Clinical trial NCT05129137
Conditions: Healthy Volunteers
Sponsor: Unither Pharmaceuticals, France
Start date: 2021-11-29; Completion date: 2021-12-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study aims to assess the pharmacokinetic profile of a Fixed Dose Combination nefopam hydrochloride (30 mg) / paracetamol (500 mg) and individual components taken alone or concomitantly after oral single dose.

Detailed description:

Arms: arm 1: Single dose: 2 tablets arm 2: Single dose: 2 tablets arm 3: Single dose: 2 tablets arm 4: Single dose: 2 tablets
Interventions: intervention 1: nefopam hydrochloride 30mg X2 intervention 2: paracetamol 500 mg X2 intervention 3: Combination Product: nefopam hydrochloride 30mg / paracetamol 500mg X2
Intervention descriptions: intervention 1: nefopam hydrochloride 30mg X2 intervention 2: paracetamol 500 mg X2 intervention 3: Combination Product: nefopam hydrochloride 30mg / paracetamol 500mg X2

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Pharmacokinetic study of a Fixed Drug Combination nefopam 
hydrochloride (30 mg) / paracetamol (500 mg) and individual 
nefopam hydrochloride and paracetamol taken alone or 
concomitantly after oral single dose. 
An open-label, randomized, four-period, four treatments, 
cross-over trial in healthy volunteers 
Clinical study protocol: UP-CLI-2019-001  
Accutest reference ARL/20/277 
Version 02 – 28 June 2021 
Sponsor 
UNITHER Pharmaceuticals 
3-5 Rue Saint-Georges 
75009 Paris 
France 
Test product 
30 mg nefopam hydrochloride / 500 mg paracetamol Fixed Dose 
Combination (FDC) (Compound number: 08P1737F0) 
Development Phase 
Pharmacokinetic study 
EudraCT number 
2019-002753-37 
Study Center 
Accutest Research Laboratories (I) Pvt. Ltd., 
A-31, M.I.D.C, T.T.C Industrial Area Khairane, 
Navi Mumbai –400709, Maharashtra, INDIA. 
Tel: + 91 22 2778 0718/19/21 
Fax: + 91 22 2778 0720 
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable 
regulatory requirements, including the archiving of essential documents. 
Confidential Information: No use or disclosure outside UNITHER Pharmaceuticals is permitted without 
prior written authorization from UNITHER Pharmaceuticals or Accutest Research Laboratories 
(India) Pvt. Ltd. 


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Table of Contents 
TABLE OF CONTENTS .................................................................................................................................. 2 
GENERAL INFORMATION ........................................................................................................................... 6 
NAME AND ADDRESS OF THE SPONSOR ................................................................................................ 6 
INSTITUTIONS INVOLVED IN THE STUDY ............................................................................................. 7 
INVESTIGATOR’S STATEMENT ................................................................................................................. 8 
SPONSOR’S STATEMENT ............................................................................................................................. 9 
PROTOCOL SYNOPSIS ................................................................................................................................ 10 
1.0 
BACKGROUND INFORMATION: ................................................................................................ 17 
1.1       DISEASE AND CONTEXT...................................................................................................................... 17 
1.2       
TREATMENT OF PAIN ..................................................................................................................... 17 
1.3      
RATIONAL FOR NEFOPAM/PARACETAMOL AS A FIXED DOSE COMBINATION (FDC) .................. 18 
1.4       NON-CLINICAL AND CLINICAL INFORMATION ................................................................................. 18 
1.4.1. 
Non-clinical development .......................................................................................................... 18 
1.4.2 
Clinical development ................................................................................................................. 18 
1.5       RATIONALE OF THE STUDY ................................................................................................................ 18 
1.6       INVESTIGATIONAL DRUG .................................................................................................................. 19 
1.6.1  
Investigational Medicinal Products ........................................................................................... 19 
1.6.2    General Pharmacology ................................................................................................................ 19 
1.6.3 
Adverse Effects  .......................................................................................................................... 22 
1.6.4    Contraindications and Drug Interactions  .................................................................................... 24 
1.7       RATIONALE OF DOSE  ........................................................................................................................ 26 
1.8 STUDY CONDUCT .................................................................................................................................. 26 
2.0 
STUDY OBJECTIVE ....................................................................................................................... 26 
3.0  
STUDY DESIGN AND STUDY RATIONALE .............................................................................. 27 
3.1  GENERATION AND HANDLING OF RANDOMIZATION ........................................................................... 29 
3.2      STUDY TREATMENT ............................................................................................................................ 29 
3.3 STUDY DURATION ................................................................................................................................. 30 
3.4 DISCONTINUATION / TERMINATION OF THE STUDY ............................................................................ 30 
3.5 INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY ............................................................ 30 
3.5.1  
Receipt ....................................................................................................................................... 30 
3.5.2  
Storage and Dispensing ............................................................................................................. 31 
3.5.3 
Reconciliation ............................................................................................................................ 31 
3.5.4    Retention ...................................................................................................................................... 31 
4.0  
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................................. 31 
4.1 INCLUSION CRITERIA ........................................................................................................................... 31 
4.2 EXCLUSION CRITERIA .......................................................................................................................... 32 
4.3       PRECAUTIONS WHILE ENROLLING FEMALES OF CHILDBEARING POTENTIAL: ................................ 33 
4.4      TIMINGS OF ASSESSMENT OF INCLUSION/EXCLUSION CRITERIA ...................................................... 33 
4.4.1    Screening Day Activities .............................................................................................................. 33 
4.4.2 
Check-in day activities (Period-I) .............................................................................................. 34 
4.4.3 
Check-in day activities for subsequent period(s) ....................................................................... 35 
4.5 SUBJECT WITHDRAWAL/ DROPOUT .................................................................................................... 35 
5.0  
TREATMENT OF SUBJECTS ........................................................................................................ 36 
5.1  DOSE ADMINISTRATION ....................................................................................................................... 36 
5.2  MEDICATION ........................................................................................................................................ 36 
5.3 MONITORING FOR SUBJECT COMPLIANCE........................................................................................... 37 
5.3.1 
Diet ............................................................................................................................................ 37 
5.3.2  
Fluid Restriction ........................................................................................................................ 37 


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5.3.3 
Physical Activity/Posture ........................................................................................................... 37 
6.0  
ASSESSMENT OF EFFICACY ....................................................................................................... 37 
6.1  BLOOD SAMPLE COLLECTION ............................................................................................................. 37 
6.2 SAMPLE HANDLING & PROCESSING .................................................................................................... 40 
6.3 BIOANALYTICAL PROCEDURE.............................................................................................................. 41 
7.0      ASSESSMENT OF SAFETY ............................................................................................................... 41 
7.1  SAFETY EVALUATION ........................................................................................................................... 42 
7.2  HANDLING AND REPORTING OF ADVERSE EVENTS ............................................................................ 43 
7.2.1 Definitions ....................................................................................................................................... 43 
7.2.2    Severity assessment ...................................................................................................................... 44 
7.2.3    Causality assessment  ................................................................................................................... 44 
7.3       REPORTING OF AES AND SAES INCLUDING DEATH ......................................................................... 45 
7.4     ADDITIONAL INFORMATION ............................................................................................................... 48 
8.0  
STATISTICAL PLAN ...................................................................................................................... 48 
8.1  PHARMACOKINETIC PARAMETERS ...................................................................................................... 49 
8.2  STATISTICAL METHOD ......................................................................................................................... 49 
8.3  SUBJECT POPULATION  ......................................................................................................................... 50 
8.4  SIGNIFICANCE ....................................................................................................................................... 50 
8.4.1  
Analysis of Variance .................................................................................................................. 50 
8.4.2  
Confidence Interval .................................................................................................................... 51 
8.5  ACCOUNTABILITY PROCEDURE ........................................................................................................... 52 
8.5.1  
Treatment of Missing Values...................................................................................................... 52 
8.5.2  
Missing samples ......................................................................................................................... 52 
8.5.3    Treatment of outliers .................................................................................................................... 52 
8.6 TREATMENT OF TIME POINT DEVIATION ............................................................................................ 52 
9.0  
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION................................................... 53 
10.0  
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................... 53 
11.0  
ETHICAL CONSIDERATIONS ..................................................................................................... 53 
11.1 RISK AND BENEFITS.............................................................................................................................. 53 
11.2  
ETHICS COMMITTEE REVIEW AND COMMUNICATIONS ................................................................. 56 
11.3  
INFORMED CONSENT PROCESS ..................................................................................................... 56 
11.4     CONFIDENTIALITY, OWNERSHIP OF DATA AND CODING PROCEDURE: .......................................... 57 
11.4.1 Confidentiality:.............................................................................................................................. 57 
11.4.2 Ownership of Data and Coding Procedure:.................................................................................. 57 
12.0     RECORDING AND ARCHIVING OF DATA: ................................................................................ 57 
13.0  
INSURANCE, COMPENSATION AND HANDLING OF STUDY RELATED 
INJURY/DEATH  .............................................................................................................................. 58 
14.0  
REPORT ............................................................................................................................................ 59 
15.0  
PUBLICATION POLICY ................................................................................................................ 59 
16.0  
CHANGES IN PROTOCOL ............................................................................................................ 59 
 
APPENDIX A (MEALS) ...................................................................................................... 60 
APPENDIX B ........................................................................................................................ 63 
APPENDIX C ........................................................................................................................ 66 
APPENDIX D ....................................................................................................................... 67 
APPENDIX E ........................................................................................................................ 72 
APPENDIX F ........................................................................................................................ 74 
APPENDIX G ....................................................................................................................... 75 
 


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LIST OF ABBREVIATIONS 
ADR
Adverse Drug Reaction
AE(s)
Adverse Event(s)  
ANOVA
Analysis of Variance
ARL
Accutest Research Laboratories (I) Pvt. Ltd. 
ATC
Anatomical Therapeutic Chemical
AUC0-t 
Area Under The Concentration Versus Time Curve Up To The Last 
Measurable Time Point 
AUC0-inf
Area Under The Concentration Versus Time Curve From Time 0 To Infinity
BA
Bioavailability
BE
Bioequivalence
β-hCG
Serum Beta Human Chorionic Gonadotropin  
BLQ
Below the Limit of Quantification
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CHO
Carbohydrate 
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
cm
Centimeter (s)
cc
Cubic Centimeter
Cmax
Maximum Observed Drug Concentration In Plasma
COA
Certificate of analysis
COVID-19
Corona Virus Disease of 2019
CRF
Case Report Form 
CS
Clinically Significant
CV
Coefficient of Variation
CYP
CYP450 enzymes
°C
Degree Celsius
dL
Deciliter
EC
Ethics Committee
ECG
Electrocardiogram 
°F
Degree Fahrenheit
FDC
Fixed Drug Combination
g
Grams
GABA
Gamma-Aminobutyric acid
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin In Blood
HBsAg
Hepatitis B Surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immuno Deficiency Virus
hpf
High power field
hr(s)
Hour(s)
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC
Independent Ethics Committee
ICF
Informed Consent Form
IP 
Investigational Product 
IMP
Investigational Medicinal Product
INR
International Normalised Ratio
IU
International Unit


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IUD
Intrauterine device
IUS
Intrauterine system
i.v.
Intravenous
Kel
Elimination Rate Constant
Kcal
Kilocalorie
kg
Kilogram(s)
L
Liter
LC-MS/MS
Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
LSM
Least Square Mean
m
Meter
mg
Milligram
mL
Milliliter
mm
Millimeter
mM
Millimolar
µg
Microgram
µL
Micro liter
µm
Micrometer
MCV
Mean Corpuscular Volume
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MSV
Missing Sample Values
NA
Not Applicable
NAPQI
N-acetyl-p-benzoquinoneimine
NCS
Not Clinically Significant 
ng
Nanogram
No.
Number
NRV
Not-reportable Value
PBS
Pharmacokinetic and Biostatistics
PCV
Packed Cell Volume
pg
Picogram
PI
Principal Investigator
PROC GLM
Procedure General Linear Model 
PK
Pharmacokinetic
QA
Quality Assurance
QAU
Quality Assurance Unit
RBC
Red Blood Cell
RPM
Revolutions per minute
SAE(s)
Serious Adverse Event(s)
SAS
Statistical Analysis System
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOC
System Organ Classification
SOP(s)
Standard Operating Procedure(s)
t1/2
Terminal Half-Life
Tmax
Time To Observe Maximum Drug Concentration In Plasma
tbsp
Tablespoon
tsp
Teaspoon
ULN 
Upper limit of normal 
U/L 
Units per liter 
WBC
White Blood Cell 
WMA
World Medical Association 












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Assessment of 
Subjects 
On Screening day 
Breath alcohol test, demographic data, medical / clinical history, 
physical 
examination 
including 
vital 
signs, 
12-lead 
Electrocardiogram (ECG), chest X-ray (P/A view) (if required 
based on any significant past medical history and/or positive 
finding in respiratory system examination), haemogram, 
biochemistry, serology (HIV, Hepatitis B and C) and urinalysis 
will be performed. 
       Note: Due to ongoing COVID-19 pandemic, the subjects will 
undergo pre-screening activities in accordance with the SOP 
titled “Handling of pre-screening activities during COVID-19 
pandemic.” The subjects will also sign the IEC approved 
additional subject information sheet and informed consent form 
for undergoing pre-screening activities and follow general 
safety instructions during COVID-19 pandemic. 
A. On Check-in day: 
Breath alcohol test, relevant medical / clinical history, physical 
examination including vital signs, Urine screen for drug abuse 
for commonly abused substances, serum pregnancy test for 
female subjects will be done. 
B. During Confinement Period:  
Well-being assessment and vital signs measurement. 
C. At check-out 
Well-being assessment, physical examination, measurement of 
blood pressure, pulse rate, respiration rate and body 
temperature. 
D. Post Study Evaluation:  
Well-being assessment, physical examination (including vital 
signs), haemogram, biochemistry and urinalysis will be 
performed. 
Note:  
1. Well-being assessment and breath alcohol analysis will be done 
during subject’s visit for follow-up and ambulatory PK samples 
if applicable. 
2. Any other assessment including laboratory test(s) will be done if 
judged necessary by the PI/Sub-investigator/Co-investigator 
person at any time during the course of study. 
Restrictions 
 
 
 
 
 










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Ethical 
consideration  
Study will be conducted as per ethical considerations. Details are 
mentioned in section 11.0 
1. Risk and Benefits 
2. Ethics committee review and communications 
3. Informed Consent Process 
4. Confidentiality and Ownership of Data and Coding Procedure 
 
 


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1.0 
BACKGROUND INFORMATION: 
1.1       Disease and context 
The International Association for the Study of Pain defines pain as an unpleasant sensory and 
emotional experience associated with, or resembling that associated with, actual or potential 
tissue damage. Pain is a major health problem that substantially alters quality of life. 
Treatment of pain is a challenge in clinical practice as not all patients respond sufficiently to 
available treatments and the burden of adverse reactions may be high. It is a complex process 
involving interactions between peripheral and central nervous system pathways with various 
neurobiological mechanisms being involved. Pain is always subjective and remains the 
leading cause of physician consultations. 
Acute pain is considered adaptive, in that it has a warning function. It is of short duration 
(generally up to a few weeks) and declines with the healing of the underlying injury or disease 
(e.g. post-surgical pain).  
1.2       Treatment of pain 
The World Health Organization (WHO) created – initially for cancer pain relief in adults - a 
three-step ladder (“pain ladder” or analgesic ladder). This ladder, proposing therapeutic 
strategy in pain control, is now widely used by medical professionals as a guideline for the 
use of drugs in the management of all types of pain. 
The WHO’s therapeutic strategy relies upon the concurrent and sequential use of a series of 
treatment procedures, which must be adapted to the needs of the individual patient. For 
patients with mild pain, the recommendation is to use a non-opioid drug, such as aspirin, 
paracetamol, or any of the non-steroidal anti-inflammatory drugs. If, in the recommended 
dosage and frequency, this is not effective in relieving the pain (patients with moderately 
severe pain) a drug such as codeine or an alternative weak opioid should be added to the given 
medication. When a weak opioid drug in combination with a non-opioid drug fails to relieve 
the pain (patients with severe pain) a strong opioid, such as morphine should be used. 
Adjuvant drugs should be added to the opioid and non-opioid drugs, if required for specific 
indications. 
According to this WHO’s recommendation, also supported by guidelines on the management 
of moderate to severe pain released by the French National Agency for the Safety of 
Medicines and Health Product (ANSM), treatment of moderate pain can be achieved with a 
combination of a weak opioid and a non-opioid. 
 
 
 
 
 
 
  
 
 
 
 


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1.3      Rational for nefopam/paracetamol as a Fixed Dose Combination (FDC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1.4       Non-Clinical and Clinical Information 
 
 
 
 
 
 
 
 
 
 
 
   
1.5       Rationale of the study 
 
 
 
 
 
 


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The aim in developing an oral fixed dose combination (FDC) of 30 mg nefopam 
hydrochloride and 500 mg paracetamol to relieve moderate to severe pain is to fill the gap in 
the therapeutic armamentarium of pain management, using a new non-opioid combination 
product. 
 
 
 
 
 
  
 
 
 
 
 
 
1.6       Investigational Drug  
1.6.1  Investigational Medicinal Products 
Test Product (T): Fixed Drug Combination (FDC) Nefopam Hydrochloride (30 
mg)/Paracetamol (500 mg) Tablets X 2 
Reference Product (R1): Paracetamol 500 mg per os (Panadol® 500mg tablet) X 
2+Nefopam 30 mg per os (Acupan® 30mg Tablets) X 2 
Reference Product (R2): Nefopam 30 mg per os (Acupan® 30mg tablet) X 2 
Reference Product (R3): Paracetamol 500 mg per os (Panadol®500mg tablet) X 2 
1.6.2    General Pharmacology (7) 
Code of investigational medicinal product: FDC 08P1737F0 
Active substances: nefopam hydrochloride and paracetamol 
Dosage form and presentation: immediate release oral FDC tablet with 30 mg 
nefopam hydrochloride and 500 mg paracetamol 
Composition: Physicochemical properties of the two active ingredients are presented 
in Table. 




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  Indication and Usage:  
  Symptomatic treatment of fever and pain. 
  Pharmacokinetics properties 
  For Nefopam 
Absorption: 
 
 
 
 
Biotransformation: 
 
 
 
 
 
Elimination:
 
 
 
 
 
 
 
  For Paracetamol 
Paracetamol is readily absorbed following oral and rectal administration. 
Bioavailability is slightly lower following rectal use, compared with oral use. 
Absorption is slower and dependent on the duration of contact with the mucosa. 
Peak plasma concentrations measured following administration of 1 g paracetamol 
are as follows: tablets: up to 17 mg/L; suppositories: up to 7 mg/L. Plasma 
concentrations are approximately half, following a dose of 0.5 g. Peak plasma 
concentration is reached approximately 1 hour after dosing for the tablets, ½ an hour 
after dosing for the effervescent tablets, and approximately 3 hours after 
administration for suppositories. At the therapeutic doses, protein binding rate is 
relatively low (approximately 10%) and is higher at toxic doses (15 to 21%). 
Bioavailability is approximately 90% for doses over 1 g and more than 60% for the 
lowest doses. 
The half-life ranges from 2 to 3 hours in adults at the therapeutic doses. It is slightly 
shorter in children, but longer in the elderly. 
Paracetamol is metabolised by the liver, and its metabolites are mainly excreted via 
the urine: up to 98% in 24 hours, predominantly in glucuronide and sulfate form. 
In case of overdose, part of the paracetamol is metabolised via biochemical 
pathways into catecholamine derivatives or cysteine conjugates. An intermediate 
product is thus created: an epoxide or similar radical thought to be the cause of 
hepatotoxicity. 


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1.6.3 Adverse Effects (6) 
 
 
 
 
 
 
 
 
 
 
- Very common (≥1/10); 
- Common (≥1/100 to <1/10); 
- Uncommon (≥1/1,000 to <1/100); 
- Rare (≥1/10,000 to <1/1,000); 
- Very rare (<1/10,000). 
Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
 


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  For Nefopam 
  Table: Undesirable effects of nefopam 
 
Very 
common
Common 
Rare 
Undetermined
frequency
Psychiatric 
disorders 
 
 
Excitability* 
Irritability*Hallucin
ation 
Abuse** 
Drug-dependence**
Confusionnal 
state 
Nervous 
system 
disorders 
Drowsiness 
Dizziness* 
Light-headedn
ess 
Paraesthesia 
Tremor 
Convulsions* 
Confusion 
Postoperative 
confusion 
Insomnia 
Headache 
Coma 
Vascular 
disorders 
 
Tachycardia* 
Palpitations* 
Hypotension 
Syncope` 
 
Gastrointestinal
disorders 
Nausea with 
or without 
vomiting 
Dry mouth* 
Abdominal 
pain 
Diarrhoea 
 
 
Renal and 
urinary 
disorders 
 
Urinary 
retention 
Decrease renal 
function Harmless 
pink discolouration 
of the urine 
 
Eye disorders 
 
 
Blurred vision 
 
Immune 
system, 
skin and 
subcutaneous 
tissue 
disorders 
Sweating* 
Allergic 
reactions 
Postoperative 
hypersensitivity 
(angioedema, 
anaphylactic 
shock) 
Pruritus 
Erythema 
Urticaria 
Faintness 
 
*Although never reported, other atropine effects than those described are likely to be observed. 
**According to the PRAC conclusions, the suggested plausible mechanism is the inhibition of 
dopamine recapture. 
For Paracetamol 
Paracetamol tablets cause few undesirable effects, providing the treatment duration 
and dose are followed. 


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 Table: Undesirable effects of paracetamol 
 
 
Very rare
Undetermined Frequency
Blood and lymphatic 
system disorders 
Thrombocytopenia 
In 
patients 
with 
glucose-6-phosphatedehydrogenase 
[G6PD] 
deficiency, 
haemolytic 
anaemia is not excluded 
Immune 
system 
disorders 
Cutaneous 
reactions 
including 
erythema, 
urticaria, 
angioedema 
and 
other 
signs 
of 
anaphylaxis, 
and 
Stevens-Johnson 
syndrome 
 
Respiratory, 
thoracic 
and 
mediastinal disorders 
Bronchospasm 
in 
patients 
sensitive 
to 
aspirin or other NSAIDs 
 
Hepatobiliary disorders
Hepatic dysfunction 
 
Skin and subcutaneous 
tissue disorders 
Very rare cases of severe 
skin reactions have been 
reported 
 
If these phenomena develop, patients should stop treatment and see a doctor immediately. 
 
 
 
 
 
 
 
 
1.6.4    Contraindications and Drug Interactions (6) 
 Contraindications: 
 For Nefopam 
 
 
 
 
 
 
 
For Paracetamol 
The contraindications of paracetamol are:  
 Hypersensitivity to the active substance, phenacetin or to any of the excipients 
listed. 
 Serious hepatic impairment. 


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 Repeated administration of paracetamol is contraindicated in patients with 
anaemia, heart disease or lung disease. 
 Drug Interactions: 
 For Nefopam 
Use of Nefopam with other substances with an anticholinergic or sympathomimetic 
activity may give rise to additive effects. 
It should be noted that many medicinal products or substances can have additive 
depressant effects on the central nervous system and contribute to a decrease in 
alertness. These include morphine derivatives (analgesics, cough suppressants and 
replacement 
therapies), 
neuroleptics, 
barbiturates, 
benzodiazepines, 
non-benzodiazepine anxiolytics (such as meprobamate), hypnotics, sedative 
antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), 
sedative H1- antihistamines, centrally-acting antihypertensives and baclofen. 
Nefopam may interfere with certain tests for benzodiazepines and opioids. These 
tests may yield false-positive results in patients taking Nefopam. 
The intensity and incidence of adverse reactions increase when nefopam is 
co-administered with codeine, pentazocine or dextropropoxyphene. 
Nefopam is intensively metabolised. However, as the enzyme responsible for the 
biotransformation of nefopam is not known, potential interactions with CYP450 
enzymes (CYP) inhibitors/inducers cannot be anticipated. Caution should therefore 
be exercised whenever nefopam is co administered with a CYP inhibitor/inducer. 
The known hepatotoxicity of paracetamol, observed in dogs given very high doses 
of paracetamol, was exacerbated when very high doses of nefopam were 
administered. These studies showed that oral doses of paracetamol 236 mg/kg/day 
and nefopam 24 mg/kg/day potentiate the hepatotoxicity of paracetamol. These 
doses are approximately six to eight times higher than the average dose in humans. 
Lower doses, equivalent to three or four times the human dose have not given rise to 
potentiation of hepatotoxicity. 
 
 For Paracetamol 
 Administration of activated charcoal reduces the absorption of paracetamol 
following 
 overdose. 
 Liver enzyme inducers (such as barbiturates, Diphantoine) and alcohol may 
increase the hepatotoxicity of paracetamol. 
 The half-life of chloramphenicol may be extended by 2 to 3 hours up to 18 to 
24 hours in the event of concomitant administration of paracetamol. 
 As paracetamol is weakly bound to plasma proteins, it may be used 
concomitantly with anticoagulants. However, use of paracetamol for several 
days may increase the risk of bleeding. In this case, regular monitoring of the 
International Normalised Ratio (INR) is recommended. 
 Due to the risk of decreased leukocyte count (leukopenia) during concomitant 
 administration of paracetamol and AZT (zidovudine), simultaneous 
administration should only take place on medical advice. 


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 The absorption of paracetamol may increase when co-administered with 
metoclopramide and decrease when co-administered with cholestyramine. 
 Concomitant administration of diflunisal increases serum paracetamol 
concentrations. Elevated serum paracetamol concentrations have been 
associated with hepatotoxicity. 
1.7       Rationale of Dose (6) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
1.8 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Ethical 
Committee (EC) and according to Good Clinical Practice (GCP) standards. Deviation 
having any impact on the safety of the subject or on study data will not be 
implemented without prior review and approval of the EC except where it may be 
necessary to eliminate an immediate risk to a study subject. In such a case, the 
deviation will be reported to the EC as soon as possible. 
2.0 
STUDY OBJECTIVE 
The primary objective of this study is to evaluate the pharmacokinetic parameters 
concentration (C°) max and Area Under the Curve (AUC)last for nefopam hydrochloride 
and paracetamol when administrated alone or as part as combination after oral single 
dose. 
The secondary objectives are:  
- 
 
 
 
 
 
 
- 
to assess other pharmacokinetic (PK) parameters obtained for nefopam hydrochloride 
and paracetamol when administrated alone or as part as combination. 


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- 
to evaluate the pharmacokinetic profiles of N-desmethyl-nefopam (active metabolite 
of nefopam per os)  
- 
 
 
 
 
 
 
 
 
 
 
 
  
- 
to evaluate the safety/tolerability of both drugs when administered separately, 
concomitantly or combined based on adverse events reported after treatment. 
3.0  
STUDY DESIGN AND STUDY RATIONALE 
 
Discussion of the Study Design 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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Formulation strength: 30 mg 
Dose: 2 Tablets 
Reference Product (R3): Paracetamol 500 mg per os (Panadol® 500mg tablet) X 2 
 
 
Dosage Form: Tablet 
Formulation strength: 500 mg 
Dose: 2 Tablets 
 
 
3.3 
Study Duration 
Excluding screening period, the duration of clinical phase will be approximately 22 
days including a washout period of at least 6 days for each study period. 
Housing: 
The subject will be housed from at least 10.50 hrs before dosing until 24.00 hrs post 
dose in the centre for each study period. Activities beyond 24.00 hrs will be conducted 
on ambulatory basis. 
Visits: 
Each eligible subject is required to return to the study centre on check-in days of each 
study period and ambulatory blood sample (s) collection. 
3.4 
Discontinuation / Termination of the Study 
If the PI terminates or suspends the study without prior agreement of the sponsor, the 
PI will promptly inform the sponsor and the EC and will provide them with a detailed 
written explanation of the termination or suspension.  
If the study is prematurely terminated or suspended by the sponsor, the sponsor will 
promptly inform the PI and the regulatory authority-(ies) of the termination or 
suspension and the reason(s) for the termination or suspension. The EC will also be 
informed promptly and will be provided with the reason(s) for the termination or 
suspension by the sponsor or by the PI.  
 
 
  
 
 
 
 
3.5 
Investigational Medicinal Product Accountability 
3.5.1  Receipt 
The IMPs will be accepted in accordance with current version of the Standard 
Operating Procedure (SOP) for ‘Handling of Investigational Medicinal Product’. The 
Pharmacist will check the IMPs for integrity and correctness of the label. The 


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products will be accompanied by the certificate of analysis (COA). The sponsor will 
be responsible for the supply of IMPs in a properly labeled pack according to the 
requirements of Good Manufacturing Practice (GMP). The quantity of IMPs should 
be sufficient as per current version of the SOP for ‘Handling of Investigational 
Medicinal Product’ or as provided by the sponsor. 
The drug content of the test product should not differ from that of the reference 
product by more than 5 percent 
3.5.2  Storage and Dispensing 
The investigational medicinal products will be stored under appropriate storage 
conditions as specified in the product label and/or as recommended by the sponsor in 
the securely locked pharmacy accessible only to authorized persons. The pharmacist 
will prepare the labels for the IMP dispensing vials/containers in accordance with the 
current version of the SOP. Labels should be approved by Quality Assurance (QA) 
prior to dispensing. The Pharmacist will carry out dispensing as per randomization 
code in accordance with the current version of the SOP for ‘Dispensing of 
Investigational Medicinal Products’ in presence of QA personnel. 
3.5.3 Reconciliation 
The PI will not allow the study drugs to be used for the purposes other than those 
indicated in this protocol. At the end of last dosing, the IMPs received, the quantity 
used for dispensing for the concerned study, the retention quantity and the balance 
quantity will be recorded in accordance with the current version of SOP ‘Handling of 
Investigational Medicinal Product’. 
3.5.4    Retention 
The IMPs for the test and reference formulations will be retained as per the current 
version of the SOP for ‘Handling of Investigational Medicinal Product’. The disposal 
of the retained samples will be done only at the end of the retention period as 
mentioned in the “IMP log” after obtaining written confirmation from the sponsor.  
4.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
The subjects will be assessed for various inclusion/exclusion criteria mentioned 
below: 
4.1 
Inclusion Criteria 
1. Male and non-pregnant female human subjects, age in the range of 18 – 45 years 
both inclusive. 
2. Body Mass Index between 18.5-30 Kg / m2 extremes included. 
3. Subjects with normal findings 
 
 
 
4. Subjects with clinically acceptable findings 
 
  
 
 


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4.2 
Exclusion Criteria 
 
1. Known history of hypersensitivity to Nefopam, Paracetamol or related drugs.  
2. Requiring medication for any ailment having enzyme-modifying activity in the 
previous 28 days, prior to dosing day. 
3. Subjects with a history of convulsive disorders. 
4. Subject with a moderate or severe renal impairment (Glomerular Filtration rate 
below 60ml/min). 
5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 


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. 
4.3       Precautions while enrolling females of childbearing potential: 
Women of childbearing potential are females who have experienced menarche and do 
not meet the criteria for “women not of childbearing potential. “Women Not of 
childbearing potential are females who are permanently sterile or postmenopausal. 
Postmenopausal is defined as 12 consecutive months with no menses without an 
alternative medical cause.  
Highly effective methods of contraception include hormonal contraceptives (e.g. 
combined oral contraceptives, patch, vaginal ring, injectables, and implants); 
intrauterine device (IUD) or intrauterine system (IUS); vasectomy of male partner and 
tubal ligation. Effective methods of contraception include barrier methods of 
contraception (e.g. male condom, female condom, cervical cap, diaphragm, 
contraceptive sponge). The allowed methods of contraception are only effective when 
used consistently, correctly and in accordance with the product label.  
The possibility of known or unknown drug interactions between the hormonal 
contraceptives and the therapeutic product under investigation always exist. 
Moreover, there is a possibility that the therapeutic product under investigation may 
lessen the effectiveness of a hormonal contraceptive agent. Hence female subjects 
with child bearing potential using hormonal contraceptives will not be included in the 
study. However, following contraceptive methods will be acceptable if followed from 
the day of screening up to the completion of the study. The Investigator will ensure 
the appropriate usage of acceptable contraceptive methods by the subjects.  
1.        Non hormonal intrauterine device (IUD)  
2.        Non hormonal intrauterine system (IUS)  
3.        Vasectomy of male partner  
4.        Tubal ligation  
5.      Double barrier methods of contraception such as male condom, female 
condom, cervical cap, diaphragm, contraceptive sponge with spermicidal 
foam, gel, film, cream, or suppository are acceptable. 
4.4      Timings of assessment of inclusion/exclusion criteria 
The evaluation of above mentioned inclusion/exclusion criteria will be done at 
different stages of the study as mentioned below. 
4.4.1    Screening Day Activities 
The screening will be done within 28 days prior to the dosing of Period-I. After 
obtaining written Informed Consent, the subjects will be identified via thumb/finger 
print using computerized software. Following activities will be performed on the day 
of screening. 
a) 
 
  


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b) Demography 
 
 
c) Complete Physical Examination of subjects 
Subject’s past and present medical / clinical history, vital signs measurement (body 
temperature, respiratory rate, pulse rate and blood pressure) and systemic examination 
will be done. 
d) 12-Lead Electrocardiogram 
A 12-lead ECG will be done. 
e) Radiological Examination 
Chest X-ray (P/A view) will be done during screening as per the discretion of the 
principal investigator/co-investigator /Sub-investigator /medical officer if required 
based on any significant past medical history and/or positive finding in respiratory 
system examination. 
f) Blood and urine laboratory tests 
The blood samples will be obtained for haematology, biochemistry and serology 
screening (HIV, Hepatitis B and C). Pre-study routine urinalysis will also be done.  
The details of these laboratory tests are given in Appendix B. 
Subjects qualifying the acceptance criteria for all above examinations and tests will be 
called on check-in day for Period-I. 
 
 
 
 
 
 
 
 
 
Note: Due to ongoing COVID-19 pandemic, the subjects will undergo pre-screening 
activities in accordance with the SOP titled "Handling of pre-screening activities 
during COVID-19 pandemic." The subjects will also sign the IEC approved 
additional subject information sheet and informed consent form for undergoing 
pre-screening activities and follow general safety instructions during COVID-19 
pandemic. 
4.4.2 Check-in day activities (Period-I) 
Subjects will be identified by thumb/finger print. Thereafter, they will undergo 
various activities like breath alcohol test, relevant medical /clinical history, physical 
examination, vital sign measurement (body temperature, respiratory rate, pulse rate 
and BP) and urine drug abuse test.  
 
 


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4.4.3 Check-in day activities for subsequent period(s) 
 
 
 
.  
In addition to the above tests, female subjects will be tested for pregnancy by Serum 
(β) Beta- hCG (Human Chorionic Gonadotropin) test. 
4.5 
Subject Withdrawal/ Dropout 
Any subject that is discontinued from the study by Medical officer/Principal 
Investigator for other than personal reasons will be considered as withdrawn. 
Subjects may be discontinued from the study for any of the following reasons: 
1.  Subjects not wishing to continue with the study, irrespective of the reason 
(dropout subjects). 
2. Any significant medical occurrence (including laboratory results) which as per the 
discretion of the Principal Investigator could be a risk to the health of the subject. 
3. Any illness requiring unacceptable medication during the study as per discretion 
of Principal Investigator. 
4. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Subject will not be evaluated for the post-study assessment, if he/she is discontinued 
from the study before dosing in Period-I. Subject may be discontinued from the study 
for any reason beneficial to his/her well-being.  
The Principal Investigator, as well as the sponsor, will decide to withdraw any 
subject’s participation in the study if, in their judgment, continuation in the study may 
prove harmful to the subject. Such a decision may be precipitated by adverse events, 
including changes in vital signs, physical examination and 12 lead ECG etc. The 
Principal Investigator may also withdraw a subject due to poor compliance to the 
study protocol. 
An attempt will be made by the Principal Investigator to find out reason for drop out.  
If a subject discontinues from the study any time after being assigned a subject 
number, the reason will be recorded in the case report form (‘withdrawn/dropped 
out’), by the Principal Investigator/Authorized trained person/Medical Officer. The 
details of withdrawn /dropped out subjects will be reported in the clinical report. 
If a subject discontinues from the study any time after being assigned a subject 
number before dosing of period I, then principal investigator can replace the dropped 
out subject with another eligible subject. 
5.0  
TREATMENT OF SUBJECTS 
5.1  
Dose Administration 
Single oral dose of Investigational medicinal product either of test product (T) or 
reference product (R1), (R2) and (R3) in sitting position in each period, after an 
overnight fast of at least 10.00 hrs as per the randomization schedule. 
 
 
  
 
 
 
 
 
 
 
 
5.2  
Medication 
If drug therapy other than that specified in the protocol is urgently required during the 
study or in the washout period, decisions to continue or discontinue the subject will be 
taken by the PI, based on the following: 
 Safety and well-being of the subject. 
 Pharmacology and PKs of the non-study medication. 


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 Likelihood of a drug interaction, which may affect the PK comparison of the study 
medications. 
 The time of administration of the non-study medication, and likelihood of 
interference in the bio-analysis. 
5.3 
Monitoring for subject compliance 
The subjects will be monitored for compliance to the following restrictions 
throughout the study period. 
5.3.1 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
6.0  
ASSESSMENT OF EFFICACY 
As this is a Pharmacokinetic study, no efficacy measurement will be done. Blood 
sample collection, handling, processing, bio-analysis and statistical analysis will be 
done to determine the pharmacokinetic profile of Fixed Drug Combination (FDC) 
Nefopam Hydrochloride (30 mg) / Paracetamol (500 mg) Tablets. 
6.1  
Blood Sample Collection 
An intravenous cannula will be inserted into the subject’s arm for the collection of the 
blood samples before the pre-dose blood sample and up to 24.00hrs post-dose. If 
difficulties occur in blood withdrawing or if the subject is not feeling comfortable 
with the cannula, then the cannula will be removed before 24.00 hrs post-dose and the 
remaining blood samples will be collected through fresh vein puncture or by 
recannulation. When meals, vitals and sample collections coincide, samples will be 
collected first followed by vitals and then meal will be served. 
 
 








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with the current version of the SOP for ‘Blood sample collection, Processing and 
Storage’.  
Transport of plasma samples from the sample storage area to analytical site will be 
done as per the current SOP of ‘Segregation, Transfer, Retention and Disposal of 
Biological Samples’ and ‘Transport of biological samples outside the study centre’ 
maintaining the appropriate storage condition during transportation. 
6.3 
Bioanalytical Procedure 
A validated LC-MS/MS analytical methodology will be used for the determination of 
Nefopam, Paracetamol and it main metabolites (Sulfate and Glucuronide), 
N-desmethyl-nefopam in plasma and will be quantified using a validated analytical 
method from the human plasma samples. Validation of the methodology will be 
carried out in accordance with applicable guidelines and the current version of the 
SOP for ‘Bio-analytical Method Validation’ and other relevant SOPs for 
Bio-analysis. 
Based on the plasma concentrations obtained from the analysis and subsequent 
statistical analysis, primary PK parameters will be used to assess. In addition, 
secondary PK parameters will be calculated from the analyzed plasma concentrations. 
The batch acceptance or rejection, repetition or reanalysis, if any, will be performed as 
per predefined criteria laid down in the relevant SOPs for “Batch acceptance of 
subject sample analysis”. 
 
 
 
 
 
 
 
 
 
 
. 
7.0      ASSESSMENT OF SAFETY 
The PI will monitor safety data throughout the course of the study. A qualified 
medical officer will be available during the housing in the clinical center. Subjects 
will be monitored throughout the study period for occurrence of AEs. A nearby 
contracted hospital capable of handling emergency situations will be informed about 
the study. The hospital has agreed to provide the necessary treatment facilities, if 
required, and the physicians attached to the hospital will carry out treatment of AEs as 
appropriate, either at the study center or at contracted hospital. Subjects experiencing 
AEs will be followed up until resolution of the AE. Subjects who at least received one 
dose of the study medication will be included in the safety analysis. 




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Additionally, any other assessment including laboratory test(s) will be done if judged 
necessary by the Principal Investigator (PI) or authorized trained personnel at any 
time during the course of study. 
 
 
 
 
 
 
 
 
 
 
The reason for not completing the study will be specified in the respective CRF and 
the clinical report. 
The subjects may also report spontaneously any inconvenience or AEs to the 
monitoring staff at any time during the study or after check-out within the total 
number of days not exceeding the washout period. 
7.2  
Handling and Reporting of Adverse Events 
Subjects will be monitored throughout the study period for adverse events. Subjects 
will be specifically asked about any adverse events during the recording of vital signs 
and will be instructed to bring to the notice of any study personnel of any adverse 
event that may occur during their stay at the clinical facility. 
A medically qualified designate will be available round-the-clock during the period of 
housing at the clinical facility. Any subject who develops an adverse event will be 
evaluated by the investigator, will be treated and / followed up until resolution as 
judged by the investigator.  
All AEs including both observed and volunteered ones will be recorded on the 
appropriate forms, irrespective of its association with the investigational products. 
The Ethics Committee (EC), Regulatory agency (ies) and the sponsor will be 
informed regarding the AE as necessary.   
7.2.1 Definitions 
Adverse Event (or Adverse Experience): Any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with this treatment. An 
adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporarily 
associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
Abnormal laboratory values will be reported as adverse events under the following 
circumstances: 
i. 
When the abnormal lab report is accompanied with associated symptoms. 
ii. 
When medical/surgical intervention is required 


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iii. 
When an additional diagnostic test is required 
iv. 
Leads to serious adverse event 
v. 
When it is considered by Principal investigator as an adverse event 
Adverse Drug Reaction (ADR) A response to a drug which is noxious and 
unintended and which occurs at doses normally used in man for prophylaxis, 
diagnosis, or therapy of disease or for modification of physiological function. 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an 
approved product).  
Serious Adverse Events (SAE) 
“serious adverse event” means an untoward medical occurrence during clinical trial 
resulting in death or permanent disability, or hospitalization of the trial subject where 
the trial subject is an outdoor patient or a healthy person, prolongation of 
hospitalization where the trail subject is an indoor-patient or significant disability or 
incapacity, congenital anomaly, birth defect or life threatening event. 
7.2.2    Severity assessment 
The severity of the adverse events will be graded as follows: 
 
Mild Adverse Event – Event results in mild or transient discomfort, not requiring 
intervention or treatment; does not limit or interfere with daily activities (e.g., 
insomnia, mild headache). 
 
Moderate Adverse Event – Event is sufficiently discomforting so as to limit or 
interfere with daily activities; may require interventional treatment (e.g., fever 
requiring antipyretic medication). 
 
Severe and undesirable Adverse Event – Event results in significant symptoms that 
prevents normal daily activities; may require hospitalization or invasive intervention 
(e.g., anemia resulting in blood transfusion). 
7.2.3    Causality assessment (5) 
Relationship to Investigational Product: 
Every effort will be made to obtain all the required information to determine whether 
the Adverse Event is related to the study procedure or investigational product (causal 
relationship).  In terms of relationship, 


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Causality term 
Assessment criteria 
Certain 

Event or laboratory test abnormality, with plausible time 
relationship to drug intake 

Cannot be explained by disease or other drugs 

Response to withdrawal plausible (pharmacologically, 
pathologically) 

Event definitive pharmacologically or phenomenologically 
(i.e. an objective and specific medical disorder or a recognized 
pharmacological phenomenon) 

Rechallenge satisfactory, if necessary 
Probable 
/Likely 

Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 

Unlikely to be attributed to disease or other drugs 

Response to withdrawal clinically reasonable 

Rechallenge not required 
Possible 

Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 

Could also be explained by disease or other drugs 

Information on drug withdrawal may be lacking or unclear 
Unlikely# 

Event or laboratory test abnormality, with a time to drug 
intake that makes a relationship improbable (but not 
impossible) 

Disease or other drugs provide plausible explanations 
Conditional 
/Unclassified 
 Event or laboratory test abnormality 
 More data for proper assessment needed, or 
 Additional data under examination
Unassessable/ 
Unclassifiable 
 Report suggesting an adverse reaction 
 Cannot be judged because information is insufficient or 
contradictory 
 Data cannot be supplemented or verified 
#Unlikely will be considered as Not Related. 
Certain, Probable/ Likely and Possible will be considered as Related. 
7.3       Reporting of AEs and SAEs including death 
Reporting of AEs 
Adverse events will be recorded in adverse event form or appropriate documents. In 
particular, the information will include description of the event, details of the timing 
of the event to administration of the study medication, frequency of adverse event, 
description of the severity of the event, any treatment or diagnostic steps taken in 
relation to the event, description of the outcome of the event, judgementby the 
medical officer of any relationship of the event to study medication or procedures.  All 
adverse events will be reported to the sponsor and IEC within 14 calendar days by 
investigator(s). 
Each AE will be evaluated for duration, severity and action taken, outcome and 
association with the study medication. The study may be suspended or terminated 
depending upon the seriousness of the AEs. 


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In the event of unexplained abnormal laboratory test values, the tests should be 
repeated immediately and followed up as per physician’s discretion. Clinically 
significant laboratory test value abnormalities should be reported as adverse event. 
Reporting of SAEs (4) 
(1) The investigator shall report all serious adverse events to the Central Licensing 
Authority, the sponsor or its representative, who has obtained permission from the 
Central Licensing Authority for conduct of clinical trial or bioavailability or 
bioequivalence study, as the case may be, and the Ethics Committee that accorded 
approval to the study protocol, within twenty-four hours of their occurrence; and if the 
investigator fails to report any serious adverse event within the stipulated period, he 
shall have to furnish the reasons for delay to the satisfaction of the Central Licensing 
Authority along with the report of the serious adverse event. 
(2) A case of serious adverse event of death shall be examined in the following 
manner, namely: - 
(i) the Central Licensing Authority shall constitute an independent expert committee 
to examine the cases and make its recommendations to the said authority for 
arriving at the cause of death and quantum of compensation in case of clinical trial 
related death; 
(ii) the sponsor or its representative and the investigator shall forward their reports on 
serious adverse event of death after due analysis to the Central Licensing Authority 
and the head of the institution where the clinical trial or bioavailability or 
bioequivalence study has been conducted within fourteen days of the knowledge of 
occurrence of serious adverse event of death; 
(iii) the Ethics Committee for clinical trial shall forward its report on serious adverse 
event of death after due analysis along with its opinion on the financial 
compensation, if any, determined in accordance with the formula specified in the 
Seventh Schedule of New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E), to 
be paid by the said sponsor or its representative, who has obtained permission from 
the Central Licensing Authority for conduct of clinical trial or bioavailability or 
bioequivalence study, as the case may be, to the Central Licensing Authority 
within a period of thirty days of receiving the report of the serious adverse event of 
death from the investigator; 
(iv) the Central Licensing Authority shall forward the report of the investigator, 
sponsor or its representative and the Ethics Committee to the Chairperson of the 
expert committee; 
(v) the expert committee shall examine the report of serious adverse event of death 
and make its recommendations available to the Central Licensing Authority for the 
purpose of arriving at the cause of the serious adverse event of death within sixty 
days from the receipt of the report of the serious adverse event, and the expert 
committee while examining the event, may take into consideration, the reports of 
the investigator, sponsor or its representative and the Ethics Committee for clinical 
trial; 
(vi) in case of clinical trial or the bioavailability or bioequivalence study related death, 
the expert committee shall also recommend the quantum of compensation, 
determined in accordance with the formula specified in the Seventh Schedule of 
New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E), to be paid by the sponsor 


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or his representative who has obtained the permission to conduct the clinical trial or 
the bioavailability or bioequivalence study, as the case may be; 
(vii) the Central Licensing Authority shall consider the recommendations of the 
expert committee and shall determine the cause of death with regards to the 
relatedness of the death to the clinical trial or the bioavailability or bioequivalence 
study, as the case may be; 
(viii) in case of clinical trial or the bioavailability or bioequivalence study related 
death, 
the 
Central 
Licensing 
Authority 
shall, 
after 
considering 
the 
recommendations of the expert committee, by order, decide the quantum of 
compensation, determined as per the formula specified in the Seventh Schedule of 
New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E), to be paid by the sponsor 
or its representative and shall pass orders as deemed necessary within ninety days 
of the receipt of the report of the serious adverse event; 
(ix) the sponsor or its representative shall pay the compensation in case the serious 
adverse event of death is related to clinical trial or the bioavailability or 
bioequivalence study, as specified in the order referred to in clause (viii) of New 
Drugs and Clinical Trials Rules 2019 G.S.R. 227(E) of the Central Licensing 
Authority within thirty days of the receipt of such order. 
(3) Cases of serious adverse events of permanent disability or any other injury other 
than deaths shall be examined in the following manner, namely: 
(i) the sponsor or its representative, and the Investigator shall forward their reports on 
serious adverse event, after due analysis, to the Central Licensing Authority, 
chairperson of the Ethics Committee for clinical trial and head of the institution 
where the trial or bioavailability or bioequivalence study has been conducted 
within fourteen days of the reporting of serious adverse event; 
(ii) the Ethics Committee for clinical trial shall forward its report on serious adverse 
event of permanent disability or any other injury other than deaths, as the case may 
be, after due analysis along with its opinion on the financial compensation, if any, 
determined in accordance with the formula specified in the Seventh Schedule of 
New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E), to be paid by the sponsor 
or its representative who has obtained permission to conduct clinical trial or the 
bioavailability or bioequivalence study, as the case may be, within thirty days of 
receiving the report of the serious adverse event; 
(iii) the Central Licensing Authority shall determine the cause of the injury and pass 
order as specified in clause (iv) of New Drugs and Clinical Trials Rules 2019 
G.S.R. 227(E), or may constitute an independent expert committee, wherever it 
considers necessary, to examine such serious adverse events of injury, and such 
independent expert committee shall recommend to the Central Licensing Authority 
for the purpose to arrive at the cause of the serious adverse event and also the 
quantum of compensation, as determined in accordance with formula as specified 
in the Seventh Schedule of New Drugs and Clinical Trials Rules 2019 G.S.R. 
227(E) in case of clinical trial or bioavailability or bioequivalence study related 
injury, within a period of sixty days of receipt of the report of the serious adverse 
event; 
(iv) in case of clinical trial or the bioavailability or bioequivalence study related 
injury, the Central Licensing Authority shall, by order, decide the quantum of 


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compensation, determined in accordance with the formula specified in the Seventh 
Schedule of New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E), to be paid 
by the sponsor or his representative who has obtained the permission to conduct the 
clinical trial or the bioavailability or bioequivalence study, as the case may be, 
within a period of ninety days of receipt of the report of the serious adverse event; 
(v) the sponsor or its representative, who has obtained permission to conduct the 
clinical trial or bioavailability or bioequivalence study, as the case may be, shall 
pay the compensation in case of clinical trial or bioavailability or bioequivalence 
study related injury, as specified in the order of the Central Licensing Authority 
referred to in clause (iv) of New Drugs and Clinical Trials Rules 2019 G.S.R. 
227(E) within thirty days of receipt of such order. 
7.4     Additional Information 
 Subjects will be confined in a climate controlled environmental condition from 
their check-in till discharge from the study facility for each study period. 
 All activities related to handling of investigational medicinal products, dosing, 
blood sample collection, sample handling, processing and sample analysis will 
be carried out under sodium vapour light. 
8.0  
STATISTICAL PLAN 
Pharmacokinetic and Statistical analysis will be done using SAS® 9.4 version. 
The drug concentration of Nefopam, Paracetamol and its main metabolites and 
N-desmethyl-nefopam in plasma for each subject, each sampling time and each 
product will be reported. 
All concentration values below the limit of quantification (BLQ) will be set to zero for 
the estimation of pharmacokinetic parameters. 
Data from subjects who complete all periods of study will be considered for 
pharmacokinetic calculations and statistical analysis. Drop-out and withdrawal of 
subjects should be fully documented. If available, concentration data and 
pharmacokinetic parameters from such subjects should be presented in the individual 
listings, but should not be included in the summary statistics. 
If the pre-dose value is >5 percent of Cmax, the subject will be dropped from all PK 
evaluations. The subject data will be reported and included in safety evaluations but 
shall be excluded from 90% CI calculation. 
 
 
 
 
 
 
 
. 










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9.0  
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
A monitor will visit sometime the study facilities in order to maintain current 
knowledge of the study through review of the records, comparison with source 
documents, observation and discussion of the conduct and the progress of the study. 
The Investigator(s)/institution(s) provide direct access to source data/documents for 
study related procedures, audits, EC review, and regulatory inspection. Prior to the 
start of the study, the Principal Investigator/authorized trained person will be 
contacted and informed of any impending visits and the frequency of such visits. At 
each visit the Principal Investigator will assist the study monitor in terms of reviewing 
and verifying those records associated with the study. 
10.0  QUALITY CONTROL AND QUALITY ASSURANCE 
The Quality Control and Quality Assurance department will confirm that the study is 
conducted in adherence to the protocol and SOPs for each activity and bioanalysis is 
performed according to the principles of Good Laboratory Practice (GLP). 
In process quality checks and review procedures carried out by The Quality Control 
and Quality Assurance department will ensure that the activities and the 
documentation of the data for clinical, bioanalytical and statistical stages are done as 
per the protocol and / or respective SOP, ICH GCP Guidelines, applicable regulatory 
requirements. Deviation from the protocol or SOP observed during the quality 
checks/review will be verified. 
11.0  ETHICAL CONSIDERATIONS 
The ethical considerations are captured as per New Drugs and Clinical Trials Rules 
2019 G.S.R. 227(E) in the applicable sections of protocol and informed consent form. 
11.1 
Risk and Benefits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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- 
elderly patients: due to their slow metabolism, they are more sensitive to 
adverse effects of the central nervous system: a few cases of hallucination and 
confusion have been reported in this group of patients. 
 
 
 
 
 
 
 
 
11.2  Ethics committee review and communications 
The study will be conducted after obtaining approval from the Ethics Committee 
(EC). Documents described in Appendix G will be submitted to the EC for review and 
approval. 
Modifications, interfering with the subject’s health interests and involving changes in 
the design of the study or its scientific significance require a new approval of the EC. 
Any modifications will be signed by investigator and sponsor. All such modifications 
or subsequent amendments to the protocol prior to commencement of the study will 
be implemented after written approval of the EC and the sponsor. During the course of 
the study, the Principal Investigator can do minor administrative or technical 
modifications that do not interfere with the subject’s interest. The same will be 
conveyed to the EC and the sponsor. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate 
an 
immediate hazard(s) 
to 
trial 
subjects 
without 
prior 
EC 
approval/favourable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted: (a) to the EC for review and approval/favourable opinion, (b) to 
the sponsor for agreement and, if required, (c) to the regulatory authority(ies). 
The EC will be informed about the study dates. All adverse events will be reported to 
EC within a specified time. 
11.3  Informed Consent Process 
This study will be conducted in accordance with the principles of the World Medical 
Association Declaration of Helsinki (Appendix D). All subjects participating in the 
study will receive detailed information about the study, the procedures, the risks and 
the medication. All subjects will be required to sign ICF in the presence of the 
Principal Investigator/authorized trained person before participation in the study. The 




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All information on CRFs will be traceable to source documents, archived in Accutest 
Research Laboratories (I) Pvt. Ltd. The source documents will have information like 
laboratory data, ECGs, chest X-ray (if done) etc., and also a copy of the signed 
informed consent which will indicate study code and study title. 
Archived documents will include all essential documents which individually and 
collectively help in evaluation of the study conduct and the quality of data generated 
in the Trial master file. These documents will be archived after completion or 
discontinuation of the study for a period specified in the master service agreement. 
Prior to destruction of study documents, the sponsor will be notified and consent will 
be obtained in writing. 
13.0  INSURANCE, COMPENSATION AND HANDLING OF STUDY 
RELATED INJURY/DEATH (4) 
The subjects will be adequately compensated as per the compensation policy for the 
 
 
 
 
  
 
 
 
 
 
The compensation will be paid in accordance with the following principles. 
1. In case of any study related injury sponsor or Accutest Research Laboratories 
(I) Pvt. Ltd, who has obtained permission to conduct the clinical trial or 
bioavailability or bioequivalence study, will provide free medical 
management as long as required or till such time it is established that the injury 
is not related to the study, whichever is earlier. 
2. In case there is no permanent injury, the quantum of compensation shall 
commensurate with the nature of the non-permanent injury, loss of wages and 
transportation to the trial subject shall be provided financial compensation by 
the sponsor or Accutest Research Laboratories (I) Pvt. Ltd, who has obtained 
permission to conduct the clinical trial or bioavailability or bioequivalence 
study. 
3. In case of any study (clinical trial) related death of the subject, Accutest 
Research Laboratories (I) Pvt. Ltd. or sponsor who has obtained permission to 
conduct the clinical trial or bioavailability or bioequivalence will provide 
compensation to subject’s nominee. 
4. Any injury or death of the subject occurring in study due to following reasons 
shall be considered as study related injury or death. 
a. adverse effect of investigational product(s); 


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b. violation of the approved protocol, scientific misconduct or negligence by 
the sponsor or his representative or the investigator; 
c. adverse effects due to concomitant medication excluding standard care, 
necessitated as part of approved protocol; 
d. for injury to a child in–utero because of the participation of parent in study; 
 
 
 
 
 
 
 
 
 
 
14.0  REPORT 
Final report containing the clinical, analytical and statistical sections will be prepared 
as per ICH E3 guideline ‘Structure and Content of Clinical Study Reports’ unless 
specified. The Study Report will contain supporting tables for various 
pharmacokinetic parameters, adverse events and conclusion. 
 
 
. 
15.0  PUBLICATION POLICY 
Publication of the results is at the sole discretion of the study sponsor. 
16.0  CHANGES IN PROTOCOL 
Any change or addition to this protocol after its approval, but prior to the initiation of 
the study, will require a written protocol amendment, which must be approved by 
Principal Investigator, sponsor and the EC before implementation. Any deviation 
from the approved protocol, during the conduct of the study will be documented as a 
‘Protocol Deviations’. 
 
















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APPENDIX D 
(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 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
     Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
    General Principles 
3. The Declaration of Geneva of the WMA 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 in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are Involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 


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9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the   
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
     Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased    
likelihood of being wronged or of incurring additional harm. 


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      All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 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 adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
      The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
      In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious AEs. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in 
a research study unless he or she freely agrees. 


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26. In medical research involving human subjects capable of giving informed consent, 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, 
post-study provisions and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed 
in writing, the non-written consent must be formally documented and witnessed. All 
medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group. 
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 


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research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33.  The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; orWhere for compelling and scientifically sound methodological reasons the 
use of any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention and the 
patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a 
result of not receiving the best proven intervention. Extreme care must be taken to avoid 
abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 
 


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APPENDIX E  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 Rounding off to next figure in multiple of 100 
Compensation Details
Compensation Head
INR (`)
Multiplier
Total Amount (`)
 






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APPENDIX G 
 
LIST OF DOCUMENT SUBMITTED TO EC 
1. Stud
2. Info
lang
3. Liter
4. Upd
5. Inve
6. Any