Combination of Supplements for Treating Autistic Spectrum Disorder
Phase: NA
Conditions: Autism Spectrum Disorder (ASD
Sponsor: Fundatia Bio-Forum

Bio-Forum Foundation 
Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
1 
 
 
APITSA Clinical Study 
"Combination of supplements for treating Autistic Spectrum Disorder " 
 
Protocol Cover Page 
 
Protocol Title: 
A pilot study to compare the eﬃcacy of a combination of 
apitherapy supplements versus placebo in children with autistic 
spectrum disorder. 
Protocol Number: 
 
Bio-Forum Foundation 045 
(B-F 045) 
 
Protocol Date: 
 
August 09, 2024 
Protocol Author:  
 
Felician Stancioiu, MD 
 
Study Phase:  
 
II 
Principal Investigator: 
Felician Stancioiu, MD 
Research Team:  
Maria Selaru, MD, Irina Chistol, MD, Ioana Bardan, PsyD, Felician 
Stancioiu, MD 
 
 
 
 
 
 
 
 
 
 Confidentiality Agreement 
 
This document is a conﬁdential and proprietary communication of The Bio-Forum Foundation and can 
be read and used only with the implicit agreement that reproduction, dissemination or re-publication 
of parts of this material is authorized only if the source is acknowledged. 
 
 
SPONSOR: 
Bio-Forum Foundation 
 
Blv D Cantemir 2B, 
Bucharest, Romania 
040245 
 
Coordinating INVESTIGATOR: 
 
Felician Stancioiu, MD 
 
Str Elena Farago 49A 
Bucuresti, Romania 

Bio-Forum Foundation 
Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
PAGE 
 
              LIST OF ABBREVIATIONS AND DEFINITIONS  
 
 
 
3 
STUDY CONTACT LIST  
 
 
 
 
 
 
3 
              PROTOCOL SYNOPSIS  
 
 
 
 
 
 
4 
1           INTRODUCTION 
 
 
 
 
 
 
 
6 
1.1 
Background 
 
 
 
 
 
 
 
 
6 
1.2 
Study Rationale 
 
 
 
 
 
 
 
6 
2 
STUDY OBJECTIVES, PLAN AND PROCEDURE                                                      10 
2.1 
Investigational Products and Treatments 
 
 
 
 
10 
2.2 
Study design   
 
 
 
 
 
 
 
12 
2.3 
Study population 
 
 
 
 
 
 
 
12 
2.3.1 Inclusion criteria 
 
 
 
 
 
 
 
12 
 
2.3.2 Exclusion criteria 
 
 
 
 
 
 
 
13 
2.3.3 Scheduled clinic visits and assessments 
 
 
 
 
13 
 
2.3.4 Criteria for discontinuation  
 
 
 
 
 
13 
2.4 
    Treatment Schedule  
 
 
 
 
 
 
14 
2.4.1     Identity of Study Treatments 
 
 
 
 
 
14 
2.4.1 Storage and Accountability  
 
 
 
 
 
15 
2.4.2 Allowed medication  
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
  
3 
STUDY MEASUREMENTS AND ENDPOINTS 
 
 
 
 
  
3.1 Primary Study Endpoints  
 
 
 
 
 
 
15 
 
3.2 Secondary Study Endpoint 
 
 
 
 
 
 
15 
3.3 Measurements at each visit 
 
 
 
 
 
 
16 
3.4 Speciﬁc detail on measurements  
 
 
 
 
 
16 
 
3.4.1 Laboratory Investigations 
 
 
 
 
 
 
17 
3.4.2 Adverse Events 
 
 
 
 
 
 
 
17 
 
 
4 STATISTICAL METHODS   
 
 
 
 
 
 
  
 
4.1 Determination of sample size 
 
 
 
 
 
 
17 
 
4.2 Statistical analysis  
 
 
 
 
 
 
 
18 
4.3 Changes to the protocol  
 
 
 
 
 
 
19 
 
5 ETHICS 
 
 
 
 
 
 
 
 
 
  
 
5.1 Ethics review 
 
 
 
 
 
 
 
 
19 
5.2 Ethical conduct of the study 
 
 
 
 
 
 
19 
5.3 Subject information and consent  
 
 
 
 
 
20 
5.4 Subject data protection   
 
 
 
 
 
 
20 
6 STUDY TIMETABLE AND TERMINATION  
 
 
 
 
20 
7 REFERENCES 
 
 
 
 
 
 
 
 
20 
8 APPENDICES 
1.1   Appendix A -  Declaration of Helsinki 
 
 
 
 
 
23 
1.2   Appendix 1 - Sample written informed consent           
 
     
 
28 
 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
The following abbreviations and specialist terms are used in this study protocol: 

Bio-Forum Foundation 
Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
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Abbreviation  
 
 
 
Explanation 
 
AE 
 
 
 
 
Adverse Event 
ASD 
 
 
 
 
Autistic Spectrum Disorder 
CNS 
 
 
 
 
Central Nervous System 
CRF 
 
 
 
 
Case Report Form 
GCP 
 
 
 
 
Good Clinical Practice 
Hgb 
 
 
 
 
Haemoglobin 
Hct 
 
 
 
 
Haematocrit 
IEC 
 
 
 
 
Institutional Ethics Committee 
IRB 
 
 
 
 
Institutional Review Board 
MCH 
 
 
 
 
Mean corpuscular haemoglobin 
MCHC  
 
 
 
Mean corpuscular haemoglobin concentration 
ml 
 
 
 
 
milliliter 
NSE 
 
 
 
 
Neuron-specific enolase 
RDW 
 
 
 
 
Red cell distribution width 
RBC 
 
 
 
 
Red Blood Cells 
SAE 
 
 
 
 
Serious Adverse Event 
SEM 
 
 
 
 
Standard error of the mean 
TSH 
 
 
 
 
Thyroid-stimulating hormone 
WBC 
 
 
 
 
White blood cells 
 
 
APITSA STUDY CONTACT LIST 
 
For questions regarding the conduct of this study, please contact: 
 
Project Leader: 
 
Felician Stancioiu, MD 
 
 
 
 
E-mail: felicians@bio-forum.net 
 
 
 
 
Mobile:  0040727500402 
Clinical Trial Manager: 
Dana Mateiu 
  
 
 
 
E-mail: dana.mateiu@dvrpharm.ro 
 
 
 
 
 
For reporting a serious adverse event, please contact: 
 
 Coordinating Investigator: 
Felician Stancioiu, MD 
 
 
 
 
E-mail: felicians@bio-forum.net 
 
 
 
 
Mobile: 0040727500402 

Bio-Forum Foundation 
Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
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PROTOCOL SYNOPSIS 
 
 
 
TITLE 
A pilot study to compare the eﬃcacy of a combination of 
apitherapy supplements versus placebo in children with autistic 
spectrum disorder. 
Investigational 
site: 
Aide Sante Clinic, Str Elena Farago 49A, Bucharest, Romania 
Cabinet Psihologie Ioana Bardan, Bucharest, Romania   
Medical Link SRL, Str Fagetului 138, Constanta, Romania 
Spitalul Judetean Piatra Neamt, Bl Traian Nr 1, Piatra Neamt 
Investigators: 
Felician Stancioiu 
Sponsor: 
Bio-Forum Foundation, Bucharest, Romania 
Representatives: 
Amalia C Alexandru 
Study number: 
B-F045 
Final Protocol: 
August 2024 
Clean File: 
August 2024 
Ethics Approval: 
August 2024  
Statistical analysis: 
 October 2025 
Clinical Phase: 
 II 
Study Report: 
 November 2025 
 
OBJECTIVES: 
 
To compare the efficacy of administering a combination of 
apitherapy supplements versus placebo in children with 
developmental disorders of the autistic spectrum (ASD). 
 
STUDY DESIGN: 
A prospective, interventional, multi-centric, randomized, placebo-
controlled, double-blind, crossover, pilot study conducted over a 6-
month period which will compare treatment efficacy of a combination 
of apitherapy supplements with placebo.  Participants will be 
screened at visit V1 and will be receiving the respective treatment: 
the active combination or placebo (A or B). At V2, at 12 weeks after 
V1; and at V3 - at 24 weeks after V1- the child will be evaluated by 
questionnaires and a psychotherapist or doctor trained in evaluating 
ASD. Parents will report adverse events and complete the ATEC and 
ASRS global questionnaires.  
Modifications of the scores on these questionnaires and the 
evaluations of the psychotherapist will be analyzed statistically as a 
quantitative measure of the child’s improvement. 
 
SUBJECTS: 
Inclusion criteria 
Males and females between 3 and 7 years of age: 
• 
parents informed of the nature of the study and will give written 
informed consent, 
• 
have body weights between 10-30 kg, 

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Clinical Study Protocol No: B-F045   
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• 
have no clinically significant abnormal values on complete 
blood count with differential during screening, 
• 
make no changes on chronic medical treatments for 6 months 
• 
have no known allergies to substances contained in 
treatments 
Exclusion criteria 
• 
Any genetic or metabolic disease or condition which might 
compromise the hematopoietic, renal, endocrine, pulmonary, 
central 
nervous, 
cardiovascular, 
immunological, 
dermatological, gastrointestinal or any other body system. 
• 
History of allergic conditions – severe asthma, anaphylactic 
shock, allergy to components of supplements tested. 
• 
History of autoimmune disorders     
TREATMENT TO 
BE EVALUATED 
Active Treatment:  A combination of 3 supplements containing 
apitherapy and plant extracts 
DURATION  
6 months per participant 
 
ENDPOINTS: 
Primary: EFFICACY 
    1.    Behavioral improvement with validated scales for autistic 
spectrum disorders - ATEC and ASRS - in each 3-month interval; 
this will be assessed by a specifically trained medical provider 
 Secondary: SAFETY   
1. Adverse events, especially frequency and intensity of 
agitation episodes 
2. Modification of laboratory tests: Hematology: RBC, MCHC, 
MCH, MCV, RDW, Hct, Hb, WBC Differential count –
lymphocytes monocytes, neutrophils, eosinophils, basophils;  
Biochemistry: NSE laboratory, serum protein electrophoresis, ESR, 
ferritin, blood count, glycosylated hemoglobin 
 Secondary: Predictive biomarkers: 
1. Modifications of plasma levels of Neuron-specific enolase (NSE), 
and correlation with efficacy 
2. Modifications of the plasma inflammatory and metabolic markers, 
and correlation with efficacy  
 
SAMPLE SIZE: 
A total of 40 patients meeting the inclusion criteria will receive 
sequentially the supplements and placebo and will be tested at 3 
and 6 months afterwards;   
 
STATISTICAL 
ANALYSIS: 
Summary statistics will describe the safety variables.  Significance 
testing will be done using analysis of variance for continuous and two-
tailed Student’s t- test for categorical variables.  (α = 0,05). Pearson 
or Spearman correlation coefficients (for parametric and non-
parametric variables) between psychometric scores and biomarkers 
will evaluate their predictive quality for treatment efficacy. 
 
 
 

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Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
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1. Introduction 
1.1 Background 
Developmental disorder of the autistic spectrum (ASD) is an extremely heterogenous 
pathology, with genetic and environmental determinants, with more than 800 genes 
(Hewitson, Havdahl, Rylaarsdam) found to be associated with ASD, and also a 
plethora of pollutants and environmental contaminants which act as metabolic or 
endocrine disruptors or produce inflammatory reactions upon contact or ingestion, 
sometimes in conjuction with genetic factors (Pugsley, Wiśniowiecka-Kowalnik). 
The inflammatory changes have most often been highlighted as an overactive 
immune system (Gesundheit, Usui) in which various inflammatory markers are 
abnormally elevated – TNF-alpha, C reactive protein (CRP), various interleukins (IL-
1beta, IL-6, IL-8, etc), NFkB, most of these being present in the alpha-2 globulin 
fraction of the serum protein electrophoresis (Vargas, Molloy, Hughes). 
Besides the inﬂammatory modiﬁcations mentioned above, which were shown 
to be present in at least 70% of the ASD children tested, recently there were 
evidenced pathological values of serum neuronal speciﬁc enolase - NSE - in ASD 
children, which point to increased neuronal destruction associated with this 
pathology ( Stancioiu 2023, 2024).  
Presenting with such heterogenous causality, ASD warrants a complex treatment – 
not just with a single substance or extract – that addresses both the rebalancing of 
the immune system and the production of healthy neurons which can replace the 
lost ones and ensure proper brain function.  
Natural products offer such a possibility, as plant extracts and apitherapy 
products are a combination of tens of substances, as opposed to pharmaceutical 
products, which offer the great benefit of standardization but are limited to 1-3 
active substances in one pill, the drawback being the individual variations between 
preparations, including quality-wise.  
A number of natural substances were found to have a beneﬁcial eﬀect on ASD 
pathology when studied in animal models (Erten, Khera, Singh), among those being 
bee pollen which was shown to improve behavior in an animal model of ASD 
(Alfawaz) 
 
1.2 Study rationale 
Another pervasive and constant aspect in ASD pathology, besides the presence of 
inﬂammation (various inﬂammation markers) and neuronal destruction (pathological values 
of NSE), is the fact that there is a much higher number of boys aﬀected by ASD compared to 
the number of girls (approximately 4:1), and this ratio remains high even after eliminating 
the inﬂuence of the known X-linked pathologies (Santomauro, Foley). 
Another observation worth considering is the simultaneous and seemingly relentless 
increase in ASD incidence in the last 2 decades, which cannot be explained by the increased 
access to healthcare and diagnostic of various populations (Chiarotti). Because it is very 
unlikely that a general and concomitant modiﬁcation in population genetics has occurred in 

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Clinical Study Protocol No: B-F045   
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the span of one generation on a global level, it is much more likely that this is due to 
environmental conditions which aﬀect the prenatal and early postnatal life.  
Putting these two things together – the recent increase in incidence and a male 
predominance in ASD-, on the top of the shortlist of suspects we can place the brain 
aromatase as a diﬀerentiating behavioral factor females vs males. Furthermore, bisphenol A, 
a common plastiﬁant and pollutant is known to inhibit the brain aromatase, and its eﬀect is 
diﬀerentiated in females vs males. Even more interesting, a recent study showed that 
inhibition of cerebral aromatase in boys by bisphenol A can be reversed by the 
administration of 10-hydroxy-2-decanoic acid (10-OH DA), followed by the improvement of 
cognitive deﬁcits resulting from aromatase inhibition (Simeonides, 2024),  
In this context it is important to observe that there are natural sources for this substance 
and 10-hydroxy-2-decanoic acid (10HDA) is found in abundance in royal jelly, and by 
administering it to ASD children, and especially in children age 8 or over in whom the 
observed progress is much less ample and diﬃcult to achieve, an eﬀective treatment can be 
conﬁrmed especially in this age group. 
The combination proposed for this clinical trial is composed of apitherapy products 
and plant extracts that have the above eﬀects; the main components of the supplement 
studied are the following: 
Royal jelly - contains 29 essential amino acids, enzymes, lipids and numerous mineral salts 
(potassium, calcium, sodium, zinc, iron, copper, manganese, etc.) and vitamins (B1, B2, B3, 
B5, B6, B7, B8, B9. 
Short-chain fatty acids are responsible for most of the biological processes of pure royal jelly. 
Pure royal jelly contains 10-hydroxy-2-decanoic acid (10HDA) called factor R and which is 
only found in pure royal jelly.  
Scientiﬁc studies show that royal jelly can contribute to increased immunity, longevity and 
promotes cell regeneration. 
Royal jelly is the only natural source of acetylcholine with an essential role in the 
transmission of nerve impulses and the proper functioning of the brain. It inﬂuences the 
emotional state, the ability to concentrate, memory and the speed with which we make 
decisions. Research has shown that pure royal jelly stimulates the production of new 
neurons and their connections from nerve stem cells, intervening in the brain's plasticity 
mechanism. 
Pure royal jelly stimulates the development of new cells by acting directly on stem cells. It is 
also beneﬁcial in inherited genetic conditions and has been used in dystrophic and 
underweight premature babies. 
The administration of pure royal jelly leads to an emotional balancing reducing depression, 
agitation, fear. It leads to healthy, healthy sleep and feelings of optimism, joy and self-
conﬁdence. It can also be administered during pregnancy, being important for the health 
and development of the fetus. 

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Clinical Study Protocol No: B-F045   
 Protocol Version I: 
  Protocol Date: August 09, 2024 
 
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Astragalus in traditional oriental medicine is a "tonic of the spleen, blood and IQ" that causes 
the growth of stem cells in the bone marrow and acts on the lymphatic tissue. 
It stimulates the activity of macrophages, T lymphocytes and the body's resistance to 
pathogenic factors. Astragalus increases the level of antibodies, IgA, IgG and induces the 
production of interferon. 
Ginseng improves nervous system functions, memory, behavior, and emotional state. In vitro 
and animal studies have shown protective eﬀects of ginseng on the brain aﬀected by free 
radicals. A study of 6422 adults, aged III, demonstrated that regular consumption of ginseng 
for at least 5 years is associated with cognitive function even in old age. Another study 
shows that taking 200 mg of American ginseng signiﬁcantly improves memory 3 hours after 
administration. It has favorable eﬀects in reducing stress, anxiety and depression due to its 
rich antioxidant content. 
Burdock has been used since ancient times for various ailments. The 1-year-old burdock root 
"cleanses the blood". Modern science has conﬁrmed that the ﬁbers in burdock root have the 
ability to incorporate toxic compounds, including those absorbed orally, making them easier 
to eliminate. The analyses showed that it contains several types of powerful antioxidants 
that protect the body's cells from the action of free radicals. 
Chamomile is a medicinal plant used since ancient times for conditions involving tissues and 
organs derived from ectoderm, rich in ﬂavonoids with anti-inﬂammatory eﬀects, adjuvant in 
the treatment of numerous ailments. 
Milk thistle is known as milk thistle and silymarin, widely used as hepatoprotection, is 
extracted from it. It supports cognitive functions and is traditionally used in various 
neurological conditions. In the laboratory, it has been shown to prevent oxidative damage to 
brain cells. 
Frankincense tree (Boswellia extract) improves bowel function by reducing inﬂammation. A 
2007 study shows that frankincense in combination with other herbal medications reduces 
abdominal pain, bloating, depression, and anxiety in people with irritable bowel. Another 
study shows that Boswellia extract taken daily for 4 weeks improved symptoms in people 
with ulcerative colitis. 
Sage is rich in vitamin K and essential minerals (Mg, Zn, Cu). 
There are a few studies that show that sage through its antioxidant content reduces 
oxidative stress and protects cells from free radicals. Various studies have found that those 
who consumed sage extract performed better on tests of measuring memory, problem-
solving, reasoning, and other cognitive skills. Sage improves memory and brain function in 
adults. 
In order to evaluate the eﬀect of these preparations in the case of children with ASD, a 
combination of phyto-apitherapy products was administered to a few children with very 
good results, these were recorded in Dr. Selaru's presentation and summarized below: 
Case 1: An 11-year-old male patient. 

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Clinical Study Protocol No: B-F045   
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  Protocol Date: August 09, 2024 
 
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Diagnosis: Autism spectrum disorders, with delayed cognitive and neuromotor 
development. The boy is completely dependent on his parents to eat, dress, go to school, 
etc. He sleeps with diﬃculty, only with his parents who have to hold him in their arms all 
night. 
Treatment: The studied beekeeping complex (10 gr. / 0 gr. / 10 gr.), Another phyto-
apitherapy complex (5 gr. / 0 gr. / 5 gr.), Royal jelly in honey 20% (5 gr. / 0 gr. / 5 gr.). At the 
same time, he also does ABA therapy. 
Results at 1 month: He sleeps much better alone (parents can rest for the ﬁrst time at night, 
after 11 years!). He can eat on his own and even cut his own bread. He can get dressed 
without help, including putting on his socks – the most diﬃcult operation for him. 
Results at 6 months: The autonomy previously gained is maintained. In addition, he asks to 
be allowed to make his own bed and even try to do his homework on his own, although he 
has great memory problems. 
Results at 18 months (in the meantime he was also introduced natural brain tonic ( 1 / 1 / 1): 
He is completely autonomous for his age and, for the ﬁrst time, he asked to go 
unaccompanied to his grandparents, packing his own bags. The ability to learn is much 
better, memory disorders being greatly improved. Parents are no longer oriented towards 
ensuring the cognitive minimum, but towards achieving school performance, especially in 
mathematics. 
Case 2: 4-year-old patients, twins, male. 
Diagnosis: autism spectrum disorders, with delayed cognitive and emotional development. 
Boys do not articulate words or even syllables, do not focus their gaze, do not communicate 
in any way with their parents. They are often very agitated and commit acts of self-harm. 
Treatment studied: apitherapy complex (10 gr. / 0 gr. / 10 gr.), phyto-apitherapy complex (5 
gr. / 0 gr. / 5 gr.), Royal jelly in honey 20% (5 gr. / 0 gr. / 5 gr.). At the same time, they do 
various forms of behavioral therapy. 
Results at 6 months: the degree of neuro-motor agitation decreased, as did the self-
aggressive ﬂare-ups. They manage to articulate a few syllables and even words. Episodically, 
they are more attentive to their parents and more present in the surrounding world. 
Results at 12 months: From the ninth month, there was what parents call a "burst of brain 
development." Children can now articulate whole words and even compose sentences, 
expressing their needs. They are much more collaborative and their curiosity has developed. 
Results at 18 months: Cognitive and communication skills developed at an accelerated pace. 
At the age of 5 and a half, they are able to speak in two languages, Romanian and English, 
they come from a mixed couple. They are able to name all colors and count to a hundred. 
When they are very stressed, they still tend to hit themselves, but much less often. Instead, 
they began to be able to have social interactions and relate to strangers. 
Case 3: 4-year-old female patient 

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Clinical Study Protocol No: B-F045   
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Diagnosis: autism spectrum disorders, with delayed cognitive development. The little girl 
does not speak coherently, the vocabulary is very restricted, being unable to communicate 
what she feels or needs. She is often very agitated, especially at night, having sleep 
disorders. 
Treatment: Studied beekeeping complex (5 gr. / 0 gr. / 5 gr.) + Royal jelly in honey 20% (5 gr. / 
0 gr. / 5 gr.). 
Results after 2 months: The child became more present in reality and more attentive. He has 
increased his vocabulary and speaks much more coherently, both in terms of diction and in 
the ordering of words in sentences. They also fall asleep more easily, as the states of 
nocturnal agitation are diminished. 
 
2 STUDY OBJECTIVES, PLAN AND PROCEDURE   
                                                                 
2.1 Investigational Products and Treatments 
Taking into consideration the good results obtained in the above children with ASD, 
we have selected a combination of three supplements which are already on the market to 
be given to the ASD children enrolled in this study: Apicol 12 gamma; Royal jelly, and Telom R 
Cerebral. 
We will also take into account the weight of the child, so that in children older than 6 years 
or with body weight greater than 30 kg will receive a higher dose of Royal Jelly (2 
teaspoons/day vs 1 teaspoon for children younger than 6 years) and Telom R Cerebral (1 
capsule/day vs 2 capsules/day) as indicated below, where details are also given on the 
ingredients in the three supplements (which are already available in stores, exempliﬁed by 
the included links): 
Apicol 12 gamma (bottle/jar, 200 ml) all participants will be administered 3 teaspoons/day, 
taken for 3 months (a total of 15 ml x 90 – approximately 6 jars per participant)   
APICOL12GAMMA - "Mierea albastră" 200 ml - ApicolScience 
Ingredients: 
Polyﬂoral honey (organic): 90.39%; Raw royal jelly: 7%; 1:10 aqueous extracts of Burdock 
(Arctium lappa): 1% and Chamomile (Matricaria chamomilla): 1%; Spirulina (Arthrospira 
platensis), hydro saline extract, with min. 25% phycocyanin: 0.2%; Siberian ginseng 
(Eleutherococcus senticosus), root, aqueous extract with min. 0.8% eleutherosides, dry: 
0.1%; Milk thistle (Silybum marianum), fruits, hydroalcoholic extract 40-50:1 (maltodextrin), 
dry, with 80% silymarin: 0.1(%); Korean ginseng (Panax ginseng), root, 4:1 hydroalcoholic 
extract (maltodextrin), dry, with 4% ginsenosides: 0.05(%); Astragalus (Astragalus 
membranaceus), root, hydroalcoholic extract 20/1 with min. 50% polysaccharides: 0.05(%); 
Frankincense tree (Boswellia serrata), concentrate of micellar emulsiﬁed extract in 
polysorbate 20, with min. 12% boswellic acid: 0.01 (%); Chamomile (Matricaria chamomilla), 

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Clinical Study Protocol No: B-F045   
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essential oil 0.06(%); Serlai/Sweet Sage (Salvia sclarea), essential oil: 0.02(%); Sage (Salvia 
oﬃcinalis), essential oil 0.02(%). 
Apicol 12 gamma (bottle/jar, 200 ml) – 1 teaspoon – 5 ml or approximately 5 g - will contain 
the following approximate amounts:  
4.5 g honey; 0.3 g – royal jelly; 0.1 g Burdock + Chamomile + Spirulina; 0.1 g Siberian 
Ginseng, Milk Thistle, Korean Ginseng, Astragalus, Boswellia, Sage 
Daily dose will be 3 x (3 teaspoons) of the above amounts (given per teaspoon) 
Activated royal jelly (bottle, 200 ml)  
LĂPTIȘOR DE MATCĂ ACTIVAT - util în anemii, depresie, oboseală - ApicolScience 
For children age 6 or more - 1 teaspoon in the morning, 1 evening, (4 bottles for 3 months) 
For children age 3-5 years – 1 teaspoon at lunchtime (3 bottles for 3 months) 
Ingredients: 
Polyﬂoral honey (organic): 161 g;  
Royal jelly gel: 64.4 g;  
Burdock leaves (Arctium lappa) 1:10 aqueous extract: 2.3 g;  
Sweet Orange peel (Citrus sinensis) 1:10 aqueous extract: 2.18 g; 
Grapefruit (Citrus paradisi) essential oils: 0.04 g; 
Lemon (Citrus limon): 0.04 g; 
Lime (Citrus aurantifolia): 0.04 g. 
 
Telom-R Cerebral  
Telom-R Cerebral, 120 capsule, Dvr Pharm : Farmacia Tei online 
Children 6 years and older will receive 2 cp/day – 180 capsules for 3 months 
Children 3-6 years old will receive 1 cp/day – 90 capsules for 3 months 
Ingredients: 
Astragalus (Astragalus membranaceus), root, hydroalcoholic extract 20:1, with min 50% 
polysaccharides, dry: 100 mg; and astragalus root, powder: 19.88 mg 
Ginkgo biloba, leaves, 24/6 hydroalcoholic extract, with 24% ﬂavonoids and 6% terpenoids: 
80 mg; Chlorella (Chlorella vulgaris), powder: 60 mg;  
Celery (Apium graveolens), fruit, powder: 60 mg;  
Freeze-dried royal jelly: 40 mg;  
Hawthorn (Crataegus oxyacantha), fruit, 4:1 hydroalcoholic extract: 40 mg;  
Peppermint (Mentha piperita), essential oil: 0.04 mg;  
Cloves (Eugenia caryophylus), essential oil: 0.04 mg;  
Ravintsara (Cinnamomum camphora), essential oil: 0.04 mg. 
hard gelatin capsule 
 

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Data from literature show that some of the components of this product may interact 
with anticoagulants, antiplatelet agents, thrombolytic agents, low molecular weight 
heparins, anticonvulsants, insulin, monoamine oxidase inhibitors, nonsteroidal anti-
inﬂammatory drugs or thiazide diuretics when administered concomitantly. 
Special attention needs to be given to patients with known allergy to celery and other plants 
of the Fam. Apiaceaea (Umbelliferae) – they should not receive this supplement. 
 
2.2 Study design  
 
 
 
 
 
 
 
 
  
 
Design: prospective, double-blind, placebo-controlled, crossover, multicenter. 
All children diagnosed with ASD (about 40) will be tested before and after the combination 
of active substances (3 months) and placebo (3 months). The duration of participation in the 
study of each child will be approximately 6 months, and the total duration of the study at a 
clinical center (investigator) will be approximately 12 months, during which it is estimated 
that the 40 children can be enrolled and the study products will be administered individually 
for 6 months. 
2.3 Study Population 
For enrollment in the APITSA study we will include children who are already diagnosed with 
ASD and have received at least one treatment for this pathology; children who are currently 
receiving psychotherapy, age group 3-14 years. Consecutive children diagnosed with ASD 
and presenting as new patients at the clinical sites which enroll in this study (4 clinical sites, 
2 in Bucharest, 1 in Constanta, 1 in Piatra Neamt), or existing children who meet the 
inclusion and exclusion criteria and will follow a stable therapy strategy for at least the 
duration of study participation (6 months for each individual child). Around 45 children will 
be enrolled, and assuming an attrition rate of 10%, we estimate that at least 40 children will 
be able to complete this study. Enrollment in the study will be positively stopped when 40 
children have completed the study. Estimated enrolment of 40 patients at the 4 study sites: 
until April 30, 2025 
 
2.3.1 Inclusion Criteria 
Patients enrolled in the APITSA study will meet the following Inclusion criteria: 
- age 3-14 years  
- diagnosed with typical or atypical autism spectrum disorder (F84.0 or F84.1) and received 
at least one therapeutic intervention before enrolling 
- the ability to follow an oral treatment, with TID/BID/QD administration 
- the availability to perform 3 sets of blood tests at a clinical laboratory within 6 months 
(initial, at 3- and 6-months) 

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- the availability to perform 3 visits to the Investigator and 3 psychometric evaluations within 
6 months 
Exclusion criteria: 
- patients enrolled in another interventional clinical trial currently or which ended less than 
1 month prior to enrolling in this study 
- known allergy to hive products or one of the substances studied 
- inability to perform the study requirements (3 visits to the Investigator, 3 psychometric 
assessments, 3 sets of blood tests) 
- diagnosis of diabetes 
- history of seizures/epilepsy 
- administration of anticoagulants, antiplatelets, thrombolytic agents, low molecular weight 
heparins, anticonvulsants, insulin, monoamine oxidase inhibitors, non-steroidal anti-
inﬂammatory drugs or thiazide diuretics 
 - allergy to celery and other plants of the Fam. Apiaceaea (Umbelliferae) 
- abnormally elevated baseline (at V1) values of ferritin, homocysteine, HgbA1c, ESR 
 
2.3.3 Scheduled clinic visits and assessments 
 
For each patient, three evaluations are made: 
- initially (upon enrollment in the study), - V1 
- after the ﬁrst treatment (12 weeks after enrollment) – V2 
- ﬁnal (24 weeks after enrollment) – V3 
At each of the three study visits, psychometric evaluation (ASRS and ATEC) and blood tests 
are performed, which include: NSE, serum protein electrophoresis, ESR, ferritin, blood count, 
glycosylated hemoglobin 
Each patient will receive 2 treatments of 12 weeks (at Visit 1 – V1, respectively V2), so that 
each patient will take for 3 months both the active preparation (Combination A) and 
Combination B in random sequences (Combination A followed by Combination B, or vice 
versa), and the sequence is secreted both at the level of the Investigator and the patient. 
2.3.4. Criteria for discontinuation 
Patients can be discontinued on the study intervention in the following situations: 
- severe allergy requiring emergency room treatment or administration of epinephrine as 
documented by a doctor or nurse 

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- new onset pathology requiring long-term treatment and which aﬀects the immune or 
nervous systems (autoimmune disorder including type 2 diabetes, convulsions, asthma, 
others) 
- at patient’s request the participation in the study can be stopped without a reason, in 
which case the participant will reimburse the value of the blood tests and the medical 
evaluations. 
2.4 Treatment administration and schedule 
The treatment consists of administering for 6 months, daily, 3 types of preparations present 
in both Combination A and Combination B, the vials will be labeled in both cases with 
"A1/A2", A2/B2 and "A3/B3" respectively: 
- Preparation 1 (A1 or B1). (blue) 1 teaspoon in the morning, lunch and evening 
- Preparation 2 (A2 or B2) – 1 teaspoon in the morning and evening (children 7-14 years old); 
1 teaspoon at lunch (2-6 years) 
- Preparation 3 (A3 or B3) – 1 capsule in the morning and evening (children 7-14 years old); 1 
capsule at lunch (2-6 years) 
The approximately 40 patients are psychometrically evaluated 3 times: initially (at V1); after 
12 weeks with Combination A, or with Combination B (at V2) and again after 12 weeks (at 
V3).   
The investigator also sends the 3 sets of blood tests to the laboratory at V1, V2, and V3 for 
collection and receives the results of these tests. 
Treatments (3 months active combination and 3 months placebo combination), 
doctor/therapist visits (350 lei x 3) and blood tests (200 lei x3) are free for the patient.  
There will be diﬀerent doses of supplement 2 and 3 for children 3-6 years old vs 
children 7-14 years; at each visit we give the following preparations that are enough for 3 
months (90 days) 
- 6 bottles of A1 or B1 (blue honey, 3 teaspoons/day) 
- 4 bottles of yellow honey A2 or B2 for children between 7-14 years old (2 teaspoons/day), 
and 3 bottles of yellow honey for children 2-6 years old (2 teaspoons/day) 
- 1 capsule/day from A3/B3 bottle for children 2-6 years old (total 90 capsules), respectively 
2 capsules/day from A3/B3 bottle for children 7-14 years old (total 180 capsules) 
 
2.4.1     Identity of Study Treatments  
 
 
 
 
 
 
 
The identity of treatments (active combination and placebo combination) will be unknown 
to both patients/family and also the medical provider administering the treatment. At V1 
and V2 the study investigator will note on the CRF the type of the combination dispensed 
(A or B). At the end of the study the manufacturer will disclose to the investigators and to 

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the sponsor the identity of treatments A and B (which is the one with the active 
substance); this way the double-blind characteristic of the study will be observed. 
 
 
2.4.2   Storage and Accountability 
 
 
 
 
 
 
  
 
Supplements and placebo kits will be stored in carton boxes at room temperature (between 
18-25 Celsius) and humidity interval between 25-60% (normal conditions), protected from 
direct sunlight, rain and temperatures outside the interval mentioned. 
The number and types of vials will be recorded upon reception by the sponsor from 
manufacturer and also at each time vials are distributed to the study investigators; the 
sponsor and the investigators are accountable for the vials received. 
In the CRF the study investigator will note the type and vials dispensed at each study visit to 
the patients, and if there are special situations (discontinuation, returns, lost vials, etc.), the 
study investigator will note the occurrence and communicate to the sponsor and to the 
manufacturer, respectively. 
 
2.4.3 Allowed medication  
 
 
 
 
 
 
  
 
 
As a general rule, there should be no modiﬁcations of treatments for the child during the 6 months 
of the study. This means that acute treatments (ex. ﬂu or colds) should be kept to a minimum of 
intervention and for the shortest possible time (ex: anti-inﬂammatories or antipyretics should be 
given for no more than 2 weeks), and treatment of other occurrences should be also minimal (ex. 
traveler’s diarrhea) and also noted in the CRF on the respective study visit. If a new pathology is 
identiﬁed during the 6 months of the study (ex: asthma, diabetes) the patient should be discontinued 
and withdrawn from the study. 
3.  STUDY MEASUREMENTS AND ENDPOINTS 
 
 
 
 
              
 
3.1 Primary Study Endpoints 
 
 
 
Primary: EFFICACY 
    1.    Behavioral improvement with validated scales for autistic spectrum disorders - ATEC 
and ASRS - in each 3-month interval; this will be assessed by a specifically trained medical 
provider acting as study investigator  
                   
3.2 Secondary Study Endpoint 
 
 
 
 
 
 
 
  
  
 Secondary: SAFETY   
1 
   Adverse events, especially frequency and intensity of agitation episodes 
2      Modification of laboratory tests: Hematology: RBC, MCHC, MCH, MCV, RDW, Hct, 
Hb, WBC Differential count –lymphocytes monocytes, neutrophils, eosinophils, 
basophils;  
Biochemistry: NSE laboratory, serum protein electrophoresis, ESR, ferritin, blood count, 
glycosylated hemoglobin 

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 Secondary: Predictive biomarkers: 
3. Modifications of plasma levels of Neuron-specific enolase (NSE), and correlation with 
efficacy 
Modifications of the plasma inflammatory and metabolic markers, and correlation with 
efficacy 
 
3.3 Measurements at each visit 
 
 
 
 
 
 
 
 
 
The speciﬁc evaluations at each visit are detailed in the table below 
 
Enrollment/ 
Initial Visit - V1 
12 weeks 
interval  
Second Visit - 
V2 
 
 
 
 
 
 
 
 
 
12 weeks 
interval 
Final study visit 
– V3 
Psychometric 
assessment 
(ASRS and 
ATEC) 
Psychometric 
assessment 
(ASRS and 
ATEC) 
Psychometric 
assessment 
(ASRS and ATEC) 
NSE laboratory, 
serum protein 
electrophoresis, 
ESR, ferritin, 
blood count, 
glycosylated 
hemoglobin 
NSE laboratory, 
serum protein 
electrophoresis, 
ESR, ferritin, 
blood count, 
glycosylated 
hemoglobin 
NSE laboratory, 
serum protein 
electrophoresis, 
ESR, ferritin, 
blood count, 
glycosylated 
hemoglobin 
 
A/B 
Combination 
Administration 
A/B 
Combination 
Administration 
 
 
3.4 Speciﬁc detail on measurements 
 
 
 
 
 
 
 
 
 
 
For ASRS administration, the answers to questions 1-36 are written down (for the 
respective age category of the child, 2-6 years or 6-14 years), scores from 0 to 4 (strictly in 
the last 4 weeks prior to the evaluation), then on the next page the corresponding ﬁgures 
are put and the subtotals are made at the bottom of the page, then the same questions 37-
71. 
Add up the scores at the bottom of the pages for the 2 pages and get the raw scores: SC, UB, 
SR, DSM IV-R, PS, AS, SER, AL, ST, BR, SS and AT 
These are noted for each of the three study visits 
For the ATEC test, the questions from the online questionnaire must be answered (it is also 
in Romanian) and the total score must be noted on the subscales 

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Understanding the ATEC score - Autism Research Institute 
3.4.1 Laboratory Investigations  
In addition to psychometric evaluations, the following blood tests will be performed at each 
of the 3 study visits: 
NSE (neuron-speciﬁc enolase)    
VSH  
Ferritin    
Serum protein electrophoresis   
Complete Blood Count with diﬀerential   
Hgb glycosylated (Hgb A1c)   
 
When receiving the blood test results from the laboratory, the following guidelines need to 
be observed: 
1. If ferritin is elevated to pathological values at V1 (>100 ng/ml), or or HgbA1c > 6.5 ESR 
>20, the patient is excluded or re-tested after speciﬁc treatment 
2. If ferritin has normal values at V1 (between 20 and 99) then ferritin analysis is no longer 
performed at visits 2 and 3 
3. If ferritin is abnormally low at V1, the ferritin analysis is repeated at Visit 2 and 3 
 
 
3.4.2 Adverse Events 
 
 
 
 
 
 
 
 
  
 
The parents will be instructed on how to look for and identify possible adverse 
events (AEs) during the study, and how to report them to study investigator or study 
coordinator. 
 
 
 
 
 
  
 
As with any medication and treatment, there may be side-eﬀects associated with the 
administered therapies, the most common being episodes of agitation   
Some procedures used in this study may cause some discomforts (e.g. the 
withdrawal of blood may cause slight bruising or possible fainting, there may be 
discomfort during infusion or after administration of sedation, etc), but these will be 
no more than that experienced in a typical medical examination.  
The observed adverse reactions are temporary and completely reversible upon 
discontinuation of administration of the respective product. 
 
4 STATISTICAL METHODS   
 
 
 
 
 
 
  
 
 
4.4 Determination of sample size 
 
 
 
 
 
 
  
 
 
Based on previous experience with the combination in study, an eﬀect size of approximately 
20% was estimated as compared to no treatment, and using the two-tailed z test, conﬁdence 
interval 95%, eﬀect size 0,5 (medium) and a diﬀerence in scores average between the groups 
of 5 and the standard deviation of group A 10, SD for group B 5, then p value in this scenario 
is 0.02 with acceptable power. 

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4.5 Statistical analysis 
 
 
 
 
 
 
 
 
  
Summary statistics will describe the safety variables.  Significance testing will be 
done using analysis of variance for continuous and two-tailed Student’s t- test for 
categorical variables.  (α = 0,05). Pearson or Spearman correlation coefficients (for 
parametric and non-parametric variables) between psychometric scores and 
biomarkers will evaluate their predictive quality for treatment efficacy. 
For randomization the following table was used from graphpad 
Subject # 
Group Assigned 
1 
B 
2 
A 
3 
B 
4 
A 
5 
B 
6 
A 
7 
A 
8 
A 
9 
B 
10 
B 
11 
A 
12 
B 
13 
A 
14 
A 
15 
A 
16 
A 
17 
B 
18 
B 
19 
B 
20 
B 
21 
B 
22 
A 
23 
B 
24 
A 
25 
A 
26 
B 
27 
A 
28 
A 
29 
A 
30 
B 
31 
A 
32 
A 
33 
A 
34 
A 
35 
B 
36 
A 
37 
B 

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38 
B 
39 
B 
40 
B 
41 
B 
42 
B 
43 
A 
44 
A 
45 
B 
46 
A 
47 
A 
48 
A 
49 
A 
50 
A 
 
 
4.6 Changes to the protocol  
 
 
 
 
 
 
  
Any changes to the protocol will be approved by the Ethics Committee of the Bio-Forum 
Foundation and will be marked in the updated version. 
 
5 
ETHICS 
 
 
 
 
 
 
 
 
 
  
 
5.4 Ethics review 
 
 
 
 
 
 
 
 
  
 
The APITSA clinical study has been reviewed and approved by the Ethical Committee of the 
Bio-Forum Foundation and found to be properly conducted, taking into consideration that 
the products tested have been sold in Romania for more than 5 years and there were no 
complaints 
 
5.5 Ethical conduct of the study 
 
 
 
 
 
 
 
 
 
The study will be performed in accordance with the ethical principles in the Declaration of 
Helsinki of the World Health Organization (see Appendix 1), and that are consistent with 
Good Clinical Practice and applicable regulatory requirements. 
 
5.6 Subject information and consent 
 
 
All participants in the APITSA clinical study will be properly informed – the children’s parents 
– and will start evaluation and administration of the treatments only after carefully reviewing 
the Informed Consent Form and signing it – both parents are required to sign. 
The investigator must store the original, signed Subject Informed Consent Form and a copy 
must be given to the subject.  Samples of the English version of the Subject Information and 
Consent Forms are enclosed (Appendix 1).   
If you are harmed by your participation in the study, you will be compensated according to 
the guidelines of the pharmaceutical industry relating to clinical trials (Association for British 
Pharmaceutical Industry ABPI guidelines). If you are harmed due to someone’s negligence 
then you may have grounds for legal action. You are not waiving your legal rights by signing 
this form. 
In case of study related questions please contact: 

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Doctor: 
 
Dr Felician Stancioiu    or     Site Investigator 
Contact Numbers: 
0727500402                              
  
 
 
 
 
 
 
  
5.7 Subject data protection   
 
 
 
 
 
 
 
The Subject Information and Consent Form will explain that study data will be stored in a 
computer database, maintaining conﬁdentiality.  Subjects in this database will be identiﬁed 
by initials or enrolment code / subject number only.   
All participant data is anonymized and will not be shared publicly or with other researchers, 
making it impossible to gather individual participant data without consent from family.  
GDPR regulations will be observed throughout the study. 
 
6 
STUDY TIMETABLE AND TERMINATION  
 
 
APITSA clinical study will begin in December, 2024 and is planned to end in September 2025. 
Termination of the study will occur after 40 patients will complete the study or if 
occurrences of serious adverse eﬀects will be deemed to jeopardize participant safety. 
 
 
 
 
 
7 
REFERENCES 
Bibliographic references 
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Pollen on Multiple Propionic Acid-Induced Biochemical Autistic Features in a Rat 
Model. Metabolites. 2022;12:571.    
Ayaydın H, Kirmit A, Celik H, Akaltun , Koyuncu C, Bilgen Ulgar.  High Serum Levels of 
Serum 100 Beta Protein, Neuron-speciﬁc Enolase, Tau, Active Caspase-3, M30 and M65 
in Children with Autism Spectrum Disorders.  Clin Psychopharmacol Neurosci 
2020;18:270-278.  https://doi.org/10.9758/cpn.2020.18.2.270 
Chiarotti F, Venerosi A. Epidemiology of Autism Spectrum Disorders: A Review of 
Worldwide Prevalence Estimates Since 2014. Brain Sci. 2020 May 1;10(5):274. doi: 
10.3390/brainsci10050274. PMID: 32370097; PMCID: PMC7288022. 
Erten F. Lycopene ameliorates propionic acid-induced autism spectrum disorders by 
inhibiting inflammation and oxidative stress in rats. J Food Biochem. 2021 
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PMid:34476820 
Foley KA, MacFabe DF, Vaz A, Ossenkopp KP, Kavaliers M. Sexually dimorphic eﬀects of 
prenatal exposure to pro-pionic acid and lipopolysaccharide on social behavior in 
neonatal, adolescent, and adult rats: implications for autism spectrum disorders. Int J 
Dev Neurosci. 2014 Dec; 39:68-78. doi: 10.1016/j.ijdevneu.2014.04.001. Epub 2014 Apr 
18. PMID: 24747144. 
Gesundheit, B., Rosenzweig, J. P., Naor, D., Lerer, B., Zachor, D. A., Procházka, V., 
… Ashwood, P. (2013). Immunological and autoimmune considerations of Autism 
Spectrum Disorders. Journal of Autoimmunity.  
https://doi.org/10.1016/j.jaut.2013.05.005 
PMid:23867105 
Havdahl, A., Niarchou, M., Starnawska, A., Uddin, M., Van Der Merwe, C., & 
Warrier, V. (2021). Genetic contributions to autism spectrum disorder. Psychological 
Medicine. https://doi.org/10.1017/S0033291721000192 
PMid:33634770 PMCid:PMC8477228 

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Hewitson, L., Mathews, J. A., Devlin, M., Schutte, C., Lee, J., & German, D. C. 
(2021). Blood biomarker discovery for autism spectrum disorder: A proteomic 
analysis. PLoS ONE, 16(2 February 2021).  
https://doi.org/10.1371/journal.pone.0246581 
PMid:33626076 PMCid:PMC7904196 
Hughes, H. K., R.J.Moreno, & Ashwood, P. (2023). Innate immune dysfunction and 
neuroinflammation in autism spectrum disorder (ASD). Brain, Behavior, and 
Immunity. https://doi.org/10.1016/j.bbi.2022.12.001 
PMid:36494048 
Khera, R.; Mehan, S.; Bhalla, S.; Kumar, S.; Alshammari, A.; Alharbi, M.; Sadhu, 
S.S. Guggulsterone Mediated JAK/STAT and PPAR-Gamma Modulation Prevents 
Neurobehavioral and Neurochemical Abnormalities in Propionic Acid-Induced 
Experimental Model of Autism. Molecules 2022, 27, 889. 
https://doi.org/10.3390/molecules27030889 
PMid:35164154 PMCid:PMC8839522 
Molloy, C. A., Morrow, A. L., Meinzen-Derr, J., Schleifer, K., Dienger, K., Manning-
Courtney, P., … Wills-Karp, M. (2006). Elevated cytokine levels in children with 
autism spectrum disorder. Journal of Neuroimmunology, 172(1-2) 
https://doi.org/10.1016/j.jneuroim.2005.11.007 
PMid:16360218 
Pugsley, K., Scherer, S. W., Bellgrove, M. A., & Hawi, Z. (2022). Environmental 
exposures associated with elevated risk for autism spectrum disorder may augment 
the burden of deleterious de novo mutations among probands. Molecular 
Psychiatry. https://doi.org/10.1038/s41380-021-01142-w 
PMid:34002022 PMCid:PMC8960415 
 
Rylaarsdam, L., & Guemez-Gamboa, A. (2019). Genetic Causes and Modifiers of 
Autism Spectrum Disorder. Frontiers in Cellular Neuroscience. 
https://doi.org/10.3389/fncel.2019.00385 
PMid:31481879 PMCid:PMC6710438 
Santomauro, Damian F et al. The global epidemiology and health burden of the autism 
spectrum: ﬁndings from the Global Burden of Disease Study 2021. The Lancet 
Psychiatry, Volume 0, Issue 0 
Șelaru, Dana Misa - The Eﬀect of Royal Jelly, Plant Extracts, Honey and Essential Oils on 
the Behavior and Cognitive Abilities of Children with Autism – presentation at Family 
Medicine Congress – Constanta 2022 
Singh R, Kisku A, Kungumaraj H, Nagaraj V, Pal A, Kumar S, Sulakhiya K. Autism 
Spectrum Disorders: A Recent Update on Targeting Inflammatory Pathways with 
Natural Anti-Inflammatory Agents. Biomedicines. 2023 Jan 3;11(1):115.  
https://doi.org/10.3390/biomedicines11010115 
PMid:36672623 PMCid:PMC9856079 
Stancioiu FA, Bogdan R, Ivanescu B, Dumitrescu R. Autologous cord blood vs 
individualized supplements in autistic spectrum disorder: CORDUS study results. World 
J Clin Pediatr 2025; 14(1): 96643 [DOI: 10.5409/wjcp.v14.i1.96643] 
Stancioiu, F.; Bogdan, R.; Dumitrescu, R. Neuron-Speciﬁc Enolase (NSE) as a Biomarker 
for Autistic Spectrum Disease (ASD). Life 2023, 13, 1736. 
https://doi.org/10.3390/life13081736 
Symeonides, C., Vacy, K., Thomson, S. et al. Male autism spectrum disorder is linked to 
brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA 
ameliorates the related mouse phenotype. Nat Commun 15, 6367 (2024). 
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Usui, N., Kobayashi, H., & Shimada, S. (2023). Neuroinflammation and Oxidative 
Stress in the Pathogenesis of Autism Spectrum Disorder. International Journal of 
Molecular Sciences. https://doi.org/10.3390/ijms24065487 
PMid:36982559 PMCid:PMC10049423 
Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. 
(2005). Neuroglial activation and neuroinflammation in the brain of patients with 
autism. Annals of Neurology, 57(1).  
https://doi.org/10.1002/ana.20315 
PMid:15546155 
Wiśniowiecka-Kowalnik, B., & Nowakowska, B. A. (2019). Genetics and epigenetics 
of autism spectrum disorder-current evidence in the field. Journal of Applied 
Genetics. https://doi.org/10.1007/s13353-018-00480-w 
PMid:30627967 PMCid:PMC6373410 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ANNEX A 
DECLARATION OF HELSINKI 
 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects  
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
Note of Clariﬁcation on Paragraph 29 added by the WMA General Assembly, Washington 2002 
 
INTRODUCTION  
 
1. The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identiﬁable human material or 
identiﬁable data. 
 
2. It is the duty of the physician to promote and safeguard the health of the people. 
The physician's knowledge and conscience are dedicated to the fulﬁllment of this 
duty. 
 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my ﬁrst consideration," and the 
International Code of Medical Ethics declares that, "A physician shall act only in the 
patient's interest when providing medical care which might have the eﬀect of 
weakening the physical and mental condition of the patient."  
 
4. Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects. 
 
5. In medical research on human subjects, considerations related to the well-being of 
the human subject should take precedence over the interests of science and society. 
 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease. Even the best-proven prophylactic, 
diagnostic, and therapeutic methods must continuously be challenged through 
research for their eﬀectiveness, eﬃciency, accessibility and quality.  
 

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7. In current medical practice and in medical research, most prophylactic, diagnostic 
and therapeutic procedures involve risks and burdens.  
 
8. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable 
and need special protection. The particular needs of the economically and medically 
disadvantaged must be recognized. Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not beneﬁt personally from the research 
and for those for whom the research is combined with care.  
 
 
9. Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for 
human subjects set forth in this Declaration. 
 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
 
10. It is the duty of the physician in medical research to protect the life, health, privacy, 
and dignity of the human subject.  
 
11. Medical research involving human subjects must conform to generally accepted 
scientiﬁc principles, be based on a thorough knowledge of the scientiﬁc literature, 
other relevant sources of information, and on adequate laboratory and, where 
appropriate, animal experimentation. 
 
12. Appropriate caution must be exercised in the conduct of research, which may aﬀect 
the environment, and the welfare of animals used for research must be respected. 
 
13. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol. This protocol 
should be submitted for consideration, comment, guidance, and where appropriate, 
approval to a specially appointed ethical review committee, which must be 
independent of the investigator, the sponsor or any other kind of undue inﬂuence. 
This independent committee should be in conformity with the laws and regulations 
of the country in which the research experiment is performed. The committee has 
the right to monitor ongoing trials. The researcher has the obligation to provide 
monitoring information to the committee, especially any serious adverse events. The 
researcher should also submit to the committee, for review, information regarding 
funding, sponsors, institutional aﬃliations, other potential conﬂicts of interest and 
incentives for subjects.  
 
14. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration.  
 

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15. Medical research involving human subjects should be conducted only by scientiﬁcally 
qualiﬁed persons and under the supervision of a clinically competent medical 
person. The responsibility for the human subject must always rest with a medically 
qualiﬁed person and never rest on the subject of the research, even though the 
subject has given consent.  
 
16. Every medical research project involving human subjects should be preceded by 
careful assessment of predictable risks and burdens in comparison with foreseeable 
beneﬁts to the subject or to others. This does not preclude the participation of 
healthy volunteers in medical research. The design of all studies should be publicly 
available. 
 
17. Physicians should abstain from engaging in research projects involving human 
subjects unless they are conﬁdent that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any 
investigation if the risks are found to outweigh the potential beneﬁts or if there is 
conclusive proof of positive and beneﬁcial results.  
 
18. Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the subject. 
This is especially important when the human subjects are healthy volunteers.  
 
19. Medical research is only justiﬁed if there is a reasonable likelihood that the 
populations in which the research is carried out stand to beneﬁt from the results of 
the research.  
 
20. The subjects must be volunteers and informed participants in the research project. 
 
 
21. The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the 
conﬁdentiality of the patient's information and to minimize the impact of the study 
on the subject's physical and mental integrity and on the personality of the subject. 
 
22. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conﬂicts of interest, 
institutional aﬃliations of the researcher, the anticipated beneﬁts and potential risks 
of the study and the discomfort it may entail. The subject should be informed of the 
right to abstain from participation in the study or to withdraw consent to participate 
at any time without reprisal. After ensuring that the subject has understood the 
information, the physician should then obtain the subject's freely given informed 
consent, preferably in writing. If the consent cannot be obtained in writing, the non-
written consent must be formally documented and witnessed.  
 
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician 
or may consent under duress. In that case the informed consent should be obtained 
by a well-informed physician who is not engaged in the investigation and who is 
completely independent of this relationship.  
 

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24. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain 
informed consent from the legally authorized representative in accordance with 
applicable law. These groups should not be included in research unless the research 
is necessary to promote the health of the population represented and this research 
cannot instead be performed on legally competent persons.  
 
25. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain that 
assent in addition to the consent of the legally authorized representative.  
 
26. Research on individuals from whom it is not possible to obtain consent, including 
proxy or advance consent, should be done only if the physical/mental condition that 
prevents obtaining informed consent is a necessary characteristic of the research 
population. The speciﬁc reasons for involving research subjects with a condition that 
renders them unable to give informed consent should be stated in the experimental 
protocol for consideration and approval of the review committee. The protocol 
should state that consent to remain in the research should be obtained as soon as 
possible from the individual or a legally authorized surrogate. 
 
27. Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. 
Negative as well as positive results should be published or otherwise publicly 
available. Sources of funding, institutional aﬃliations and any possible conﬂicts of 
interest should be declared in the publication. Reports of experimentation not in 
accordance with the principles laid down in this Declaration should not be accepted 
for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
 
28. The physician may combine medical research with medical care, only to the extent 
that the research is justiﬁed by its potential prophylactic, diagnostic or therapeutic 
value. When medical research is combined with medical care, additional standards 
apply to protect the patients who are research subjects. 
29. The beneﬁts, risks, burdens and eﬀectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic methods. 
This does not exclude the use of placebo, or no treatment, in studies where no 
proven prophylactic, diagnostic or therapeutic method exists. See footnote  
 
30. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best-proven prophylactic, diagnostic and therapeutic 
methods identiﬁed by the study. 
 
31. The physician should fully inform the patient which aspects of the care are related to 
the research. The refusal of a patient to participate in a study must never interfere 
with the patient-physician relationship. 
 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineﬀective, the physician, with informed consent 
from the patient, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician's judgement it oﬀers hope of saving life, re-

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establishing health or alleviating suﬀering. Where possible, these measures should 
be made the object of research, designed to evaluate their safety and eﬃcacy. In all 
cases, new information should be recorded and, where appropriate, published. The 
other relevant guidelines of this Declaration should be followed.  
 
 
FOOTNOTE: 
NOTE OF CLARIFICATION ON PARAGRAPH 29 of the WMA DECLARATION OF HELSINKI  
The WMA hereby reaﬃrms its position that extreme care must be taken in making use of a placebo-
controlled trial and that in general this methodology should only be used in the absence of existing 
proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven 
therapy is available, under the following circumstances: 
- Where for compelling and scientiﬁcally sound methodological reasons its use is necessary to 
determine the eﬃcacy or safety of a prophylactic, diagnostic or therapeutic method; or  
- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition 
and the patients who receive placebo will not be subject to any additional risk of serious or 
irreversible harm.  
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for 
appropriate ethical and scientiﬁc review. 
 
 
The Declaration of Helsinki (Document 17.C) is an oﬃcial policy document of the World Medical 
Association, the global representative body for physicians. It was ﬁrst adopted in 1964 (Helsinki, 
Finland) and revised in 1975 (Tokyo, Japan), 1983 (Venice, Italy), 1989 (Hong Kong), 1996 (Somerset-
West, South Africa) and 2000 (Edinburgh, Scotland). Note of clariﬁcation on Paragraph 29 added by 
the WMA General Assembly, Washington 2002. 
  
 
 
 
 
 
 
 
 
 
 

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ANNEX B 
INFORMED CONSENT 
(translation from Romanian) 
 
Clinical Study "Apitherapy for Autistic Spectrum Disorder - APITSA" 
Principal Investigator: Dr Felician Stancioiu 
Date ___ / _______ / _____ Name_____________________________________________ 
Date of birth _______________________ Diagnosis_Autistic Spectrum Disorder (ASD) 
F84.0/F84.1 
 
 
I (family name, first name) _______________________________________________ 
declare that I agree that my child will participate in the clinical study "Apitherapy for Autistic 
Spectrum Disorder - APITSA" 
 
I understand that during this study my child will have to consume for 3 months (12 
weeks) either a supplement containing honey, royal jelly, astragalus and other plant extracts, 
or a placebo (a substance without direct physiological effects on the body).  
These supplements can be purchased directly by consumers from specialized stores or 
online, so they have a good established safety profile; they will be provided for free during 
the study visits. The combination of supplements evaluated in this study was previously 
administered to a few children with autistic spectrum disorder (ASD) and was observed to 
have beneficial effects in children with ASD after several weeks of treatment. To date, there 
is no known treatment that will cure this pathology. This study will help to understand the 
benefit and to establish the limits of the effect on children with ASD and possibly shed new 
light onto this pathology. 
 
Speciﬁcally, I understand that my child will have to take for 3 months, 2-3 times a day, 2-3 
teaspoons and 1-2 capsules of the three supplements according to the body weight of the child. Each 
of the 3 supplements will have speciﬁc administrations schedule and for 3 months the child will be 
administered the supplement tested which contains the active ingredients, and for another 3 
months, the placebo; the order in which the active combination will not be known by the patient nor 
the medical provider administering the treatments. It will also be necessary that three times during 
this study the child will be evaluated by a doctor or therapist, and to have blood tests done (initially 
at ﬁrst visit, after 12 weeks – second visit- and after 24 weeks – third and last study visit). 
 
 
I acknowledge that my child was previously evaluated by a clinician (medical doctor or 
psychotherapist) to assess the diagnosis of ASD, and it was established that the child has the 
diagnosis of ASD (F84.0 – developmental disturbance fron the autistic spectrum) or F84.1 (atypical 
ASD). 
  
If I choose that my child will participate fully in the study, (ie to take the supplements and placebo for 
a total of 24 weeks and to do the 3 sets of blood tests at the three study visits during the 24 weeks of 

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participation). For these blood tests, as well as for the supplement administered and the 3 study 
visits, I will not have to pay.  
 
If I choose that the child will not complete the study in the absence of objective reasons (illness, 
accident, etc.), I accept to pay the value of the tests and treatments performed as follows: each study 
visit - 300 lei, blood tests (hemoleucogram) - 250 lei. The respective amounts will be paid within 7 
days from the date of withdrawal from the study to the study sponsor, The Bio-Forum Foundation, 
bank account at Banca Transilvania, SWIFT BTRLRO22, IBAN RO72BTRLRONCRT0056512501. 
 
However, the decision of not continuing to participate in this study for whatever reason will 
not interfere with other medical care which the child is reasonably expected to receive in the future. 
 
During the last five years in which these supplements were on the market, no adverse 
effects were reported when administering this type of supplement to patients without known 
allergies; however if there is an adverse reaction please report it as soon as possible to the 
study investigator or Dr Felician Stancioiu at 072750042; in the case of severe adverse 
reactions – difficulty breathing, swelling of tongue, throat, dizziness, first seek urgent 
evaluation and medical care.   
 
 
 
 
By signing below, I acknowledge that I was informed about the following: 
 
1. Variants and alternatives of treatment (medication, neurofeedback, psychotherapy, 
other supplements, oxygenotherapy, stem cells, etc.), and the natural evolution of 
ASD without treatment; 
2. Possible benefits (improved behavior, cognitive status, verbalization, socialization, 
etc.), and side effects (allergic type reactions, including anaphylactic shock) as well as 
treatment needed in such situations (discontinuation of the supplement, and if allergic-
type reaction - administration of anti-histamine medication, epinephrine or cortisone-
based treatment) 
3. The necessary or recommended analyzes (laboratory tests done from blood samples 
harvested from the antecubital vein via venipuncture), the treatment stages, the 
duration of my participation in this study and the fact that participation is free, but 
unmotivated withdrawal will incur costs on my part 
 
 
I have understood the benefits and the risks of the administration of the treatment, I agree 
with the child’s participation in the study in the above conditions, and I sign below: 
 
Child’s Name ______________________________________________________________ 
Mother’s Name 
____________________________________________Signature_________________ 

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Father’s Name ____________________________________________Signature 
_________________ 
Date of signature ____ / _______ / ______ 
 
 
Study Investigator Name (Person obtaining the Informed Consent)  
 
_________________________________________________ Signature___________Date__________