Management of peripheral neuropathy

symptoms with a fixed dose combination

of vitamin B1, B6 and B12
12 weeks prospective non-interventional study

1
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

2
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

3
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy

Peripheral neuropathy
is a pathologic condition characterised by impairment
and damage of nerves of the peripheral nervous system
(PNS)

can affect different parts of the PNS

is chronic in most cases
can have various causes
should be diagnosed and treated in early stages
is difficult to treat in severe stages and has a significant
impact on quality of life of the patient

4 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy - causes

Possible causes of nerve damage

genetics14
chronic diseases such as diabetes14
environmental toxins4
smoking1
alcoholism14
nutritional deficiencies, e.g. B vitamin deficiency14
side effects of certain medications such as chemotherapy drugs14
surgery3,5
other unexplained causes3,4

1. Head KA. Altern Med Rev. 2006;11: 294329.

2. Hanewinckel R, et al. Eur J Epidemiol. 2016; 31: 5–20.
3. Callaghan BC, et al. JAMA. 2015;314: 21722181.
4. Landmann G. Ars Medici. 2013;1: 1821.
5. Perkins FM, Kehlet H. Anasthesiology. 2000;93: 1123–1133.
5 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy - causes
diabetes mellitus (34.8%)

unclear etiology (22.0%)

alcohol (11.1%)

Guillan-Barré-Syndrome (6.3%)

infections (5.4%)

vasculitis (4.1%)

chronic inflammatory demyelinating

polyneuropathy (4.1%)
malabsorption (3.8%)
Diabetes is the most common
paraneoplastic (2.7%) cause of peripheral neuropathy
hereditary polyneuropathies (2.2%) Patients with idiopathic
paraproteinemia (1.1%) neuropathy are the second
biggest group
toxins (excl. alcohol) (0.9%)

amyloidosis (0.5%)

tomaculous neuropathy (0.2%)

others (0.9%)

6 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018 Landmann G. Ars Medici. 2013;1: 1821.
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy - symptoms

Symptoms of peripheral neuropathy can be

multifaceted and are sometimes misinterpreted or
ignored
In most cases symptoms are mild in the beginning
and develop over time into more painful stages
Painful neuropathy is a severe disease and is often
difficult to treat
Symptoms of peripheral neuropathy can affect the
quality of life of patients significantly
Diagnosis and treatment in early stages is key

7 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy - symptoms

Depending on which part of PNS is affected the patients can experience

sensory symptoms e.g. burning, tingling, allodynia, pins-and-needles
motor symptoms e.g. muscle wasting, muscle cramps
autonomic symptoms e.g. hyperhidrosis, gastrointestinal symptoms

Positive symptoms: symptoms which were not present before, the patient might notice and
report e.g. burning, tingling, stabbing pain
Negative symptoms: symptoms which the patient does not feel and might not report e.g.
numbness

In most cases patients are diagnosed and treated in moderate to severe stages of peripheral
neuropathy when the symptoms already are affecting their quality of life

Boulton AJM, et al. Diabetes Care. 2004;27: 14581486.

Freynhagen R, et al. Curr Med Res Opin. 2006;22:19111920.
Miranda-Massari JR, et al. Curr Clin Pharmacol. 2011; 6: 260273.
Azpiroz F, Malagelada C. Diabetologia. 2016;59: 404–408.
8 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Peripheral neuropathy – treatment options
The cause of peripheral neuropathy (if known) should be treated to avoid
further development of the disease
Symptomatic treatment: treatment options according to guidelines and
others
Guideline treatments:
focus on treatment of painful neuropathy/neuropathic pain
Pregabalin, Gabapentin, Duloxetin, others
can have significant side effects
Other treatment options:
Neurotropic B vitamins (B1, B6, B12), ALA, etc.
can help to restore nerve function
are well tolerated
can be used in all stages of neuropathy (also as co-treatment)
Treatment of underlying nerve impairment: B vitamins, Antioxidants etc.
Head KA. Altern Med Rev. 2006;11: 294329.
Elmofty DH, et al. Pain Manage. 2013;3: 475–483.
Finnerup NB, et al. Lancet Neurol 2015; 162–173.
9 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

10
 Management of peripheral neuropathy with B1, B6 and B12
Study rationale

Purpose of the study is to evaluate the efficacy and safety of a fixed dose
combination of neurotropic B vitamins (B1, B6, B12) in treatment of peripheral
neuropathy
in patients with different etiology of peripheral neuropathy as most published studies
are performed in diabetic neuropathy only
to observe improvement of different symptoms to show that different symptoms can be
treated
to observe improvement of symptoms with different tools to show validity of results
to observe improvement of quality of life. When peripheral neuropathy develops, different
aspects of patients life's might be affected and QoL changes
to observe safety profile of the high dose B vitamin combination is over a longer period
to observe when the treatment starts showing an effect and what happens when
treatment is maintained on longer term

11 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Study objectives

Primary objective:
Evaluation of improvement in clinical symptoms of peripheral
neuropathy (PN) according to Total Symptom Score (TSS) from baseline
after 14 days and up to 3 months of treatment in patients with PN of
different etiology.

Secondary objectives:
Evaluation Quality of Life (QoL) improvement after up to 3 months of
treatment.
Assessment of clinical symptoms of peripheral neuropathy (e.g. pain,
burning, paresthesia, numbness, etc.,) according to visual analogue scale
(VAS) from baseline up to 3 months of treatment.
Evaluation of safety of the fixed dose combination of B1, B6 and B12
during the course of study duration.

12 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

13
 Management of peripheral neuropathy with B1, B6 and B12
Study design
Project name NENOIN = Neurobion non-interventional study

Study design Prospective, open label, non-interventional

(observational), single arm study
Study treatment Vitamin B1 = 100mg
Vitamin B6 = 100mg
Vitamin B12 = 5mg
Posology Once a day after meals

Visit schedule V1=baseline/day 0

V2=14 days; V3=30 days; V4=60 days; V5=90 days
Study duration 90 days

Patient profile Patients with mild to moderate peripheral

neuropathy of different etiology (diabetic, idiopathic,
carpal tunnel, others).
Sample size 411 patients (Full Analysis Set = FAS)

Study parameters Total symptom score (TSS):

Stabbing pain, burning pain, paresthesia, numbness

Visual Analogue Scale (VAS):

Pain, burning, paresthesia, numbness, tingling
Quality of life (SF8); Safety (AEs, ADRs)
Study centers 8 centers in Indonesia

14 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Inclusion criteria

Subjects must meet the following criteria in order to participate in this study:
Subjects aged ≥ 18 years (completed) and ≤ 65 years
Subjects willing to provide signed informed consent
Subjects with peripheral neuropathy diagnosed by using either Michigan Neuropathy Screening
Instrument (MNSI score of ≥ 7 in patient administered questionnaire and healthcare
professional score of ≥ 2.5) or Toronto Clinical Neuropathy Score (TCNS) of ≥ 6
Peripheral neuropathy of various etiology which includes diabetic neuropathy, nutritional (e.g.
alcoholic neuropathy, dietary deficiency etc.,), carpal tunnel syndrome, idiopathic, others.

15 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Exclusion criteria (1/2)

Subjects who met any of the following criteria have been excluded from
participation in this study:
Subjects with known clinically significant cardiovascular, pulmonary, gastrointestinal, hematological,
hepatic, renal or endocrine diseases (except diabetes mellitus)
Subjects who are on any treatment like methotrexate which interferes with neuropathy or any other
cytostatic drug treatment to be excluded as per investigator's discretion
Subjects with known hypersensitivity to any component of the study treatment
Subjects with history/sign/symptoms suggestive of genetic neuropathy
Subjects taking Vitamin B complex supplements/products (Vitamin B1 = 100 - 300mg, B6 = 50 –
600mg and B12 = 200 - 5000mcg; oral or parenteral) more than 1 week consecutively in the last 3
months before consent

16 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Exclusion criteria (2/2)
Subjects who met any of the following criteria have been excluded from
participation in this study:
Participation in other clinical trials in last one month
Subjects with pregnancy, planning to become pregnant or breast feeding
Subjects who underwent any gastrointestinal surgery in the last 6 months before consent or plan
for surgery during the study
Any clinically significant or unstable medical or psychiatric condition that in the opinion of the
investigator would affect the subject’s ability to participate in the study
Subjects with severe neuropathy (Severe: ≥12 with TCNS / ≥7 with VAS for pain) who are
prescribed, or who are on therapy with NSAIDs, gabapentin, pregabalin, or any other pain relieving
medication e.g. anti-inflammatory drugs

17 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Subject recruitment

Recruitment of subject has been done according to local regulation for observational studies
Recruitment started after Ethics Committee approval
Investigators decide for the best treatment strategy for each respective patient after diagnosis
has been performed
In case the prescribed medication is in line with the study protocol and inclusion criteria are
met, investigator considers the possibility of including the subject into the study

18 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Screening tools used for inclusion of subjects (1/2)

Michigan Neuropathy Screening Instrument (MNSI)

MNSI is used to assess distal symmetrical peripheral neuropathy in diabetes
includes two separate assessments: a 15-item self-administered questionnaire and a lower
extremity examination that includes inspection and assessment of vibratory sensation and
ankle reflexes by healthcare professional
Patient administered questionnaire score: patient is asked to complete 15 specific questions on
symptoms of peripheral neuropathy in his extremities. A score is calculated according to his
answers.
Healthcare professional score: a healthcare professional inspects each foot for deformities, dry
skin, calluses, infections and fissures. Additionally the physician performs a reflex test,
sensory testing with a 128Hz tuning fork. Abnormalities are rated according to a scoring
system.

Moghtaderi A. et al; 2006; Clin Neurology and Neurosurgery (108) 477-481

see back up slides for more information

19 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Screening tools used for inclusion of subjects (2/2)

Toronto Clinical Neuropathy Score

The score is used for screening of PN.
The investigation consists of three parts: symptom scores (numbness, tingling, weakness,
etc), reflex scores (knee reflexes, ankle reflexes) and sensory test scores (pinprick,
temperature sensation, vibration, etc).
Assessment of severity of peripheral neuropathy is done according to a score system.

Bril V. et al; 2002; Diabetes Care (25) 2048-2052

see back up slides for more information

20 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Primary parameter: Total Symptom Score (TSS)

Change in TSS from baseline after 14 days and up to 3 months of treatment

Improvement of total TSS for all patients (FAS)
Improvement of each symptom observed in the study for all patients (FAS)
Improvement of TSS for each patient subgroup (different etiologies of peripheral
neuropathy)

Total symptom score (TSS) is assessing the experience of common peripheral neuropathy
symptoms reported by the patient: lancinating/stabbing pain, burning/burning pain,
paraesthesia and numbness. The patient is also asked to report how frequent he is
experiencing the respective symptom (occasional, frequent, continuous (almost)) and how
severe he is experiencing the respective symptom (absent, mild, moderate, severe).

Bastyr E. J. et al; 2005 Clinical Therapeutics; (27) 8, 1278-1294

see back up slides for more information

21 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Secondary parameter: Visual Analogue Scale (VAS)

Change in VAS from baseline after 14 days and up to 3 months of treatment

Improvement of each symptom observed in the study for all patients (FAS)
Improvement of each symptom observed in the study for each patient subgroup (different
etiologies of peripheral neuropathy)

Visual Analogue Scale (VAS) is an instrument to assess intensity of symptoms on a scale

from 0 to 10. 0 means no symptom, 10 means worst possible symptom.
The patient is assessing peripheral neuropathy symptoms according to the scale
(lancinating/stabbing pain, burning, paraesthesia, numbness, tingling).

Gould D. etal; 2001, Journal of Clinical Nursing (10) 697-706

see back up slides for more information

22 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Secondary parameter: Quality of Life questionnaire (SF-8)

Change in SF-8 from baseline up to 3 months of treatment

Improvement of QoL for all patients (FAS)
Improvement of QoL for each patient subgroup (different etiologies of peripheral
neuropathy)

Short Form 8 (SF-8) is a validated tool to assess health related quality of life and general
health (physical and mental health status). SF-8 is the most recent version of the short form
health survey.
SF-8 measures the same eight health domains as the more extended SF-36 Health Survey,
using only eight questions.

Ware J. E. 1990; SF-36 survey

see back up slides for more information

23 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Secondary parameter: safety monitoring

All kind of safety relevant reports have been monitored, assessed and recorded*
during the whole study period
Adverse Events (AE): Any untoward medical occurrence in a subject or clinical investigation
subject administered a medicinal product and which does not necessarily have to have a causal
relationship with this treatment.
Adverse Drug Reactions (ADRs): All noxious and unintended responses to a medicinal product
related to any dose should be considered ADRs. The phrase “response to a medicinal product”
means that a causal relationship between a medicinal product and an AE is at least a reasonable
possibility, i.e., the relationship cannot be ruled out.
Serious Adverse Events(SAEs): is any adverse, event as defined above, which also fulfills at
least one of the following seriousness criteria: results in death, is life-threatening, requires in-
patient hospitalization or prolongation of existing hospitalization, results in persistent or
significant disability/incapacity, is a congenital anomaly/birth defect, is otherwise considered as
medically important.**

* Severity and causality to treatment of an adverse events is assessed and recorded by the investigator according to criteria listed in the study protocol. All SEAs
and ADRs are reported in compliance with Merck pharmacovigilance process.
**Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered as serious when, based upon
appropriate medical judgment, they may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in this
definition.

24 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

25
 Management of peripheral neuropathy with B1, B6 and B12
Demographics: patients characteristics
Factors FAS n = 411(% of patients)

Etiology of peripheral neuropathy

Diabetic neuropathy n = 104 (25.3)%
Carpal tunnel Syndrome n = 44 (10.7)%
Idiopathic n = 112 (27.3)%
other n = 25
Combination (more than one cause of neuropathy) n = 126 (30.7)%
Severity of peripheral neuropathy (baseline)
Mild n = 196 (47.7)%
Moderate n = 201 (48.9)%
Severe n = 12 (2.9)%
Symptom intensity (baseline, VAS: 0-10) Mean ± SD: 4.50 ± 1.578
Range: 1.0 - 8.3
Patient age (18-65 y included)
< 45 y 76 (18.5)%
45 - <55 y 184 (44.8)%
55 - 65 y 151 (36.7)%
Gender M: 114 (27.7%) / F: 297 (72.3%)

BMI
2
<25 kg/m 211 (51.3)%
2
26 ≥25 -kg/m
NENOIN Management of peripheral neuropathy with B1, B6 and B12 | January 2018 195 (47.4)%
 Management of peripheral neuropathy with B1, B6 and B12
Demographics: concomitant use

Factors FAS n = 411 (% of patients)

Other "high dose" B Vitamins (Vitamin B1 = 100 - 300 n = 1 (0.2%)

mg, B6 = 50 - 600 mg and B12 = 200-5000 µg; oral or
parenteral)
Antacids / H2 blocker / PPIs n = 3 (0.7%)

Pain medication (NSAIDS / gabapentin / pregabalin) n = 2 (0.5%)

Tobacco use
Smoker n = 43 (10.5%)
Nonsmoker n = 368 (89.5%)
Alcohol use
Yes (mild to moderate use, only one alcoholic) n = 6 (1.5%)
No n = 405 (98.5% )
Coffee / Tea use
Yes n = 291 (70.8%)
No n = 120 (29.2%)

27 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Overview on study results

Primary parameter: TSS

TSS (FAS)
TSS by neuropathy symptom
TSS by neuropathy symptom in %
TSS by subgroups with different etiology of PN
Secondary parameter:
VAS by neuropathy symptom
VAS by neuropathy symptom in %
Quality of life
Safety

28 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Overview on study results

Primary parameter: TSS

TSS (FAS)
TSS by neuropathy symptom
TSS by neuropathy symptom in %
TSS by subgroups with different etiology of PN
Secondary parameter:
VAS by neuropathy symptom
VAS by neuropathy symptom in %
Quality of life
Safety

29 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Patients are relieved of neuropathy symptoms significantly
with progressive improvement according to TSS (FAS)

8.00 Statistically significant

reduction of the TSS
7.00 * after 14 days
**
6.00 *
TSS Score (0-14.64)

Reduction of TSS is
5.00 * statistically
* significant at each
4.00
following visit
3.00
The TSS reduction is
2.00 progressive over time in
1.00
favor of long term
411 402 399 393 390 treatment
0.00
V1 V2 V3 V4 V5
Total Score

** As patients with mild to moderate peripheral neuropathy have been recruited into the study, the maximal TSS at baseline has been lower than 8.

V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)

30 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Patients are relieved of all neuropathy symptoms observed
in the study with progressive improvement (TSS)
3.00
Statistically significant
2.50 reduction of the TSS
after 14 days
* * All symptoms have
*
Individual Score (0-3.66)

2.00 been treated effectively

* *
* The TSS reduction is
* *
1.50 * progressive over time in
* * favor of long term
*
* * treatment
1.00
*

0.50
*

411 402 399 393 390 411 402 399 393 390 411 402 399 393 390 411 402 399 393 390
0.00
V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5
Stabbing pain Burning Pain Paresthesia Numbness
V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)

31 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Improvement has been observed across all measured
symptoms (mean TSS in %)
100

90

80 All symptoms have

TSS % Change from Baseline

been treated effectively

70
Symptom relief of
60 63% (total TSS) is
clinically significant and
50 of high relevance for the
patient
40

30

20

10 +63% +65% +81% +61% +56%

0
V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5
Total Score Stabbing Pain Burning Pain Paresthesia Numbness

V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)

32 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
All patients experienced significant relieve of neuropathy
symptoms independently of the cause of their neuropathy
9.00

8.00
All subgroups
7.00 * experienced significant
*
* reduction of the TSS
6.00 * * after 14 days
** *
* * *
TSS Score (0-14.64)

5.00 * The TSS reduction is

* * * progressive over time in
4.00 * * all subgroups in favor of
* *
* * long term treatment
3.00 *
2.00

1.00
104 101 101 98 97 44 44 44 44 44 112 111 111 109 107 25 22 21 20 20 126 124 122 122 122
0.00
V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5
Diabetic Carpal tunnel Idiopathic Other Combination
syndrome
** As patients with mild to moderate peripheral neuropathy have been recruited into the study, the maximal TSS at baseline has been lower than 8.

V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)
33 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Overview on study results

Primary parameter: TSS

TSS (FAS)
TSS by neuropathy symptom
TSS by neuropathy symptom in %
TSS by subgroups with different etiology of PN
Secondary parameter:
VAS by neuropathy symptom
VAS by neuropathy symptom in %
Quality of life
Safety

34 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Patients have been relieved of all observed neuropathy
symptoms significantly with progressive improvement
10.00 Statistically significant
symptom relief has been
9.00
observed after 14 days
8.00 All observed symptoms
have been treated
7.00
effectively
VAS Score (0-10)

6.00 The results are

* * * * * consistent with outcomes
5.00 * * * * measured by primary
*
4.00 * * * * parameter TSS
* *
* *
3.00 *
2.00
*
1.00
196 188 166 143 118 60 48 45 40 30 29 22 15 10 7 216 204 210 196 189 279 266 241 242 215
0.00
V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5 V1 V2 V3 V4 V5
Pain Burning Paresthesia Numbness Tingling
V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)

35 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Patients have been relieved of all observed neuropathy
symptoms significantly with progressive improvement

All observed symptoms have

Symptom Visit 2 Visit 3 Visit 4 Visit 5 been treated effectively
For all symptoms the relief was
Pain 22.2 38.7 51.1 69.1 higher than 50-60% at visit 5
Burning 14.6 29.0 52.3 63.5
Paresthesia 9.4 18.2 47.5 89.6
Numbness 16.7 29.5 44.3 57.8
Tingling 21.0 36.2 49.1 65.2

36 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Secondary parameter: quality of life

Quality of life has been significantly

improved from baseline to visit 5
Both domains – physical
component and mental
component have been improved
The improvement was consistent
across all etiologies of peripheral
neuropathy

Physical component summary Mental component summary

37 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Secondary parameter: safety monitoring
The combination of vitamin B1, B6 and B12 has been well-tolerated over the whole study
period (90 days)

14 patients in total experienced adverse events (AEs)

3 ADRs – the following AEs have been assessed by the investigator as related to study
medication
1 dyspepsia (0.2%)
1 nausea (0.2%)
1 diabetic foot (0.2%) - this AE is most likely related to the disease peripheral
neuropathy not the study treatment; reason for assessment not clear

3 subjects terminated the study due to AEs (dyspepsia, nausea, diabetic foot)

38 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Agenda

Peripheral neuropathy
Short overview on causes, prevalence, symptoms, treatment options

NENOIN
Study rationale and objectives

NENOIN
Study design, inclusion and exclusion criteria

NENOIN
Study results (TSS, VAS, QoL, safety)

Conclusion
How relevant are NENOIN study results for the patient?

39
 Management of peripheral neuropathy with B1, B6 and B12
Conclusion
Symptoms improvement:
Tingling, numbness, burning pain, paresthesia, stabbing pain – all documented symptoms have
been improved significantly
Different etiologies of peripheral neuropathy:
Diabetic, idiopathic, carpal tunnel syndrome, others – the combination of vitamin B1, B6 and B12
reliefs patients with different neuropathy causes
Noticeable onset of action already after 14 days:
After 14 days the patients felt symptom relief
Need for long term treatment:
The effect was increasing progressively with longer treatment duration; no plateau at 3 months
when the study has been stopped
Quality of life:
Quality of life has been improved significantly in patients with different etiologies
Safety:
The combination of vitamin B1, B6 and B12 was well tolerated within the study duration of 3
months

40 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 BACK UP

Additional information on screening and monitoring tools used in the

study, additional data on primary and secondary parameters, etc.

In case of questions please contact Dr. Inna Eiberger [email protected]

41
 Management of peripheral neuropathy with B1, B6 and B12
Michigan Neuropathy Screening Instrument (1/2)

The Michigan Neuropathy Screening

FOR MEDICAL TRAINING PURPOSE ONLY

Instrument questionnaire is self administered

by the patient.

Responses are added to obtain a total score.

’Yes‘ responses to questions 1–3, 5–6,

8–9, 11–12, 14–15 are counted as one point
each.
’No‘ responses to questions 7 and 13 count as
one point each.
Question 4 is considered to be a measure of
impaired circulation and question 10 a
measure of general asthenia.
A score of ≥ 7 is considered abnormal. All 15
questions are included in the new scoring
algorithms.

42
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Michigan Neuropathy Screening Instrument (2/2)
A healthcare professional inspects each foot for
deformities, dry skin, calluses, infections and fissures.
Each foot with any abnormality receives a score of 1. Each
FOR MEDICAL TRAINING PURPOSE ONLY

foot is also inspected for ulcers and each foot with an ulcer
receives a score of 1.
The ankle reflexes are also elicited. If the reflex is absent,
the patient is asked to perform the Jendrassic manoeuver
and, if present, the reflex is designated as present with
reinforcement and is scored as 0.5. If the reflex is absent
with the Jendrassic manoeuver, the reflex is designated as
absent and is scored as 1.
Vibration sensation is then tested in the great toe using a
128 Hz tuning fork. In general, the examiner should be
able to feel vibration in his or her hand for 5s longer than
a subject can at the great toe. Vibration is scored as
present if the examiner senses the vibration on his or her
finger for <10s longer than the subject feels it in the great
toe, decreased if sensed for ≥10 s (scored as 0.5) or
absent (scored as 1). The total possible score is 8 points
and, in the published scoring algorithm, a score of ≥2.5 is
considered abnormal.
43
 Management of peripheral neuropathy with B1, B6 and B12
Toronto Clinical Neuropathy Score
FOR MEDICAL TRAINING PURPOSE ONLY

Toronto clinical neuropathy score is used

for screening of PN.

It consists of three parts: symptom

scores, reflex scores and sensory test
scores.
The maximum score is 19 points.
The PN will be classified according to the
score mentioned below:

0 to 5 points, without PN
6 to 8 points, mild PN
9 to 11 moderate PN
12 to 19 points, severe PN

44
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Total Symptom Score
TSS has been documented at:
FOR MEDICAL TRAINING PURPOSE ONLY

V1 (Baseline)
V2 (day 14)
V3 (day 30)
V4 (day 60)
V5 (day 90)
The patient is asked by the physician,
the physician documents the result.

Scale: 0 – 14.64 (in the study only patients

with mild to moderate symptoms were
included, therefore the average score is lower
than 10).

A certain amount of point is allocated to each

box, which are calculated at the end for each
symptom and for all symptoms together.
0 means no symptoms and 14.64 means that
all symptoms are severe and more or less
continuously present.

45
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Visual Analogue Scale
VAS has been documented at:
FOR MEDICAL TRAINING PURPOSE ONLY

V1 (Baseline)
V2 (day 14)
V3 (day 30)
V4 (day 60)
V5 (day 90)
The patient records himself in the
study center at each visit.
0 10
No symptom Worst possible Scale: 0 – 10
symptom (0 = no symptoms/the respective
symptom is not present; 10 = worst
possible symptoms/the respective
symptom is experienced at worst
possible intensity)

No/mild symptoms: 0 – 3.9

Moderate symptoms: 4 – 6.9
Severe symptoms: 7 -10

46
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Short Form 8 (SF-8)
SF-8 has been documented at:
V1 (Baseline)
FOR MEDICAL TRAINING PURPOSE ONLY

V3 (day 30)
V4 (day 60)
V5 (day 90)
The patient records himself in the
study center at each visit.

Scale: 0 – 100

8 individual, 2 pooled components for:

Mental health
Physical health

47
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
TSS data summary table, mean % reduction from baseline
Etiology of neuropathy Severity of neuropathy at Baseline
Total TSS/ Carpal tunnel
Visit Diabetic Idiopathic Other Combination$ Mild Moderate Severe
Symptom syndrome

n 104 44 112 25 126 196 201 12

Visit 2 24 20.4 13.1 28 21.1 17.8 21.2 29

Total Symptom Visit 3 37.4 38.3 28.6 39.3 35.8 32.1 36.2 50
Score (TSS) Visit 4 49.1 50 46.2 51.5 50 45.8 50.4 64.7
Visit 5 66 64.7 57.7 62.6 64.3 60.1 64.3 77.5

Stabbing Pain Visit 2 23.4 26.8 9.9 24.7 17.9 16.1 19.2 26.3
Visit 3 41 43.4 28.7 38.6 31.7 34.3 34.2 43.7
Visit 4 51.7 63.1 47.2 53.8 52.8 50.7 52.1 64.4
Visit 5 67.7 72 58.4 60.5 65.7 62.2 66 67.8

Burning Pain Visit 2 40.7 1.5 16 13 28.7 27.4 26.5 4.2

Visit 3 54.6 27.9 34.2 5 59.1 41.3 53.6 42.9
Visit 4 63.4 45.9 58.7 29.3 66.7 58.7 63.1 57.2
Visit 5 83.6 79.1 73.8 33.3 86.5 77.6 81.9 100

Paresthesia Visit 2 23.9 21.7 15 27.5 19.3 16.5 22.7 16.4

Visit 3 37 36.5 27.8 42.2 33.4 30 35.9 39.2
Visit 4 48.6 47.6 45.4 44.7 49 44.9 48.9 57.1
Visit 5 68.3 60.2 55.2 64.6 62.5 59.8 61.7 78.5

Numbness Visit 2 16.5 20.2 12.3 35.3 22.7 17.1 19.3 56

Visit 3 25.7 39.7 27.5 45.1 31.8 29.3 31.1 74.1
Visit 4 40.1 45 41.1 61.5 40.9 37.8 44.6 75.9
Visit 5 53.2 60.3 54.2 69.2 54.8 51.9 57.8 83.3

48 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
VAS data summary table, mean % reduction from baseline
Type of neuropathy Severity of neuropathy at Baseline
Carpal tunnel
Symptom Visit Diabetic Idiopathic Other Combination$ Mild Moderate Severe
syndrome

n 104 44 112 25 126 196 201 12

Visit 2 20.7 29.1 16.2 25 25.2 13.9 21.5 32

Visit 3 41 49.8 32.2 42.6 38.1 21.7 39.8 51.1
Pain
Visit 4 50.6 76.7 48.7 58.2 45 43.8 52 54.5
Visit 5 65.9 84.9 69.1 72.3 65.3 62.2 71.1 71.2

Visit 2 5.6 15.9 17.3 - 17.2 14.2 13.8 -

Visit 3 19.7 31 30.1 25 36.4 27.9 27.6 71.4
Burning
Visit 4 56.6 48.6 47.3 65 48.7 50.4 56.1 28.6
Visit 5 56.3 65.7 60.1 50.9 74.6 72.7 56.1 -

Visit 2 -40.9 32.7 20.5 - 6.4 19.7 4.4 -

Visit 3 - 38.8 33.4 - 19.7 20.9 13.2 -
Paresthesia
Visit 4 100 - 40.7 100 35.5 37.8 50.5 -
Visit 5 95.5 - 75.7 - 66.8 85.8 93.9 -

Visit 2 20.6 10.5 15 -2.8 20.3 15.6 18.7 7.1

Visit 3 34.9 27.8 27.6 4.8 30.7 27.9 32.1 21.4
Numbness
Visit 4 47.9 38.6 42.8 34.4 45.9 41.5 47.9 35.7
Visit 5 62.2 56.8 57.9 46.2 56.3 54.5 61 57.1

Visit 2 19.5 20.8 18.8 37 20.9 19.4 20.6 27.8

Visit 3 35.1 33.3 34.3 48.5 36.9 33.6 37 44.1
Tingling
Visit 4 48.9 45 50.2 61.2 46.7 46.3 51.3 55.9
Visit 5 67.9 59.6 68.8 65.9 62.9 61.2 68.9 62.9
$Combination included Diabetic & Nutritional or Diabetic & Carpal tunnel syndrome & Idiopathic etc. Mean Percentage reduction from Baseline = 100-((Follow-up/Baseline)*100) '-' Mean
49 Percentage reduction was not calculated since there was no data available.
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Reference

Hakim M. etal; Asian Journal of Medical Sciences; Jan-Feb 2018 (9) 1; 32-40

https://www.nepjol.info/index.php/AJMS/article/view/18510

DOI: 0.3126/ajms.v9i1.18510
E-ISSN: 2091-0576
P-ISSN: 2467-9100

50
NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018
 Management of peripheral neuropathy with B1, B6 and B12
Abbreviations
ADRs = Adverse Drug Reactions
AEs = Adverse Events
FAS = Full Analysis Set
MNSI = Michigan Neuropathy Screening Instrument
NENOIN = Neurobion non-interventional study
PN = Peripheral Neuropathy
PNS = Peripheral Nervous System
QoL = Quality of Life
SF-8 = Short Form 8
TSS = Total Symptom Score
V = Visit
VAS = Visual Analogue Scale

51 NENOIN - Management of peripheral neuropathy with B1, B6 and B12 | January 2018