Clinical trial NCT05406752
Conditions: Acute Pain
Sponsor: Unither Pharmaceuticals, France
Start date: 2022-07-22; Completion date: 2022-07-23
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to assess the pharmacokinetic profile of a new paracetamol formulation (paracetamol Uniflash 125mg/1.25mL) for buccal use after single dose.

Detailed description:

Arms: arm 1: 1 sachet of paracetamol Uniflash 125mg / 1.25 mL
Interventions: intervention 1: paracetamol Uniflash (125 mg/ 1.25 mL)
Intervention descriptions: intervention 1: Oromucosal solution (125 mg/ 1.25 mL) for buccal route

Protocol documents:
Prot_000.pdf: 
PHARMACOKINETICY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 
1.25 ML) UNDER FASTING CONDITION 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
Page 1 of 47 
CONFIDENTIAL 
AN 
OPEN-LABEL, 
SINGLE 
TREATMENT, 
SINGLE 
PERIOD, 
SINGLE 
BUCCAL 
DOSE
PHARMACOKINETIC STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 ML) IN HEALTHY,
ADULT, HUMAN SUBJECTS UNDER FASTING CONDITIONS. 
Clinical study protocol: UP-CLI-2021-002 
Version: 1.0 – 01 Mar 2022 
Sponsor 
UNITHER Pharmaceuticals 
3-5 Rue Saint-Georges
75009 Paris
France
Test product 
Paracetamol Uniflash (Compound number: 08P1703F0) 
Development Phase 
Pharmacokinetic Study 
EudraCT number 
2021-005315-31 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property of the Study Sponsor (or under its control). No part of it 
may be transmitted, reproduced, published, or used by other individual or organization without prior written 
authorization from the study Sponsor. This document is therefore provided to you in confidence as an Investigator, 
potential Investigator or consultant, for review by you, your staff and an applicable Independent Ethics Committee. 
It is understood that this information will not be disclosed to others without written authorization from the Sponsor, 
except to the extent necessary to obtain informed consent document from those subjects to whom the drug may be 
administered. 
CRO  
Raptim Research Pvt. Ltd., 
PAP-213, PAP-A-218 and PAP-A-219 
(Screening Facility), A-226 (Clinical Unit); ; 
A-242 (Bioanalytical and Biostatistical Unit);
T.T.C., Industrial Area, Mahape M.I.D.C.,
Navi Mumbai - 400 710, India. 
Tel. No.: +91 22 27781889 
Fax No.: +91 22 27781884 










 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 6 of 47 
CONFIDENTIAL 
TABLE OF CONTENT 
STUDY APPROVAL AND MANAGEMENT TEAM .............................................................................................. 2 
FACILITIES INVOLVED IN THE STUDY ............................................................................................................... 4 
TABLE OF CONTENT ............................................................................................................................................... 6 
LIST OF TABLES ....................................................................................................................................................... 7 
LIST OF ABBREVIATIONS ...................................................................................................................................... 8 
STUDY SYNOPSIS .................................................................................................................................................. 10 
1. 
BACKGROUND INFORMATION .............................................................................................................. 14 
1.1. 
Disease and context.................................................................................................................................... 14 
1.2. 
Paracetamol as part of the therapeutic strategy for pain management ....................................................... 14 
1.3. 
Rational for paracetamol UNIFLASH ....................................................................................................... 15 
1.4. 
Pharmacokinetics ....................................................................................................................................... 16 
1.5. 
Indication and usage .................................................................................................................................. 17 
1.6. 
Potential risk related to Investigational Medicinal Product ....................................................................... 17 
1.6.1. 
Contraindication ................................................................................................................................. 17 
1.6.2. 
Special Warnings and special precautions for use ............................................................................. 17 
1.6.3. 
Interaction .......................................................................................................................................... 18 
1.6.4. 
Adverse reactions ............................................................................................................................... 18 
1.6.5. 
Overdose, drug abuse and dependence .............................................................................................. 19 
1.6.6. 
Effects on ability to drive and use machine ....................................................................................... 19 
2. 
STUDY RATIONALE .................................................................................................................................. 20 
3. 
STUDY OBJECTIVES .................................................................................................................................. 20 
4. 
INVESTIGATIONAL PLAN ........................................................................................................................ 20 
4.1. 
Study design ............................................................................................................................................... 20 
4.2. 
Selection and handling of study population ............................................................................................... 20 
4.2.1. 
Inclusion criteria ................................................................................................................................ 21 
4.2.2. 
Exclusion criteria ............................................................................................................................... 21 
4.2.3. 
Discontinuation criteria ...................................................................................................................... 22 
4.3. 
Identity of Investigational Medicinal Products .......................................................................................... 23 
4.4. 
Randomization ........................................................................................................................................... 24 
4.5. 
Blinding ..................................................................................................................................................... 24 
4.6. 
Packaging, labelling and shipment ............................................................................................................. 24 
4.6.1. 
Packaging ........................................................................................................................................... 24 
4.6.2. 
Labelling ............................................................................................................................................ 24 
4.6.3. 
Shipment of IMP ................................................................................................................................ 25 
4.7. 
Handling of Investigational Medicinal product ......................................................................................... 25 
4.7.1. 
Receipt ............................................................................................................................................... 25 
4.7.2. 
Storage conditions .............................................................................................................................. 26 
4.7.3. 
Dispensing ......................................................................................................................................... 26 
4.7.4. 
Method of IMP Administration .......................................................................................................... 26 
4.7.5. 
Accountability and retentions of Investigational medicinal product .................................................. 26 
4.8. 
Clinical operation procedures .................................................................................................................... 27 
4.8.1. 
Screening activities ............................................................................................................................ 27 
4.8.2. 
Check-in activities and housing period .............................................................................................. 28 
4.8.3. 
Restrictions ........................................................................................................................................ 28 
4.8.4. 
Dosing and its compliance assessment .............................................................................................. 29 
4.8.5. 
Concomitant medication .................................................................................................................... 29 
4.8.6. 
Blood sampling procedures and processing ....................................................................................... 30 
4.8.7. 
Safety monitoring............................................................................................................................... 31 
4.8.8. 
Post-study safety evaluations ............................................................................................................. 32 
4.8.9. 
Check-out ........................................................................................................................................... 32 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 7 of 47 
CONFIDENTIAL 
4.8.10. 
Total blood loss .................................................................................................................................. 32 
5. 
SAFETY CONSIDERATIONS ..................................................................................................................... 33 
5.1. 
Risk and benefits to study subjects ............................................................................................................ 33 
5.2. 
Definitions related to safety ....................................................................................................................... 33 
5.2.1. 
Adverse event .................................................................................................................................... 33 
5.2.2. 
Adverse drug reaction ........................................................................................................................ 33 
5.2.3. 
Unexpected adverse drug reaction ..................................................................................................... 34 
5.2.4. 
Serious adverse event or adverse drug reaction ................................................................................. 34 
5.3. 
Adverse event documentation and reporting .............................................................................................. 34 
5.4. 
Reporting of serious adverse events ........................................................................................................... 36 
5.4.1. 
Central licensing authority requirements for expedited reporting of SAE ......................................... 36 
6. 
BIOANALYTICAL PROCEDURES ............................................................................................................ 37 
7. 
STATISTICAL CONSIDERATIONS ........................................................................................................... 37 
7.1. 
Pharmacokinetic parameters ...................................................................................................................... 37 
7.2. 
Estimation of sample size and justification ................................................................................................ 38 
7.3. 
Pharmacokinetic analysis ........................................................................................................................... 38 
8. 
DOCUMENTATION .................................................................................................................................... 38 
8.1. 
Direct access to source data/Documentation .............................................................................................. 38 
8.2. 
Quality control and quality assurance ........................................................................................................ 39 
8.3. 
Data confidentiality and audits .................................................................................................................. 39 
9. 
ETHICAL CONSIDERATIONS ................................................................................................................... 39 
9.1. 
Ethical conduction and regulatory compliance .......................................................................................... 39 
9.2. 
Ethics committee approval ......................................................................................................................... 40 
9.3. 
Protocol amendments ................................................................................................................................. 40 
9.4. 
Informed consent process .......................................................................................................................... 40 
9.5. 
Subject participation compensation ........................................................................................................... 41 
9.6. 
Compensation to the subjects in clinical trial injury .................................................................................. 41 
9.7. 
Insurance policy and finance...................................................................................................................... 42 
10. 
RECORDING OF DATA, REPORT PREPARATION AND ARCHIVAL ................................................. 42 
10.1. 
Record keeping ...................................................................................................................................... 42 
10.2. 
Final study report ................................................................................................................................... 43 
10.3. 
Archival ................................................................................................................................................. 43 
10.4. 
Record retention and archiving .............................................................................................................. 43 
11. 
TERMINATION OF THE STUDY ............................................................................................................... 43 
12. 
PUBLICATION ............................................................................................................................................. 43 
13. 
REFERENCES .............................................................................................................................................. 44 
14. 
APPENDICES ............................................................................................................................................... 45 
APPENDIX-A:  Schedule of Study Events ............................................................................................................... 46 
APPENDIX-B: STUDY SPECIFIC REQUIREMENT ............................................................................................. 47 
 
 
LIST OF TABLES 
 
Table 1: Brief introduction of investigational medicinal product .............................................................................. 15 
Table 2: Identity of Investigational Medicinal Products (IMPs) ................................................................................ 23 
Table 3: Laboratory Investigations ............................................................................................................................ 27 
Table 4: Meal Schedule ............................................................................................................................................. 28 
Table 5: Total Blood Loss during Study for a Subject ............................................................................................... 32 
Table 6: AE Evaluation Based on Severity, Causality and Outcome ........................................................................ 35 
Table 7: Sponsor and IEC Contact Details ................................................................................................................ 36 
Table 8: Primary and Secondary PK Parameters ....................................................................................................... 37 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 8 of 47 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Full Form 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ANOVA 
Analysis of Variance 
API 
Active Pharmaceutical Ingredient  
AUC0-inf 
Area under the plasma concentration versus time curve extrapolated to infinity. 
AUC0-inf is calculated as a sum of the AUC0-t and the ratio of last measurable plasma 
concentration to the elimination rate constant, calculated using the formula AUC0-t + 
Ct/Kel. Where Ct is the last measurable drug concentration and Kel is the elimination 
rate constant. 
AUC0-t 
Area under the plasma concentration versus time curve, from time 0 to the last 
measurable concentration time, calculated using the trapezoidal rule. 
AUC%Ratio 
Percent ratio of AUC0-t and AUC0-inf 
AUC%Extrapolated 
Percentage area extrapolated from last measurable time point to infinity, calculated 
using the formula {(AUC0-inf - AUC0-t) / AUC0-inf} X 100 
BA 
Bioavailability 
BE 
Bioequivalence 
°C 
Degree Celsius  
CDSCO 
Central Drugs Standard Control Organization 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum measured plasma concentration of drug 
CHMP 
Committee for Medicinal Products for Human Use 
CPMP 
Committee For Proprietary Medicinal Products 
CPU 
Clinical Pharmacology Unit 
 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCGI 
Drugs Controller General of India 
ECG 
Electrocardiogram  
EMA 
European Medicine Agency 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen  
hCG 
Human Chorionic Gonadotropin  


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 9 of 47 
CONFIDENTIAL 
Abbreviation 
Full Form 
HCV 
Hepatitis C Virus  
HIV 
Human Immunodeficiency Virus  
HPLC 
High Pressure Liquid Chromatography 
ICF 
Informed Consent Form 
ICH 
International 
Council for Harmonization 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
ISCV 
Intra-subject Coefficient of Variation  
K3EDTA 
Tripotassium Ethylene Diamine Tetra Acetic Acid 
Kel 
Apparent first–order terminal elimination rate constant calculated from a semi-log 
plot of the plasma concentration versus time curve, using the method of least squares 
regression. The parameter will be calculated by linear least-squares regression 
analysis in the terminal log-linear phase (using three or more non-zero plasma 
concentrations) 
LC-MS/MS 
Liquid Chromatography - Mass Spectrometer/Mass Spectrometer 
LSM 
Least Squares Mean 
Ln 
Natural Logarithm 
OTC 
Over The Counter 
PK 
Pharmacokinetic 
QA 
Quality Assurance 
QWP 
Quality Working Party 
RCF 
Relative Centrifugation Force 
RPM 
Revolutions per minute 
SAS 
Statistical Analysis Software 
SAE 
Serious Adverse Event 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
SIS 
Subject Information Sheet 
SOP 
Standard Operating Procedures 
t1/2 
The apparent first-order terminal half-life will be calculated as 0.693/Kel  
Tmax 
Time of the maximum measured plasma concentration. If the maximum value occurs 
at more than one time point, Tmax is defined as the first time point with this value. 
WBC 
White Blood Cell 
 










 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 14 of 47 
CONFIDENTIAL 
1. 
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. Paracetamol as part of the therapeutic strategy for pain management 
Management of patients with acute pain begins by identifying the underlying cause and 
using a disease-specific treatment as necessary. Treatment of pain should aim to decrease 
the intensity of acute pain and to reduce or prevent permanent changes in the nervous 
system that may result in chronic pain. 
The World Health Organization (WHO) created 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. 
Paracetamol has analgesic and antipyretic effects and is the only remaining para-
aminophenol used in clinical practice. It is the most widely used over-the-counter and 
prescription analgesic worldwide and is part of the first step of the WHO pain ladder. 
Paracetamol is recommended as a first-line therapy in several international guidelines for 
the management of a variety of acute and chronic conditions 12. 
The mechanism of action of paracetamol remains unclear. In contrast with opioids, 
paracetamol has no known endogenous binding sites, and, unlike nonsteroidal anti-
inflammatory drugs (NSAID), it does not inhibit peripheral cyclo oxygenase activity. 
The analgesic efficacy of paracetamol may be due to central antinociceptive effects 
through direct and indirect inhibition of central cyclo-oxygenases, and also through 
activation of the endocannabinoid system and spinal serotonergic pathways 13, 14, 15, 16. In 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 15 of 47 
CONFIDENTIAL 
addition, independent of any cyclo-oxygenase activity, paracetamol down-regulates 
prostaglandin production at the cellular transcriptional level 17. 
Under normal conditions of use, paracetamol is generally considered to be safer than 
other commonly used analgesics such as NSAIDs or opioids. The long-term 
observational evidence of the harmful effects of paracetamol has been summarized in a 
systematic review of studies investigating the association between paracetamol and 
major adverse events (AEs) in the general adult population18. This review demonstrated 
a consistent dose-response relationship between paracetamol at standard analgesic doses 
and AEs that are often observed with NSAIDs. Mortality, cardiovascular, gastrointestinal 
and renal AEs were all increased with increasing doses of paracetamol.  
In order to markedly reduce the risk of drug-induced side effects, paracetamol daily dose 
intake should be reduced. One possibility of achieving this, is modifying the form of 
intake as lower doses of paracetamol are required for effective pain relief. 
1.3. Rational for paracetamol UNIFLASH 
Paracetamol UNIFLASH is a new form of paracetamol dissolved in an ethanol/water 
solution (50/50), which has been developed for buccal use. 
Table 1: Brief introduction of investigational medicinal product 
Chemical Name 
N-(4-hydroxyphenyl) acetamide, N-(4 hydroxyphenyl) ethanamide 
Empirical formula 
C8H9NO2 
Molecular weight 
151.163 g/mol 
Structural formula 
 
General description 
Paracetamol, also known as acetaminophen, is a medication used to 
treat fever and mild to moderate pain. 
The solvent ethanol is able to pass through oral mucosal tissues by disrupting 
intercellular lipids 19, and dissolving drugs in this solvent allows them to be transported 
through oral mucosa 20. The development of a form of paracetamol dissolved in ethanol 
and water will enhance drug absorption from the oral mucosa and bypass first pass 
metabolism by the liver thereby allowing a rapid onset of action. 






 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 18 of 47 
CONFIDENTIAL 
Potential risks related to paracetamol: 
- use of enzyme inducers, such as barbiturates and anticonvulsants, excessive alcohol 
consumption, 
- hepatic and / or renal impairment, 
- chronic consumption of paracetamol may cause kidney failure, 
- glutathione depletion – especially in patients with severe malnutrition, low body mass 
index, anorexics, chronic alcoholics, in case of gluthatione deficiency like in 
septicaemia case, IMP can increase the risk of metabolic acidosis, 
- elderly patients are more sensitive and more at risk of liver or kidney failure. 
Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults 
should not take more than 4000 milligrams (4 grams) of acetaminophen a day. People 
with liver problems and children should take less acetaminophen. 
1.6.3. Interaction 
Interactions do not differ from those of the paracetamol indicated in the SmPCs of 
Panadol®. 
- 
administration of activated charcoal decreases the absorption of paracetamol in case 
of overdose, 
- 
hepatic enzyme inducers (such as barbiturates, diphantoin) and alcohol may increase 
the hepatotoxicity of paracetamol, 
- 
the half-life of chloramphenicol can be prolonged from 2 to 3 hours to 18-24 hours 
when concomitant use of paracetamol is used, 
- 
the low binding of paracetamol to plasma proteins allows its association with 
anticoagulants. However, taking paracetamol for several days may increase the risk 
of bleeding. In this case, the regular check of the International Normalized Ratio 
(INR) is recommended, 
- 
due to the risk of decreased leukocyte (leukopenia) levels when concomitant 
administration of paracetamol and AZT (zidovudine), simultaneous administration 
will only be with medical advice, 
- 
paracetamol absorption may increase with metoclopramide and decrease with 
cholestyramine. Concomitant administration of diflunisal increases serum 
paracetamol levels. High serum paracetamol levels have been associated with 
hepatotoxicity. 
1.6.4. Adverse reactions 
Adverse reactions expected do not differ from those of the paracetamol. 
The tables below are presented according to the MedDRA system organ classification 
(SOC) and Preferred Term Level.   


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 19 of 47 
CONFIDENTIAL 
According to the Belgian SmPC of Panadol® (comparator of the phase III study), the 
expected frequency of adverse reactions is presented in the tables below in CIOMS 
frequency categories:   
- 
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.  
Undesirable effects of paracetamol 
 
Very rare 
Undetermined Frequency 
Blood and lymphatic 
system disorders 
Thrombocytopenia 
In patients with glucose-
6-phosphate 
dehydrogenase 
[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. 
- 
1.6.5. Overdose, drug abuse and dependence  
Recommendations regarding overdose, drug abuse and dependence do not differ from 
those of the paracetamol and are detailed in the Investigator Brochure. It will not be 
applicable for this study as only a single dose is given to the patient. 
1.6.6. Effects on ability to drive and use machine  
Paracetamol has no effect on the ability to drive and use machines. 




















 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 29 of 47 
CONFIDENTIAL 
 
 
 
 
4.8.4. Dosing and its compliance assessment 
  
 
 
 
 
 
 
 
 
 
4.8.5. Concomitant medication 
The restrictions regarding any medication or OTC products or herbal products will be 
followed as per the exclusion and restriction criteria. If a drug other than that specified in 
the protocol is required to be administered to the subject during study or washout period, 
decisions to continue or discontinue the subject will be taken by the Clinical Investigator 
and will be based on the following: 
 Safety and well-being of subject 
 Pharmacodynamic and PK interaction 
 The time of administration of the non-study medication, and likelihood of 
interference in bioanalysis. 
Subject must inform the Clinical Investigator/Clinical Co-Investigator regarding any 
medication consumed during course of the study. Medications received other than the 
investigational medicinal product will be documented in the case report forms. The 
details of all the concomitant medications used in the study will be provided to the 
bioanalytical team before bioanalysis. 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 30 of 47 
CONFIDENTIAL 
4.8.6. Blood sampling procedures and processing 
4.8.6.1. 
Cannulation 
 
 
 
 
 
 
 
.  
4.8.6.2. 
Sampling schedule and collection 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
4.8.6.3. 
Sample processing and transfer 
Blood samples will be centrifuged at 4000 RPM for 10 minutes at 5°C ± 3°C to separate 
the plasma. The plasma samples will then be separated as mentioned in below table into 
pre-labeled polypropylene tubes, and will be stored in the deep freezer maintained at -
20°C (-15°C to -25°C) within 60 minutes of blood sample collection of each time point. 








 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 34 of 47 
CONFIDENTIAL 
Regarding marketed medicinal products, an adverse drug reaction in the post-marketing 
setting is a response to a drug which is noxious and unintended and which occurs at 
doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or for 
modification of physiological function. 
5.2.3. Unexpected adverse drug reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed. 
5.2.4. Serious adverse event or adverse drug reaction 
A SAE is any untoward medical occurrence that at any dose: 
 results in death; 
 permanent disability; 
 is life-threatening [The term "life-threatening" in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more 
severe; 
 requires inpatient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity, or; 
 is a congenital anomaly/birth defect. 
Medical and scientific judgment will be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These will also usually be considered serious. 
5.3. Adverse event documentation and reporting 
All AE complaints, signs or symptoms that are reported will be recorded in the AE Form 
as part of CRF. In particular the information will include details of administration of the 
investigational medicinal product and details of AE with its date and onset time, 
causality, frequency, severity, outcome, and if any treatment or diagnostic steps taken in 
relation to it. All AEs will be followed until resolution, except in case of lost to follow 
up. This may involve additional visits of the subject to the clinical facility. 
All the AEs will be evaluated on the basis of severity, causality and outcome as given in 
the below table. 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
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Table 6: AE Evaluation Based on Severity, Causality and Outcome 
 Parameter 
Description 
Severity 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Causality  
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. 
Outcome 
Resolved / Resolved with sequel / Ongoing / Lost to follow-up/ Stable chronic condition / Continuing at 
death / Death 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Pre-existing medical conditions or symptoms occurring prior to the initiation of the study 
will not be reported as AEs. A worsening of a pre-existing medical condition or 








 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
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CONFIDENTIAL 
8.2. Quality control and quality assurance 
Raptim Research Pvt. Ltd., India has a plan in place for the quality of the research being 
conducted and has standard SOPs for quality management, which describes:  
1) How data will be evaluated for compliance with the protocol and for accuracy in 
relation to source documents.  
2) The documents to be reviewed by the Quality Assurance auditor (e.g. CRFs, source 
documents, product accountability, final study report), who is responsible. 
3) The frequency for reviews will be identified in the QA audit plan either in a formal 
quality management plan or in-house SOPs. 
4) Training of the staff on the Protocol requirements by means of classroom/self-reading 
methods. Methods of training for staff will be specified.  
The final report will contain a statement for quality assurance (QA) duly signed by the 
Head or designated person of quality assurance department.  
8.3. Data confidentiality and audits 
Subject confidentiality along with the information disclosed/provided/produced by the 
CRO/sponsor during the clinical study, including, but not limited to, the study protocol, 
the CRFs, ICFs and results, are strictly held in trust by the sponsor, sponsor’s authorized 
personnel, clinical investigator/clinical co-investigator and their staff members. This 
confidentiality may extend to cover testing of biological samples in addition to the 
clinical information relating to participating subjects. No information concerning the 
study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
The clinical investigator will permit study-related monitoring, audits and inspections by 
the IEC, sponsor or its designated study personnel, licensing authority and QA groups of 
all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.) Further, clinical investigator will allow the 
auditors or inspectors to have direct access to study records for review, being understood 
that these personnel are bound by professional secrecy, and as such will not disclose any 
personal identity or personal medical information. The confidentiality of the data verified 
and the protection of the subjects will be respected during these inspections.  
9. 
ETHICAL CONSIDERATIONS 
9.1. Ethical conduction and regulatory compliance 
The present study will be conducted in accordance with Declaration of Helsinki (Ethical 
Principles for Medical Research Involving Human Subjects, 64th  World Medical 


 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 40 of 47 
CONFIDENTIAL 
Association – General Assembly, Fortaleza, Brazil, October 2013)1, Good Clinical 
Practice (International Council for Harmonization – E6 (R2) Guidelines, Current Step 4 
Version, dated 9 Nov 2016)2, New Drugs and Clinical trials Rules, 19 March 2019, 
Ministry of Health and Family Welfare, Government of India3, CDSCO Guidelines for 
Bioavailability & Bioequivalence Studies Mar 20054, Indian Council of Medical 
Research (Ethical Guidelines for Biomedical Research on Human Participants, 2017)5 
Guidance 
on 
the 
Investigation 
of 
Bioequivalence, 
CHMP 
– 
EMA 
(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**, Jan 2010), ethical requirements of Directive 
2001/20/EC6 and other applicable regulatory requirements. 
9.2. Ethics committee approval 
The study protocol and related study documents [including English and vernacular 
informed consent forms (ICFs) and drug related literature] will be reviewed by an IEC. 
The study will commence only after obtaining the written approval of the study protocol 
and its related documents by the IEC, with or without modifications.  
9.3. Protocol amendments 
All protocol amendments, interfering with the subject’s health interests and involving 
changes in the design of the study or its scientific significance will be implemented only 
after written approval of the Sponsor and IEC. All such changes will be documented in 
the amended version of protocol and a list of changes with reference to previous version 
will be generated. 
9.4. Informed consent process 
 
 
 
 
 
 
 
 
  
 
 
 
 






 
BIOAVAILABILITY STUDY OF PARACETAMOL UNIFLASH (125 MG/ 1.25 
ML) UNDER FASTING CONDITION 
 
PROTOCOL 
Version: 1.0 
Study Code: UP-CLI-2021-02 
Sponsor: UNITHER 
Pharmaceuticals 
 
 
Protocol UP-CLI-2021-002 – V1.0 – 01 Mar 2022 
 
Page 43 of 47 
CONFIDENTIAL 
All the bioanalytical data generated during the course of the study will be compiled and 
to be checked by QA wherever applicable for completeness. Further, the concentration 
data will be transferred to the statistical department for evaluation.  
10.2. Final study report 
Final study report will be prepared as per the ICH-E3 guidelines and will be submitted in 
electronic Common Technical Documentation format including CDISC data14. 
10.3. Archival 
All the data related to the study will be checked by the archivist as per in-house SOP 
before archiving.  
10.4. Record retention and archiving 
All the raw and final data generated in connection with this study and one copy of the 
final report will be retained at least 2-years after the last approval of a marketing 
application in an ICH region or as per the Sponsor’s requirement (at least 25 years for 
clinical trial master file and medical file of subject shall be archived in accordance with 
national law), whichever is earlier. 
After the completion of the retention period or the discontinuation of the study, the 
Sponsor will be notified about the same. If the Sponsor wants to extend the retention of 
the study documents, then suitable arrangements will be made for the same. The consent 
from the Sponsor will be taken prior to destruction of any study specific documents. 
 
 
 
 
 
 
 
 
 
12. 
PUBLICATION 
The Sponsor will hold the right to publish the results of present study at any time. Any 
information published will not reveal the identity of the subject and their confidentiality