high dilution, coupled with high dilution of IL-1, tends to reduce the recruitment of 
eosinophils in the inflammatory site (located at the ENT or bronchial mucosa). 
The SNA-HLA-II is in high dilution to directly decrease the expression of HLA class II 
molecules. 
TGF-β is in low dilution to increase the inhibition of cytokine production and the expression of 
class II molecules. 
IL-12 is on average dilution to modulate the differentiation of T lymphocytes of Th1 type [34], to 
compensate for the antagonistic effect of IL-4 and IL-10, IL-12, and to reduce probable mucosal 
alterations in bronchopulmonary level. 
 
Our objective is now to confirm the efficacy of 2L®ALERG, highlighted in the previous study [1], 
which results were the basis of the actual calculation for this study. 
X. Van der Brempt et al. / Revue française d’allergologie 51 (2011) 430–436: Pollen count and over-time 
modification of the global score (mean and standard deviation) in the active and placebo groups during the study 
period. 
 
Patients suffering from grass pollen allergy will be randomized into 2 groups: a control group 
and a treatment group. 
The evaluation will focus on the 5 symptoms of allergic rhinitis/rhino-conjunctivitis assessed 
daily by patients on a scale from 0 (no symptoms) to 3 (severe symptoms) for a total score 
ranging from 0 to15 (T5SS or Total 5 Symptoms Score) [35-36]. 
Rescue medication (RM) will be allowed in case of failure or insufficient treatment. The use of 
rescue medication will be recorded daily by the patient in his/her diary.  
Given the link between the use of rescue medication and the symptoms, an overall score will be 
calculated, expression of symptoms score, weighted by rescue medication score, according to the 
methodology currently advocated for the development of anti-allergy medications.[35-37]   
 
 
 

 
Version 1.0, 04 February 2016, Page 14 
1.3. Benefits and risks for people involved in the study 
 
Benefits 
The person who participates in research can expect a personal benefit. 
 
This benefit will be objectified by decreased symptoms, a decreased consumption of rescue 
medication, and an improved quality of life. 
 
Risks 
Given the type of study medication, its perfect tolerance, given that the study does not require 
any invasive procedure, and that rescue medication is allowed, there is no potential risk for the 
patients. 
To date 98,000 boxes of 2L®ALERG were sold and no side effects have been reported. 
Risk-benefit balance 
Given the potential impact on the quality of life of patients and given that no side effect are 
expected with 2L®ALERG, the balance is strongly in favour of the benefit, and without any 
potential risk for patients who may use rescue medication. 
 
 
1.4. Description and justification of the therapeutic schema 
 
The study drug is 2L®ALERG. 
The treatment consists of taking one capsule a day, before breakfast, following the order of 
numbering: 1 through 10. When the number 10 has been taken, start another blister on the next 
day. 
 
Method of administration: open the capsule, pour the contents (granules) under the tongue and 
let it dissolve. The pellets will be taken on an empty stomach, 15-30 minutes before the morning 
meal, or if taking has been forgotten, one hour after the meal. 
 
The duration of treatment will be about 6 months. 

 
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2. Objectives and endpoints  
2.1. Primary objective and primary endpoint  
 
The main objective is to demonstrate the efficacy of 2L®ALERG versus placebo on the 
symptoms of allergic rhinitis and allergic rhino-conjunctivitis in patients with seasonal allergy to 
grass pollen. 
 
The primary endpoint will be the area under the curve (AUC) of the overall score established 
according to the total 5 symptoms score (T5SS) and medication score (MS) according to time 
from the start of treatment until the end of the patient follow-up. 
The five symptoms (sneezing, rhinorrhoea, nasal pruritus, eye itching and tearing, and nasal 
obstruction) will be assessed daily by patients on a scale from 0 (no symptoms) to 3 (severe 
symptoms) giving a total score ranging from 0 to15. 
The rescue medications (RM) allowed in the first-line adjuvant treatment will be codified to 
establish a score.  
The allowed RM are the oral antihistamines (two points per day of use) or local treatment (nasal 
or eye; a point per day), and the ocular cromoglycate (one point per day). 
In case of failure or in case of insufficiency of rescue medications mentioned above, the nasal 
topical corticosteroids (one point per day of use) will be allowed. 
 
2.2. Secondary objectives and secondary endpoints  
The secondary objectives will be to compare the effect of 2L®ALERG versus placebo on: 
- Symptoms of allergy (not corrected by the use of rescue medication),  
- Use of rescue medication,  
- Evolution of the quality of life (QoL) using 3 daily specific questions included in the 
patient’s diary card: Did you sleep well? – Can you work normally? – How do you feel?  
- Safety (AEs and SAEs). 
The secondary endpoints will be: 
 
- Total 5 symptoms score (T5SS) and individual scores of 5 symptoms 
 
- Consumption of rescue medications 
- Evaluation of the QoL: AUC (total score of 3 questions of QoL included in the diary card on the Y-
axis, and time on X axis) during the entire follow-up period 
 
- Frequency, severity and causality relationship of AEs and SAEs. 
 
 

 
Version 1.0, 04 February 2016, Page 16 
3. Study design  
3.1. Methodology 
 
It is a double-blind, randomized, placebo-controlled, 2 parallel groups, interventional 
study, performed with a notified homeopathic medicine, available on the market since 
2002. 
 
3.2. Study design  
 
- 
The study will last maximum 9 months: duration of inclusion = 1 month and patient’s 
follow up = 6-8 months. 
- 
The duration of 2L®ALERG exposure will be 6 months. 
 
 
3 months 
before the 
expected 
grass pollen 
peak 
 
Selection of eligible patients 
 
 
Calling of patients 
Checking of inclusion/exclusion criteria 
Give information about the study 
 
 
 
 
2 months 
before the 
expected  
grass pollen 
peak 
= V0 
 
 
Signature of the Informed Consent Form 
Verification of eligibility 
Randomization 
CRF filling 
Delivery of treatment and patient diary  
Start of treatment 
 
 
 
V1 = V0  
+ 
 3 months 
 
3 months evaluation 
Recovery and verification of patient diary 
CRF filling  
Evaluation of compliance (counting of the 
remaining capsules) 
Evaluation of safety 
Delivery of treatment and patient diary 
 
 
 
V2 = V0  
+   
6 months        
  or end of 
grass 
  pollen peak 
 
Final evaluation 
Recovery and verification of the patient diary 
CRF filling   
Evaluation of compliance (counting of the 
remaining capsules) 
Evaluation of safety 
Study conclusion 
 

 
Version 1.0, 04 February 2016, Page 17 
4. Study population  
4.1. Description of the population  
 
Hundred patients to achieve 80 completed cases (50 patients per group to achieve 40 
completed cases). 
 
4.2. Inclusion criteria 
  
 
- Age ≥18 years, male and female 
- Woman of childbearing age using effective contraceptive means 
- Patient having the faculties to understand and respect the constraints of the study  
- Symptomatic since at least two seasons and confirmed by positive skin test and/or the 
presence of IgE for grasses (prick test defined as positive if higher than or equal to half 
the negative control; IgE positive if at least class 3 (≥ 3.5 kU / L); these tests must have 
been performed at the latest at the first screening visit 
- Signature of the Informed Consent Form 
 
4.3. Exclusion criteria  
 
- Pregnant woman or woman wishing to become pregnant 
- Breastfeeding woman 
- Patient with an acute exacerbation of allergic rhinitis 
- Patient with uncontrolled asthma 
- Immunotherapy received within the last two years 
- Patient with a known lactose intolerance 
- Patient who participated in a clinical study in the previous three months 
- Patient who is not sufficiently motivated to engage on a follow-up period of 6 months or 
more, unable to complete the patient diary, or likely to travel or to move before the end of the 
study, 
- Patient taking nasal or bronchial inhaled corticosteroids on a long term basis 
(intermittent consumption during the season is permitted provided it is mentioned in the 
patient’s records) 

 
Version 1.0, 04 February 2016, Page 18 
5. Study drugs and concomitant medications 
5.1. Description of the study drugs and manufacturing process 
 
The composition of 2LALERG® and placebo are described in the table below: 
2LALERG® 
PLACEBO 
Impregnated 
solution: 
Interleukin 1: 17 CH 
Interleukin 4: 17–27 CH 
Interleukin 5:  17 CH 
Interleukin 6: 17 CH 
Interleukin 10: 17 CH 
Interleukin 12: 9 CH 
Interleukin 13: 17 CH 
Tumor Necrosis Factor Alpha: 17 CH 
Transforming Growth Factor Beta: 5 CH 
Pulmo histaminum: 15 CH 
SNA-HLA-II: 18 CH 
No impregnation 
Excipients : 
Lactose saccharose globules 
(380mg/capsule) 
Lactose saccharose globules 
(380mg/capsule) 
Primary 
packaging : 
Red capsules (color degradation ranging 
form dark red to pink, 5 colors) 
Red capsules (color degradation 
ranging form dark red to pink, 5 
colors) 
Secundary 
packaging : 
Aluminium sealed blister of 10 capsules 
numbered from 1 to 10, 
Labelled 2LALERG-PLACEBO 10A16-
15A16 
Aluminium sealed blister of 10 
capsules numbered from 1 to 10, 
Labelled 2LALERG-PLACEBO 
10A16-15A16 
Final packaging : 
Printed cardboard box (see annex 1) 
containing 3 blisters and one leaflet 
explaining how to take the medicine (see 
annex 2) 
Printed cardboard box (see annex 1) 
containing 3 blisters and one leaflet 
explaining how to take the medicine 
(see annex 2) 
 
The manufacturing process consists of 4 steps: 
STEP 1: DILUTION PREPARATIONS 
STEP 2: IMPREGNATION 
STEP 3: GLOBULES ENCAPSULATION: PRIMARY PACKAGING 
STEP 4: SECUNDARY PACKAGING and FINISHED PRODUCT PACKAGING 
The placebo is manufactured exactly as the 2LALERG®, except that it contains only the neutral 
globules without the homeopathic dilutions impregnated on it. The capsulation, blisterisation and 
final packaging process are exactly identical for both. 

 
Version 1.0, 04 February 2016, Page 19 
5.2. Administration of study drugs  
 
Treatment used: 2L®ALERG - Placebo 
Pharmaceutical form: Capsules - doses containing impregnated granules 
Excipients: Lactose, Sucrose (granules) to a capsule. 
 
Dosage: 1 capsule daily, fasting morning, following the numerical order of 1 to 10 capsules. 
When capsule 10 has been taken, start the next blister at capsule 1. 
 
Administration mode: 
Open the capsule, pour the contents (granules) under the tongue and let it dissolve. The pellets 
will be taken on an empty stomach, 15-30 minutes before the morning meal, or one hour after the 
meal if forgotten. 
 
 
1. Open carefully the capsule maintaining the capsule’s head upward 
 
2. Pour the content (granules) under the tongue and allow melting 
 
 
Contraindications: None 
 
Warnings and precautions: 
This medicine contains lactose. Lactose intolerance cases have been described. The amount 
of lactose present in the capsules is theoretically sufficient to trigger symptoms of 
intolerance. In cases of outbreaks of diarrhoea, the patient should consult his/her doctor. 
As with any homeopathic medicine, it is advisable to avoid taking mint or its derivatives and 
stimulant products (coffee, chocolate) during one hour before the intake. 
 
Adverse reactions (frequency and seriousness) 
 
Exceptionally, it may appear dyspepsia when taken during fasting. In this case, the granules 
will be taken one hour after the meal. 
Difficulties falling asleep can occur when taken after 16 hours. 
As with all homeopathic treatment, worsening of symptoms printing can occur, which 
usually disappears after a few days. If this impression persists, a physician should be 
contacted. 
 

 
Version 1.0, 04 February 2016, Page 20 
Dosage adjustment: Not applicable 
 
5.3. Permitted and prohibited drugs and treatments  
 
 Allowed treatments: 
- 
Already established treatments for associated pathologies not liable to have an impact on 
the proper conduct of the study, 
- 
Rescue medication allowed in the first-line adjuvant treatment is: oral or topical 
antihistamines (nasal or eye) and eye cromoglycate, topical nasal corticosteroids (in case 
of failure or insufficiency of those above). 
 
Not allowed treatments: 
- 
Oral or injectable corticosteroids 
- 
Anti-leukotrienes 
 
5.4. Randomization and blinding 
 
The randomization list will be prepared by a Data Manager (independent from the clinical team 
involved in the study) from the Data Management Department of the CRO, using the 
randomization module of nQuery Advisor (Version 7.0), ensuring a ratio 1:1 between the study 
drug and the placebo in each centre. 
The investigator of each centre will assign treatment in an ascending order to his/her patients. 
The study will be double-blind, meaning that nor the investigator, nor the patient will know the 
treatment group (active or placebo) to which the patient belongs. The study drug and the placebo 
will have exactly the same aspect, form, odour and colour. Their packaging will also be exactly 
the same. 
5.5. Monitoring of compliance 
 
The drugs will be sent to investigators (GPs in private practice). 
The treatment beginning two months before the expected grass pollen peak, the investigator will deliver it 
to the patient for 3 months (3 boxes) at V0, then for three other months at V1.  
 
 
The investigator will ask the patient to bring back drug boxes (full and empty blisters) at each visit. 
 
The counting of the remaining capsules will be made by the investigator. 
In case the patient would come in consultation a few days before the end of the treatment period, the 
patient will be allowed to keep the blister to complete the sequence. 
 
A global compliance will be calculated for each patient on the total duration of treatment. Global 
compliance will be acceptable if it is between 80% and 120%. If values <80% or> 120%, the patient will 
be eliminated from the analysis according to the protocol and will be taken into account in the analysis by 
intention to treat. 
 

 
Version 1.0, 04 February 2016, Page 21 
5.6. Labelling and packaging of investigational medicinal products 
 
The sponsor Labo'Life will provide drugs to investigational centres. 
The labelling and packaging will be handled by Labo'Life according to Good Manufacturing 
Practice Annex 13. 
At the end of the study, Labo’Life will recover the remaining treatments and ensure their 
destruction. 
 
 
Drug storage conditions 
- In the investigational centre: at room temperature, in its original packaging and in a locked 
cabinet. 
- At patient's home: at room temperature, in its original packaging and out of reach of 
children. 

 
Version 1.0, 04 February 2016, Page 22 
6. Conduct of the study  
6.1. Study procedures  
 
The following demographic data will be collected during the first visit: date of birth, gender, 
ethnic group, weight, height, smoking habits and alcohol use status. 
 
Medical history, treatment history, concomitant treatments and patient's physical examination 
will also be documented during V0. 
 
The allergy must be confirmed by positive skin test and/or the presence of IgE for grasses (prick 
test defined as positive if higher than or equal to half the negative control; IgE are positive if at 
least class 3 (≥ 3.5 kU / L); these tests must have been made at the latest during the first visit. 
 
A patient diary will be given to each patient. 
- For evaluation of the total 5 symptoms score T5SS and rescue medication RS, it is essential 
that patients note every day the symptoms (sneezing, rhinorrhoea, nasal pruritus, itching 
and/or eye tearing and nasal obstruction) intensity, and the rescue medications, in their 
patient diary. 
- It is also essential that the patient takes note every day of his/her QoL by filling in three 
questions included in his/her diary card: Did you sleep well? – Can you work normally? – 
How do you feel? 
- It is also imperative that patients note the date of the start of treatment and the date of onset 
of symptoms. 
 
This patient diary will be given to the patient at each visit, and will be brought back at the next 
visit, it will be reviewed and validated by the investigator and will be part of the CRF (Case 
Report Form). 
  
All relevant (related to allergy) concomitant medications (except rescue medications) taken by 
the patient during the study period will be recorded at each visit in the CRF. 
 
The AEs and SAEs will be recorded at V1 and V2 in order to assess safety. 
 

 
Version 1.0, 04 February 2016, Page 23 
6.2. Study schedule  
Study flow chart 
 
 
Screening  
(– 1 month) 
 
 
V0  
 (2 months before 
grass pollen peak) 
 
V1  
(3 months 
after V0) 
 
V2 
(6 months after V0 or 
end of grass pollen 
peak) 
Selection of patients 
Verification of 
inclusion/exclusion criteria 
Performance of allergy tests if 
needed 
● 
 
 
 
Give information about the study 
Give the Inform Consent Form to 
the patient  
● 
 
 
 
Eligibility check 
 
● 
 
 
Signature of the Informed 
Consent Form 
 
● 
 
 
Randomization 
 
● 
 
 
Demography 
 
● 
 
 
Medical history 
 
● 
 
 
Physical examination 
 
● 
○ 
○ 
Allergy treatment history 
 
● 
 
 
Delivery of treatment for 3 
months 
 
● 
● 
 
Distribution of the patient diary 
 
● 
● 
 
Start of treatment 
 
● 
 
 
Diary card filling by the patient 
 
● 
● 
● 
Patient diary card control 
 
 
● 
● 
Compliance control 
 
 
● 
● 
Relevant (allergy-related) 
concomitant medications (except 
rescue medications) 
 
● 
● 
● 
Safety control (AE/SAE) 
 
 
● 
● 
Study conclusion 
 
 
 
● 
● Compulsory 
○ Optional 
 
 

 
Version 1.0, 04 February 2016, Page 24 
6.3. Identification of all the data sources that are not in the medical file  
 
All data collected in the CRF have to be recorded in the patient medical file.  
 
Patient diary data are source data which will be directly captured by the data management. 
 
6.4. Rules for study discontinuation   
 
Criteria for premature discontinuation of the study 
- Withdrawal of consent, 
- Protocol violation, 
- Intolerance to treatment, 
- Voluntary discontinuation of treatment, 
- Intake of a forbidden treatment during the study, 
- Proved pregnancy, 
- Decision at the discretion of the investigator. 
 
Criteria for stop the study 
The study will be considered terminated at the end of the participation of the last patient entered 
into the study, and when all collected data needed for evaluation have been verified and 
validated. 

 
Version 1.0, 04 February 2016, Page 25 
7. Data Management and statistics 
7.1. Data collection and handling of study data  
Data collection 
Data collection will be done on paper CRF for each patient, 
The patient will fill in the patient diary card given by the investigator and bring it back at the 
next visit. The investigator will check the patient diary card and will keep it in the patient CRF 
The sponsor will be responsible for the printing of CRFs (NCR carbon paper) and patient diaries, 
which will be sent to each investigator. 
The persons allowed to fill in the CRF are identified in the delegation of responsibilities sheet 
witch is to be kept in the Trial Master File. 
  
Data coding 
By signing this protocol the investigator and all the staff are committed to keep confidential the 
identities of the patients participating in the study. 
 
Each patient will be identified by a numerical code consisting of 4 digits: YY/ZZ (YY 
corresponding to the centre number and ZZ to the patient number). 
 
A form will be made available to the investigator so he could note the correspondence between 
the numeric code and the patient's identity. He/she must keep this document in his/her Trial 
Master File. 
 
Collection Data Processing 
The compilation of clinical data will be based on the structuration of a clinical database (IBM 
SPSS Data Entry Builder) and the creation of input screens in the image of CRF and diary card 
in accordance with the Protocol and the legislation currently in force. 
This database will be validated and documented appropriately. 
All data will undergo a double data entry process in the database, by two independent encoders, 
using the IBM SPSS Data Entry Interviewer software. 
Based on the regular cleaning of data, queries will be generated to the investigational centres. 
The answers to these queries will also be encoded in the database. 
 
7.2. Biostatistics 
Sample size calculation and justification 
The objective of the study will be to show the superiority of 2L®ALERG over placebo in the 
treatment of patients suffering from seasonal allergy to grass pollen. 
For the sample size calculations two references have been used. The first is a study conducted 
with 2®LALERG versus placebo in patients with a pollen allergy. [1] 
The second is a more theoretical publication from Clark and Schall (2007) supporting the 
recommendations made in a World Allergy Organization document on methodological aspects of 
immunotherapy trials. The average of the Average Rhinoconjunctivitis Total Symptom Score 
(ARTSS) and Average Rescue Medication Score (ARMS) should be considered as a primary 
efficacy variable in clinical trials of immunotherapy for allergic rhinoconjunctivitis. [35] 

 
Version 1.0, 04 February 2016, Page 26 
The global score calculated in the paper of Van der Brempt et al. (2011) [1], taking into account 
the T5SS total score and the RMS total score, fits very well with the recommendation from Clark 
and Schall (2007) [35]. 
The Figure 5 of Van der Brempt et al.’s paper has been used to evaluate the area under the curve 
(AUC) of global score for the placebo and 2L®ALERG groups. [1]  
 
  
The values were approximately 80 for the placebo group and 55 for the treated group (a 
reduction of about 30% with the active treatment. These values have been used to build several 
sample size scenarios. 
 
Scenario 
1 
2 
3 
4 
5 
Test significance level, a 
  0.050 
  0.050 
  0.050 
  0.050 
  0.050 
1 or 2 sided test? 
   2 
   2 
   2 
   2 
   2 
Group Placebo mean, µ1 
   80.000 
   80.000 
   80.000 
   80.000 
   80.000 
Group 2L®ALERG mean, µ2 
   55.000 
   55.000 
   55.000 
   55.000 
   55.000 
Difference in means, µ1 - µ2 
   25.000 
   25.000 
   25.000 
   25.000 
   25.000 
Common standard deviation, s 
   20.000 
   25.000 
   30.000 
   35.000 
   40.000 
Effect size, d = |µ1 - µ2| / s 
    1.250 
    1.000 
    0.833 
    0.714 
    0.625 
Power ( % ) 
     90 
     90 
     90 
     90 
     90 
n per group 
 15 
 23 
 32 
 43 
 55 
Total N completed patients 
30 
46 
64 
86 
110 
 
A sample size of 32 patients in each group will have 90% power to detect a difference in means 
of 25 (the difference between a placebo group mean, μ1, of 80 and a 2L®ALERG group mean, 
μ2, of 55) assuming that the common standard deviation is 30 using a two group t-test with a 
0.05 two-sided significance level. 
With a sample size of 43 patients in each group, the same assumptions are valid with a common 
standard deviation of 35. 
The final recommendation will be to include 50 patients per group in order to achieve at least 
40 evaluable patients per group taking into account a potential drop-out rate of 20%. 
 
 

 
Version 1.0, 04 February 2016, Page 27 
Statistical analyses 
A Statistical Analysis Plan (SAP) will be written by the Biostatistician of the CRO in charge of 
the study. This document will constitute the reference document as far as statistical analyses and 
statistical methodologies are concerned. It will be approved and signed by the Sponsor and the 
Principal Investigator before the last patient last visit at the latest. 
 
Study cohorts 
 
Two cohorts will be defined: 
- 
Intention-to-treat (ITT) cohort including all patients having been exposed to at least one 
dose of the investigational product and in whom at least one efficacy or safety 
information has been collected after V0. 
- 
Per protocol (PP) cohort including of the ITT having strictly adhered to the protocol and 
having a compliance between 80% and 120%. 
The primary cohort for the statistical analyses will be the ITT cohort. 
The patients who will prematurely stop the study will not be replaced. 
 
Statistical methods 
 
The IBM SPSS Statistics (Version 21.0 and eventual upgrades) software will be used throughout 
statistical analyses. 
Missing values will not be replaced, nor extrapolated. 
Classical descriptive statistics will be used to describe the patient population at baseline. 
The two groups will be compared at baseline using independent Student’s t tests for continuous 
variables and Mann-Whitney’s tests, Chi-square tests or Fisher’s exact tests for discrete 
variables. 
The superiority of the active treatment over placebo will be demonstrated using an independent 
Student’s test comparing the over-time T5SS (corrected with RM) evolution (AUCs) of the two 
study groups over the whole treatment period. A P value lower than 5% will be considered 
statistically significant. 
The comparisons between the two study groups in terms of secondary endpoints will be done 
using the appropriate statistical methods, as they will be described in the SAP. No correction 
being applied for the multiplicity of endpoints, p values lower than 5% will be considered with 
caution, as indicative only of potential statistically significant differences between the two 
groups for the secondary endpoints. 
  

 
Version 1.0, 04 February 2016, Page 28 
8. Pharmacovigilance and management of adverse events  
8.1. Definitions  
Adverse events  
An adverse event is defined as any untoward medical occurrence in a patient or a participant in a 
clinical trial, whether or not considered drug related. 
 
All adverse events encountered during the study, which are observed by the physician or patient-
reported, will be recorded in the CRF in the section provided for this purpose. 
 
The intensity of adverse events will be quoted as follows: 
1 = mild 
2 = moderate 
3 = severe  
For each adverse event, the investigator will have to rule on the causal relationship to the 
medical product on the following scale: none, possible, probable or certain. 
 
Adverse events or serious adverse events (AEs or SAE) 
An AE is considered as SAE when it: 
- Results in death, 
- Involves life-threatening, 
- Results in incapacity or temporary or permanent disability, 
- Requires or prolongs patient hospitalization, 
- Causes congenital anomaly or neonatal 
- Is medically significant (requires care to avoid worsening) 
 
Serious Adverse Reaction (SAR) 
A SAR is a SAE considered related to the investigational study product. 
 
Expected adverse reaction or events 
 
An expected adverse event is an event mentioned in the most recent version of the Summary of 
Product Characteristics (SmPC) for drugs already having a marketing authorization. 
The expected effects or serious adverse events will be subject to a delayed declaration by the 
sponsor to the competent authorities. 
 
Unexpected Serious Adverse Reactions (SUSARs) 
Unexpected Serious Adverse Reactions (SUSARs) are events where the nature, severity, 
frequency or developments are not consistent with product information, with practiced acts and 
with methods used during the study, as defined in the SmPC. 
Unexpected serious adverse events will be subject to a statement within 7 days after their 
knowledge by the sponsor to the competent authorities. 
 

 
Version 1.0, 04 February 2016, Page 29 
8.2. Safety endpoints  
Collecting data and analysis of safety endpoints described above will be performed by 
spontaneous statement or during monitoring. 
An SAE report form will be attached to the CRF (collecting symptoms, dates, evolution, 
judgment of causality by the physician, actions taken) 
 
All AEs / SAEs / SARs / SUSARs will be subject to coding in terms of System Organ Class and 
Preferred Terms, using the latest version of the dictionary MedDRA (Medical Dictionary for 
Regulatory Activities). 
 
8.3. List of expected AEs   
In the framework of this study, expected AEs are those mentioned in the SPC: 
- In exceptional cases, it may appear dyspepsia when taken fasted (in this case, the 
granules will be taken one hour after the meal) 
- Difficulties in falling asleep can occur if taken after 16 hours 
- As with all homeopathic treatment, print of worsening symptoms can occur, that usually 
disappears after a few days. 
 
8.4. Management of adverse events  
 
All SAEs require filling a SAE report, whether expected or not expected. The investigator must 
ensure that the information entered on this report is accurate and clear. 
SAE should be reported immediately to the sponsor (within 24 hours of being highlighted by the 
investigator). 
 
After being scanned, the SAE report can be sent by e-mail to the following person in charge of  
pharmacovigilance: 
 
Dr. Paul Willems 
Semaphar sprl 
31, Rue Francourt 
1370 Lathuy (Jodoigne) 
Belgium 
Mobile: 0476/777.987 
E-mail address: pwillems.md@icloud.com 
 
The person in charge of pharmacovigilance will have a copy of the randomization list available 
in case unblinding is unavoidable after his/her discussion with the investigator. 
 
After receipt of notification of a SUSAR, the sponsor shall declare to the regulatory authorities. 
Once a year, the sponsor will prepare an annual safety report. 
 
8.5. Modalities and duration of follow up after the occurrence of adverse events  
 
Given the nature of the study treatment, the follow up shall be two months after the end of the 
study. 

 
Version 1.0, 04 February 2016, Page 30 
9. Administrative and regulatory aspects  
9.1. Right of access to source data  
The medical data of each patient will only be transmitted to the sponsor or to any person duly 
authorized by him, and, as appropriate to relevant health authorities, under conditions ensuring 
their confidentiality. 
The sponsor and the regulatory authorities may request direct access to medical records for 
verification of procedures and/or clinical trial data, without violating confidentiality and as 
permitted by laws and regulations. 
The data collected during the test will be subject to computerized processing in accordance with 
the requirements in place in Europe. 
 
9.2. Monitoring  
Clinical monitoring will be ensured by the CRO.  
A Clinical Research Associate (CRA) will regularly visit the site to carry out quality control of 
data reported in the CRFs. 
The on-site monitoring visits will be organized after appointment with the investigator. The CRA 
will be allowed to consult: 
- CRFs 
- Patient’s diary cards 
- Medical files 
- Trial Master File. 
 
9.3. Inspection / Audit 
 
In the context of this study, an inspection or an audit by the regulatory authorities may take 
place. 
The sponsor also reserves the right to audit the investigational centres, either itself or by a third 
person appointed by him. 
 
9.4. Ethical considerations  
Written informed consent: 
 
The entire informed consent process involves giving a participant adequate information 
concerning the study, providing adequate opportunity for the participant to consider all options, 
responding to the participant's questions, ensuring that the participant has understand this 
information, obtaining the participant's voluntary agreement to participate, and continuing to 
provide information as the participant or situation requires. To be effective, the process should 
provide ample opportunity for the investigator and the participant to exchange information and 
ask questions. 
The investigator undertakes to inform the patient clearly and after taking time for reflection the 
patient will sign and date the Inform Consent Form (ICF). The investigator must also sign and 
date the ICF. 
Both documents will be issued on paper in 2 copies so the patient and the investigator can each 
keep a copy. The original one is for the investigator and will be archived in the Trial Master File. 
 

 
Version 1.0, 04 February 2016, Page 31 
Ethics Committee: 
 
The sponsor undertakes to submit the study protocol, the diary card and the EQ-5D scale to the 
prior approval of the Ethics Committee. 
Amendments to the protocol: change requests will be sent for authorization in accordance with 
current legislation, by the sponsor, to the competent authorities. The modified protocol will then 
undergo an updated version dated. 
 
9.5. Declaration to the competent authorities  
An EudraCT application will be submitted to the regulatory authorities (AFMPS/FAGG). 
9.6. Financing and insurance  
The sponsor shall finance the study and an insurance policy covering the financial consequences 
of its civil liability in accordance with the regulations. 
 
9.7. Publication rules  
The data collected in this study are the property of the study Sponsor, no publication can be 
made without its agreement. 
 
 
 
 
 
 
 
 

 
Version 1.0, 04 February 2016, Page 32 
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