Clinical trial NCT04318535
Conditions: Antifungal Agents
Keywords: Griseofulvin Bioequivalence Dose proportionality Dermatophytosis
Sponsor: GlaxoSmithKline
Start date: 2020-01-13; Completion date: 2020-02-06
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Griseofulvin is an antifungal agent used in treatment of Dermatophytosis caused by Microsporum spp. (species), Trichophyton spp., Epidermophyton spp., where topical therapy is considered inappropriate or has failed. Approved dose of Griseofulvin in Adults (greater than or equal to 50 kg) in India is 500 to 1,000 mg daily, but not less than 10 mg/kg bodyweight daily. As per the World health organization (WHO) guidance, Griseofulvin belongs to Biopharmaceutical Classification System (BCS) Class 2 ("low" solubility-"high" permeability). A Bioequivalence (BE) study will be conducted in India to estimate in vivo behavior (Pharmacokinetic characteristics) of Griseofulvin 500 tablets and dose proportionality study for Griseofulvin 250 mg and 500 mg tablets. This is an open label, randomized, balanced, three treatment period, three sequence, single dose, crossover study that will evaluate the bioequivalence of Griseofulvin tablets 500 mg test product (T1) versus Griseofulvin tablets 500 mg reference product (R) as well as dose proportionality of Griseofulvin tablets 250 mg test product (T2) with Griseofulvin tablets 500 mg T1 in healthy, adult participants under fed conditions. Eligible participants enrolled will be randomized to either of the three treatment sequence periods, T1T2R, T2RT1 or RT1T2 according to 1:1:1 ratio. The total duration of clinical phase will be approximately 20 days from Day-1 to Day 19 including a washout period of at least 7 days (not more than 14 days) for each treatment period. A total of 36 healthy, adult participants will be enrolled in this study and the above mentioned doses of Griseofulvin will be administered under fed conditions. Participants will be followed up 5 days after last dosing.

Detailed description:

Arms: arm 1: Participants will receive a single oral dose of Griseofulvin T1: 1 x 500 mg Tablet once in Period 1 on Day 1 followed by a washout period of at least 7 days. In Period 2 on Day 8, same participants will receive Griseofulvin T2: 1 x 250 mg Tablet once followed by a washout period of at least 7 days. In Period 3 on Day 15, same participants will receive Griseofulvin R: 1 x 500 mg Tablet once. All the above-mentioned doses will be administered with 240 +- 2 milliliters (mL) of water at ambient temperature under fed condition. arm 2: Participants will receive a single oral dose of Griseofulvin T2: 1 x 250 mg Tablet once in Period 1 on Day 1 followed by a washout period of at least 7 days. In Period 2 on Day 8, same participants will receive Griseofulvin R: 1 x 500 mg Tablet once followed by a washout period of at least 7 days. In Period 3 on Day 15, same participants will receive Griseofulvin T1: 1 x 500 mg Tablet once. All the above-mentioned doses will be administered with 240 +- 2 milliliters (mL) of water at ambient temperature under fed condition. arm 3: Participants will receive a single oral dose of Griseofulvin R: 1 x 500 mg Tablet once in Period 1 on Day 1 followed by a washout period of at least 7 days. In Period 2 on Day 8, same participants will receive Griseofulvin T1: 1 x 500 mg Tablet once followed by a washout period of at least 7 days. In Period 3 on Day 15, same participants will receive Griseofulvin T2: 1 x 250 mg Tablet once. All the above-mentioned doses will be administered with 240 +- 2 milliliters (mL) of water at ambient temperature under fed condition.
Interventions: intervention 1: Griseofulvin 500 mg intervention 2: Griseofulvin 250 mg intervention 3: Reference Griseofulvin 500 mg
Intervention descriptions: intervention 1: Griseofulvin 500 mg will be administered as an oral tablet once in each treatment period under fed condition. intervention 2: Griseofulvin 250 mg will be administered as an oral tablet once in each treatment period under fed condition. intervention 3: Reference Griseofulvin 500 mg will be administered as an oral tablet once in each treatment period under fed condition.

Protocol documents:
Prot_001.pdf: 
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CONFIDENTIAL 
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2019N413557_00 
GlaxoSmithKline group of companies 
Approval Date: 11-DEC-2019 
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
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TABLE OF CONTENTS 
PAGE 
1.
PROTOCOL SUMMARY .......................................................................................... 8 
1.1. 
Synopsis ....................................................................................................... 8 
1.2. 
Schema ...................................................................................................... 10 
1.3. 
Schedule of Activities (SoA) ........................................................................ 11 
2.
INTRODUCTION .................................................................................................... 20 
2.1. 
Study Rationale .......................................................................................... 20 
2.2. 
Background ................................................................................................ 20 
2.3. 
Benefit/Risk Assessment ............................................................................ 21 
2.3.1. 
Risk Assessment ......................................................................... 22 
2.3.2. 
Benefit Assessment ..................................................................... 26 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 26 
3.
OBJECTIVES AND ENDPOINTS ........................................................................... 26 
4.
STUDY DESIGN .................................................................................................... 27 
4.1. 
Overall Design ............................................................................................ 27 
4.2. 
Scientific Rationale for Study Design .......................................................... 28 
4.3. 
Justification for Dose .................................................................................. 28 
4.4. 
End of Study Definition ............................................................................... 29 
5.
STUDY POPULATION ........................................................................................... 29 
5.1. 
Inclusion Criteria ......................................................................................... 29 
5.2. 
Exclusion Criteria ........................................................................................ 31 
5.3. 
Lifestyle Considerations .............................................................................. 32 
5.3.1. 
Meals and Dietary Restrictions .................................................... 32 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 33 
5.3.3. 
Activity ......................................................................................... 33 
5.4. 
Screen Failures........................................................................................... 33 
6.
STUDY TREATMENT ............................................................................................ 34 
6.1. 
Study treatment (s) Administered ................................................................ 34 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 35 
6.4. 
Study treatment Compliance ....................................................................... 35 
6.5. 
Concomitant Therapy.................................................................................. 36 
6.6. 
Dose Modification ....................................................................................... 36 
6.7. 
Treatment after the End of the Study .......................................................... 36 
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ..................................................................... 36 
7.1. 
Discontinuation of Study Treatment ............................................................ 36 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 36 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 37 
7.3. 
Lost to Follow Up ........................................................................................ 37 
8.
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 38 
8.1. 
Efficacy Assessments ................................................................................. 38 
8.2. 
Safety Assessments ................................................................................... 39 
 
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8.2.1. 
Physical Examinations ................................................................. 39 
8.2.2. 
Vital Signs .................................................................................... 40 
8.2.3. 
Electrocardiograms ...................................................................... 40 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................... 40 
8.2.5. 
Suicidal Ideation and Behaviour Risk Monitoring ......................... 40 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 40 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 41 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 41 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 41 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 41 
8.3.5. 
Pregnancy ................................................................................... 42 
8.4. 
Treatment of Overdose ............................................................................... 42 
8.5. 
Pharmacokinetics ....................................................................................... 42 
8.6. 
Pharmacodynamics .................................................................................... 46 
8.7. 
Genetics ..................................................................................................... 46 
8.8. 
Biomarkers ................................................................................................. 47 
8.9. 
Immunogenicity Assessments ..................................................................... 47 
8.10. 
[Health Economics] OR [Medical Resource Utilization and Health 
Economics] ................................................................................................. 47 
9.
STATISTICAL CONSIDERATIONS ........................................................................ 47 
9.1. 
Statistical Hypotheses................................................................................. 47 
9.2. 
Sample Size Determination ........................................................................ 48 
9.3. 
Populations for Analyses ............................................................................ 49 
9.4. 
Statistical Analyses ..................................................................................... 50 
9.4.1. 
Analysis of Variance .................................................................... 50 
9.4.2. 
Confidence Interval ...................................................................... 51 
9.4.3. 
Acceptance Criteria for Bioequivalence ....................................... 51 
9.4.4. 
Accountability Procedure ............................................................. 51 
9.4.4.1. 
Treatment of Missing Values ...................................... 51 
9.4.4.2. 
Missing samples ......................................................... 52 
9.4.4.3. 
Treatment of outliers ................................................... 52 
9.4.5. 
Treatment of Time Point Deviation ............................................... 52 
9.4.6. 
Safety Analyses ........................................................................... 52 
9.5. 
Interim Analyses ......................................................................................... 53 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ............................................................................................... 54 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 55 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 55 
10.1.2. 
Financial Disclosure ..................................................................... 55 
10.1.3. 
Informed Consent Process .......................................................... 56 
10.1.4. 
Data Protection ............................................................................ 56 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 57 
10.1.6. 
Data Quality Assurance ............................................................... 57 
10.1.7. 
Source Documents ...................................................................... 58 
10.1.8. 
Study and Site Start and Closure ................................................. 58 
10.1.9. 
Publication Policy ......................................................................... 58 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 60 
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 65 
10.3.1. 
Definition of AE ............................................................................ 65 
10.3.2. 
Definition of SAE .......................................................................... 66 
10.3.3. 
Recording and Follow-Up of AE and SAE .................................... 67 
10.3.4. 
Reporting of SAE to GSK ............................................................. 69 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 70 
10.4.1. 
Definitions: ................................................................................... 70 
10.4.2. 
Contraception Guidance: ............................................................. 70 
10.4.3. 
Collection of Pregnancy Information: ........................................... 71 
10.5. 
Appendix 5: Country-specific requirements ................................................. 73 
10.6. 
Appendix 6: Abbreviations and Trademarks ................................................ 74 
11. REFERENCES ....................................................................................................... 76
 
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1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: An open label, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover study to evaluate the bioequivalence of test Griseofulvin 
tablets, 500 mg versus reference Griseofulvin tablets, 500 mg as well as dose 
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions. 
Short Title: BE study of Test Griseofulvin 500mg tablets versus reference and Dose 
Proportionality Study of test Griseofulvin 250mg and 500mg tablets under fed conditions. 
Rationale: 
Griseofulvin is an antifungal agent used in treatment of Dermatophytosis (ringworm) 
caused by Microsporum spp., Trichophyton spp., Epidermophyton spp., where topical 
therapy is considered inappropriate or has failed11.
Approved dose of Griseofulvin in Adults (greater than or equal to 50 kg) is 500 to 1,000 
mg daily, but not less than 10 mg/kg bodyweight daily. A single daily dose is often 
satisfactory, but divided doses may be more effective in patients who respond poorly.
Griseofulvin is recommended 500 mg twice a day dose to manage the dermatophytosis in 
the current scenario10. Griseofulvin 1000 mg/ day dose is needed for the treatment of
infections that are more difficult to eradicate, such as tinea pedis. Hence, Griseofulvin 
500 mg tablet twice a day dose will be useful for patients requiring 1000 mg daily dose12.
As mentioned above, in the current scenario, Griseofulvin 1000 mg/ day dose is needed 
for managing infections which are difficult to treat. Poor compliance being the major 
factor for increasing menace of dermatophytosis in India, It is important to have a 
formulation (500 mg) which can be used to overcome this challenge.  
Griseofulvin 500: It is decided to launch Griseofulvin 500 mg SKU in India to manage 
patients with Dermatophytosis. As per the WHO guidance the Griseofulvin is 
Biopharmaceutical Classification System (BCS) Class 2 (“low” solubility” – “high” 
permeability) and not eligible for Biowaiver. Griseofulvin is single market product 
(formerly POLO- Product of Local Opportunity) in India. Hence BA/BE study will be 
conducted in India to estimate in vivo behavior (Pharmacokinetic characteristics) of 
Griseofulvin 500. 
Griseofulvin 250: State regulatory authority in India has requested to submit the BE data 
for approval of the new Griseofulvin 250 mg formulation. In view of the same, 
Griseofulvin 250 mg tablet is added as an additional arm for the planned 
GRISEOFULVIN 500 BE study. Since the reference product (Comparator product) for 
GRISOVIN 250 mg is not available, dose proportionality study is planned.  The dose 
proportionality study involving administration of only one tablet of each formulation is 
expected to overcome the problem of multiple peaks and incorrect AUC observed after 
 
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administration of two 250 mg tablets of the test product to match the dose of 500 mg 
tablet of the comparator product. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Primary 

To determine whether the Test
Product (T1): Griseofulvin Tablets,
500 mg is bioequivalent to Reference
Product (R): Griseofulvin Tablets,
500 
mg 
(Grisovin) 
in 
healthy
participants.

To evaluate the dose proportionality
across the dose range of 250 mg to
500 
mg 
after 
single 
dose
administration of Test Product (T2):
Griseofulvin Tablets, 250 mg and
Test Product (T1): Griseofulvin
Tablets, 
500 
mg 
in 
healthy
participants.

Cmax, 
AUC0-t
and 
AUC0-inf 
for 
griseofulvin

AUC0-t and Cmax
Secondary 
Secondary 

To 
monitor 
the 
safety 
and
tolerability of a single oral dose
of 
Test 
Product 
(T1):
Griseofulvin Tablets, 500 mg;
Test Product (T2): Griseofulvin
Tablets, 250 mg and Reference
Product 
(R): 
Griseofulvin
Tablets, 500 mg (Grisovin).

Safety and tolerability as measured
by adverse events, vital signs and
clinical laboratory measurements.
Overall Design: 
This is an open label, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover study to evaluate the bioequivalence of test Griseofulvin 
tablets, 500 mg versus reference Griseofulvin tablets, 500 mg as well as dose 
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions. This study includes a screening period (within 21 days 
prior to dosing of period-I) and three open-label treatment periods. Participants will be 
followed up 5 days after last dosing.  
 
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The whole study will be divided into three periods. For each period, eligible participants 
will be randomized to either T1T2R, T2RT1 or RT1T2 treatment sequence according to 
1:1:1 ratio.  
Disclosure Statement: This is an open label study with 3 periods and only the bio-
analytical investigator will be blinded to the treatments administered to the subjects. 
Number of Participants: 
A maximum of 36 participants will be randomly enrolled to study treatment such that 
approximately 27 evaluable participants complete the study.  
Treatment Groups and Duration: 
Excluding screening period, the duration of clinical phase will be approximately 20 days 
from Day-1 to Day 19 including a washout period of at least 7 days (not more than 14 
days) for each study period. 
The participants 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. 
In each period, single oral dose [Test Product (T1): 1 x 500 mg Tablet or Test Product 
(T2): 1 x 250 mg Tablet or Reference Product (R): 1 x 500 mg Tablet] of the study 
treatments will be administered to the participants as per randomization with 240 ± 2 mL 
of water at ambient temperature under fed condition. 
Data Monitoring or Other Committee: No 
1.2. 
Schema 
  
       
 Participants 
Randomization 
T1 
T2 
R 
 washout 
T2 
R 
T1 
 washout 
R 
T1 
T2 
  Period 
1
2
3
 
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1.3. 
Schedule of Activities (SoA) 
 
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Procedure 
Screening 
(within 21 days 
prior to dosing 
of period-I) 
First Period 
Washout [at least 7 
days (not more than 
14 days) between 
subsequent dosing] 
Day 6 
Check-in 
Day -1 
Dosing day 
Day 1 
Checkout day 
Day 2 
Ambulatory sample visit 
Day 3 
Day 4 
Day 5 
Issue of   Participant 
informed consent form 
X 
Breath Alcohol 
test a, c 
X 
X 
X 
X 
X 
Questionnaire about 
smoking c
X 
X 
X 
X 
Weight a 
X 
Height a 
X 
Medical / clinical history
a
X 
X 
Vital Signs 
measurement a, b, i 
X 
X 
X 
X 
X 
X 
X 
Physical examination a, 
b, i
X 
X 
X 
 
 
 
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12 Lead ECG a 
X 
Serology a  
X 
Haematology  a, i 
X 
Biochemistry  a, i 
X 
ALT (Alanine 
transaminase) test e 
X 
Urinalysis  a, i 
X 
Serum pregnancy test 
for female e 
X 
Urine examination for 
drugs of abuse  h 
X 
Admit to Clinical 
Research Center 
X 
Meals d 
X 
X 
Study medication 
administration  f   
X 
PK Samples g 
X 
X 
X 
X 
X 
Concomitant medication 
AE 
SAE 
 
 
 
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Procedure 
Second Period 
Washout [at least 7 
days (not more than 14 
days) between 
subsequent dosing] 
Day 13 
Check-in 
Day 7 
Dosing day 
Day 8 
Checkout day 
Day 9 
Ambulatory sample visit 
Day 10 
Day 11 
Day 12 
Issue of  Participant  
informed consent form 
Breath Alcohol 
test  a, c 
X 
X 
X 
X 
Questionnaire about 
smoking  c 
X 
X 
X 
X 
Weight a 
Height a 
Medical / clinical history a 
X 
Vital Signs measurement  a, 
b, i
X 
X 
X 
X 
X 
X 
Physical examination  a, b, i 
X 
X 
 
 
 
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12 Lead ECG  a 
Serology  a  
Haematology  a, i
Biochemistry  a, i 
ALT test e
X 
Urinalysis  a, i 
Serum pregnancy test for 
female e 
X 
Urine examination for 
drugs of abuse  h 
X 
Admit to Clinical Research 
Center 
X 
Meals d 
X 
X 
Study medication 
administration  f 
X 
PK Samples g 
X 
X 
X 
X 
X 
Concomitant medication 
AE 
SAE 
 
 
 
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Procedure 
Third Period 
Post Study (Day 19)  
OR 
Early Discontinuation 
of Participant M 
Check-in 
Day 14 
Dosing day 
Day 15 
Checkout day 
Day 16 
Ambulatory sample visit 
Day 17 
Day 18 
Day 19 
Issue of  Participant 
informed consent form 
Breath Alcohol 
test  a, c 
X 
X 
X 
X 
Questionnaire about 
smoking c 
X 
X 
X 
X 
Weight a 
Height  a 
Medical / clinical history a 
X 
Vital Signs measurement 
measurement  a, b, i 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
measurement  a, b, i 
X 
X 
X 
 
 
 
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12 Lead ECG a 
Serology a  
Haematology  a, i
X 
Biochemistry  a, i
X 
ALT test e
X 
Urinalysis  a, i 
X 
Serum pregnancy test for 
female e 
X 
X 
Urine examination for 
drugs of abuse h 
X 
Admit to Clinical Research 
Center 
X 
Meals d 
X 
X 
Study medication 
administration f 
X 
PK Samples  g 
X 
X 
X 
X 
X 
Concomitant medication 
AE 
SAE 
 
 
 
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Note: Additionally, any other assessment including laboratory test(s) will be done if judged necessary by the Principal Investigator (PI) or medical officer at any time 
during the course of study. 
a.
Breath alcohol test, demographic data (Weight, Height and BMI), medical / clinical history, physical examination including vital signs, 12-lead
Electrocardiogram (ECG), Haematology, biochemistry, serology (HIV, Hepatitis B and C) and urinalysis will be performed at screening.
b.
Physical examination and vital signs examination (blood pressure, pulse rate, respiration rate and body temperature) will be done at check-in and check-out of
each study period.
Physical examination and vital examination can be started approximately 02.00 hours prior to the scheduled time in each study period.
Intravenous cannula site will be observed by principal investigator/co-investigator /Sub-investigator /medical officer for any swelling or thrombophlebitis.
Measurement of Vital signs (blood pressure, pulse rate, respiration rate and body temperature) will be done at pre-dose and at 01.00, 03.00, 05.00, 08.00hrs ±
45 minutes of scheduled time in each study period and at each ambulatory visits.
c.
Breath alcohol test and questionnaire about smoking (history of smoking) will be carried out before check-in and before each ambulatory blood sample
collection for each study period.
d.

Standardized meal will be given during check-in night. The check-in night dinner will be served in a way to maintain at least 10.00 hours fasting before 
receiving high-fat and high-calories breakfast.  

On dosing day, standardized high-fat and high-calories breakfast will be given 30 minutes prior to drug administration. Participants should eat the high-
fat and high-calorie breakfast completely within 25 minutes.

Participants will be given standardized meal at around 04.00, 09.00 and 13.00 hours post-dose.
e.
For all participants, ALT will be done before check-in for each study period. For female participants, serum pregnancy test (Serum (β) Beta- hCG) will be
done before check-in for each study period.
f.
Single oral dose of the either of two test product or reference product will be administered as per randomization with 240 ± 2 mL of water at ambient
temperature under fed condition.
g.
Total number of blood samples (5 mL per sample): 22 per period.
Sampling times: Pre-dose (collected within 01.00 hour prior to dosing) and at 00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50,
06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 48.00, 72.00 and 96.00 hours post dose. The detailed description on blood sample collection is provided in
section 8.5 Pharmacokinetics.
Blood samples will be collected in Na-Heparin Vacutainer.
Blood samples after 24.00 hours will be collected on ambulatory basis.
h.
Urine examination for drugs of abuse test will be done on check-in Day for each study period.
i.
Physical examination, measurement of blood pressure, pulse rate, respiration rate and body temperature, serum pregnancy test (Serum (β) Beta- hCG) (for
female participants), Haematology, biochemistry and urinalysis will done at post study or on early discontinuation of participant.
 
 
 
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√indicates the occurrence, * indicates day starts from post-dose.
 
 
 
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2.
INTRODUCTION
2.1. 
Study Rationale
This is an open label, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover study to evaluate the bioequivalence of test Griseofulvin 
tablets, 500 mg versus reference Griseofulvin tablets, 500 mg as well as dose 
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions.  
GSK will manufacture new GRISOVIN 500mg as well as 250mg products with SLS 
enhanced new formulations for better absorption. In the view of same, a three-period 
cross-over design was selected so that within participant comparisons can be utilized. 
Three-way crossover study with Test GRISOVIN 250 mg, GRISOVIN 500 mg and 
Reference GRISOVIN 500 (ASPEN) is selected along with Dose normalization – where 
GRISOVIN 250 mg single dose is given and the results are multiplied by 2. 
The Pharmacokinetic (PK) sampling and washout period are designed to ensure that PK 
parameters are well-estimated and pre-dose concentrations are completely negligible in 
subsequent periods. 
Sampling time points were decided based on the pharmacokinetic parameters of 
Griseofulvin in past successful global BE study 15, the pharmacokinetic data available in
SPC6 and previously conducted studies by Accutest. The last sampling time point was
selected as 96 hours (> 3 half-lives) considering the elimination half-life of around 9.5 
hrs – 21 hours. The study is planned in fed condition as the SPC6, 15 of griseofulvin
recommends it‟s intake with food. 
2.2. 
Background 
Griseofulvin is an antifungal antibiotic which is active in vitro against common 
dermatophytes. It exerts its antifungal effect by disrupting the cell division spindle 
apparatus of fungal cells, thereby arresting cell division. 
When griseofulvin is given orally for systemic treatment of fungal infections, it enables 
newly-formed keratin of the skin, hair and nails to resist attack by the fungi. As the new 
keratin extends, the old infected keratin is shed. Griseofulvin is effective against the 
dermatophytes causing ringworm (tinea), including: Microsporumcanis, T. verrucosum, 
T. mentagrophytes, E. floccosum and T. rubrum11
Griseofulvin is not effective in infections caused by Candida albicans (monilia), 
aspergilli, Malassezia furfur (Pityriasis versicolor) and Nocardia species11
After oral dosing there is a phase of rapid absorption followed by slower prolonged 
absorption. Peak plasma levels (0.5 to 1.5 micrograms after a 500 mg oral dose) are 
achieved by 4 h and are maintained for 10 to 20 h. The absorption of griseofulvin from 
the gastrointestinal tract is variable and incomplete. On average, less than 50% of the oral 
 
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dose is absorbed, but fatty foods and a reduction in particle size will increase the rate and 
extent of the absorption11
In plasma griseofulvin is approximately 84% bound to plasma proteins, predominantly 
albumin. There is selective deposition of griseofulvin in newly-formed keratin of hair, 
nails and skin, which gradually moves to the surface of these appendages. 6-
desmethylgriseofulvin or its glucuronide conjugate are metabolites of griseofulvin. The 
absorbed griseofulvin is excreted in the urine mainly as 6-desmethylgriseofulvin or its 
glucuronide conjugate. The terminal plasma half-life ranges from 9.5 to 21 h, there being 
considerable intersubject variability11
As per the WHO guidance16 the Griseofulvin is Biopharmaceutical Classification System
(BCS) Class 2 (“low” solubility” – “high” permeability) and not eligible for Biowaiver. 
Griseofulvin is single market product (formerly POLO- Product of Local Opportunity) in 
India. Hence BA/BE study will be conducted in India to estimate in vivo behavior 
(Pharmacokinetic characteristics) of new Griseofulvin 500 tablet compared to the current 
Griseofulvin 500mg.  It is micronized formulation. Since there are no reference 
Griseofulvin 250mg tablets available, a dose proportionality comparison will be made 
between the new Griseofulvin 250mg and the new Griseofulvin 500mg tablet.  As only a 
single 250mg tablet will be administered in this study, the PK parameters (AUC and 
Cmax) for the Griseofulvin 250mg tablet will be multiplied by 2 prior to the statistical 
comparison to the Griseofulvin 500mg tablet. 
2.3. 
Benefit/Risk Assessment 
The benefit/risk assessment is positive because Griseofulvin is a marketed product 
approved in India by the DCGI, and by TGA in Australia, and MHRA in UK.  The 
following section outlines the risk assessment and mitigation strategy for this protocol. 
 
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2.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [Griseofulvin Tablets] 
Concurrent treatment with 
oral contraceptives 
Concurrent treatment with griseofulvin may 
reduce the effectiveness of oral contraceptives, 
so additional non-hormonal contraceptive 
precautions 
should 
be 
taken 
during 
griseofulvin treatment and for a month after 
stopping griseofulvin. 
As per inclusion criteria (Section 5.1), participants 
will be included if they agree to follow the 
contraceptive guidance described in Appendix 4.  
Photosensitivity reaction 
Since 
a 
photosensitivity 
reaction 
is 
occasionally 
associated 
with 
griseofulvin 
therapy, patients should be warned to avoid 
exposure to intense natural or artificial 
sunlight. 
As per the study requirement, participants will be 
housed in clinical facility up to 24.00 hours post dose 
and thereafter will be advised to avoid exposure to 
intense natural or artificial sunlight until completion 
of 5 days post last dose. 
Allergic reaction 
Hypersensitivity to any ingredient of the 
preparation 
The participants will be closely monitored by medical 
personnel for occurrence of any allergic reaction. 
Appropriate medication required to treat allergic 
reaction will be kept ready. 
 
 
 
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Carcinogenicity 
and 
Mutagenicity  
Long-term administration of griseofulvin with 
food has been reported to induce hepatomas in 
mice and thyroid tumours in rats but not in 
hamsters. The clinical significance of these 
findings in man is not known. In view of these 
data, 
griseofulvin 
should 
not 
be 
used 
prophylactically. 7
Griseofulvin was mentioned in the report of a 
cohort study designed to screen 215 drugs for 
carcinogenicity. Although an excess of thyroid 
cancer 
was 
reported 
among 
users 
of 
griseofulvin in a 9-year follow-up, no results 
for this drug were reported in a 15-year follow-
up, implying that no significant association 
was observed for cancer. 17
Being a single dose study this risk can be considered 
as negligible. 
Use in Pregnancy (Category 
B3)  
Griseofulvin is contraindicated in pregnancy 
and in women intending to become pregnant 
within one month following cessation of 
treatment. Griseofulvin is teratogenic in 
animals and some case reports suggest that it 
produces human foetal abnormalities. As 
griseofulvin is capable of inducing aneuploidy 
(abnormal 
segregation 
of 
chromosomes 
following cell division) in mammalian cells 
exposed to the compound in vitro and in vivo, 
women should not take the drug during 
pregnancy or become pregnant within one 
month following cessation of treatment. 
As per inclusion criteria (Section 5.1), female 
participant is eligible to participate only if she is not 
pregnant and intending to become pregnant or 
breastfeeding 
and 
agreeing 
to 
use 
effective 
contraceptive measures as stated in Appendix 4 
during the period of study and for at least 1 month 
after the last dose of study treatment. 
 
 
 
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Use in Men 
Griseofulvin is capable of inducing aneuploidy 
(abnormal 
segregation 
of 
chromosomes 
following cell division) in mammalian cells 
exposed to the compound in vitro. In the 
absence of the relevant in vivo data, it is 
prudent to warn men that they should not 
father children within six months of treatment. 
Male participants are eligible to participate if they 
agree to follow the instructions mentioned in point 
no. 9 of section 5.1 Inclusion Criteria during the 
treatment period and for at least six months after the 
last dose of study treatment. 
 
 
 
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Interaction with Other Drugs 
Barbiturates may reduce the effectiveness of 
griseofulvin 
by 
interference 
with 
the 
gastrointestinal absorption of griseofulvin. The 
concurrent 
use 
of 
substances 
such 
as 
phenylbutazone and sedative and hypnotic 
drugs which induce metabolizing enzymes 
should be avoided as the blood level, and 
hence efficacy, of griseofulvin may be 
reduced.  
Griseofulvin may decrease the response to 
coumarin 
anticoagulants 
administered 
concomitantly. Dosage adjustment of the 
anticoagulant may be required during therapy 
and after griseofulvin therapy. 
Patients should be warned that an enhancement 
of the effects of alcohol by griseofulvin has 
been reported. 
This is a single dose study in healthy Participants 
where in Griseofulvin will be given for PK evaluation 
and not for efficacy evaluation. The Participants 
included in the study will already be free of 
prescription medications or over-the-counter (OTC) 
products (including vitamins and minerals) within 14 
days prior to administration of study treatment. 
Moreover, participants taking enzyme modifying 
drugs will not be allowed to participate. All 
Participants will be advised not to take any medicine 
during the entire period of study to avoid PK 
interaction. 
As per inclusion criteria (Section 5.1), participants 
with no history of significant alcoholism will be 
included. Participation also requires the subject‟s 
willingness to abstaining from any alcoholic products 
from 48.00 hours before the start of dosing until after 
collection of the final pharmacokinetic (PK) sample. 
 
 
 
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2.3.2. 
Benefit Assessment 
Participants enrolled in the study will be healthy volunteers. There will be no direct 
benefits gained from the participation in this study.  The participant‟s involvement will be 
contributing towards the PK and safety analysis of test griseofulvin formulations versus 
reference. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Griseofulvin has a well-characterised safety profile since it is an approved product, been 
marketed for many years for chronic use. Taking into account the measures taken to 
minimized risk to participants participating in this study, the potential risks identified in 
association with the Griseofulvin Tablets are justified by the anticipated benefits that may 
be afforded to patients for the treatment of fungal infections. 
3.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints 
Primary 
Primary 

To determine whether the Test Product
(T1): Griseofulvin Tablets, 500 mg is
bioequivalent to Reference Product
(R): Griseofulvin Tablets, 500 mg
(Grisovin) in healthy participants.

To evaluate the dose proportionality
across the dose range of 250 mg to 500
mg after single dose administration of
Test 
Product 
(T2): 
Griseofulvin
Tablets, 250 mg and Test Product
(T1): Griseofulvin Tablets, 500 mg in
healthy participants.

Cmax, 
AUC0-t
and 
AUC0-inf 
for 
griseofulvin

AUC0-t and Cmax
Secondary 
Secondary 

To monitor the safety and tolerability
of a single oral dose of Test Product
(T1): Griseofulvin Tablets, 500 mg;
Test 
Product 
(T2): 
Griseofulvin
Tablets, 
250 
mg 
and 
Reference
Product (R): Griseofulvin Tablets, 500
mg (Grisovin).

Safety and tolerability as measured by
adverse events, vital signs and clinical
laboratory measurements.
 
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4.
STUDY DESIGN
4.1. 
Overall Design
This is an open label, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover study to evaluate the bioequivalence of test Griseofulvin 
tablets, 500 mg versus reference Griseofulvin tablets, 500 mg as well as dose 
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions. This study includes a screening period (within 21 days 
prior to dosing of period-I) and three open-label treatment periods. Participants will be 
followed up 5 days after last dosing.  
The whole study will be divided into three periods. For each period, eligible participants 
will be randomized to either T1T2R, T2RT1 or RT1T2 treatment sequence according to 
1:1:1 ratio.  
On Day -1 
After obtaining the Informed Consent Form signed by the participants, they will be 
verified against the inclusion and exclusion criteria to confirm his/her eligibility to 
participate in the study.  
Participants will be admitted into the clinical facility to complete vital signs, physical 
examination; eligibility for enrolment will be confirmed; and the participant‟s 
concomitant therapies and adverse reactions information will also be collected and 
recorded.  
On Day 1, each enrolled participant will take a single oral dose of Test Product (T1): 1 x 
500 mg Tablet or Test Product (T2): 1 x 250 mg Tablet or Reference Product (R): 1 x 500 mg 
Tablet once. Blood samples will be collected at a set of timepoints (refer to SoA) pre and 
post dosing from Day1 to Day 5 for determination of single-dose pharmacokinetics of 
Griseofulvin T1 or T2 or R.  
Following a washout of at least 7 days (not more than 14 days), participants will be 
crossed over in Period 2 to receive the treatment according to the assigned sequence. 
They will be admitted into the clinical facility to complete physical examination and 
confirm eligibility again on Day 7. Eligible participants will take Test Product (T1): 1 x 
500 mg Tablet or Test Product (T2): 1 x 250 mg Tablet or Reference Product (R): 1 x 500 
mg Tablet once on Day 8 and blood samples will be collected at a set of timepoints (refer 
to SoA) pre and post dosing from Day 8 to Day 12. 
Following a washout of at least 7 days (not more than 14 days), participants will be 
crossed over in Period 3 to receive the treatment according to the assigned sequence. 
They will be admitted into the clinical facility to complete physical examination and 
confirm eligibility again on Day 14. Eligible participants will take Test Product (T1): 1 x 
500 mg Tablet or Test Product (T2): 1 x 250 mg Tablet or Reference Product (R): 1 x 500 mg 
Tablet once on Day 15 and blood samples will be collected at a set of time points (refer to 
SoA) pre and post dosing from Day15 to Day 19. Post study evaluation will be done at 
the time of collection of last PK sample in last study period.  
 
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The analyst from bioanalytical facility will be blinded to the sequence of administration 
of Test and Reference product to the individual participant. 
Safety data collection includes physical examinations, laboratory tests, vital signs 
measurements and recording of adverse events. Other clinical assessments will also be 
performed as appropriate. Planned time points for all safety assessments are provided in 
the SoA. 
Participants will complete follow-up 5 days after last dosing, and complete monitoring of 
any adverse events. 
4.2. 
Scientific Rationale for Study Design 
This is an open label, randomized, balanced, three treatment, three period, three 
sequence, single dose, crossover study to evaluate the bioequivalence of test Griseofulvin 
tablets, 500 mg versus reference Griseofulvin tablets, 500 mg as well as dose 
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions.  
GSK will manufacture new GRISOVIN 500mg as well as 250mg products with SLS 
enhanced new formulations for better absorption. In the view of same, a three-period 
cross-over design was selected so that within participant comparisons can be utilized. 
Three-way crossover study with Test GRISOVIN 250 mg, GRISOVIN 500 mg and 
Reference GRISOVIN 500 (ASPEN) is selected along with Dose normalization – where 
GRISOVIN 250 mg single dose is given and the results are multiplied by 2.  
The Pharmacokinetic (PK) sampling and washout period are designed to ensure that PK 
parameters are well-estimated and pre-dose concentrations are completely negligible in 
subsequent periods. 
Sampling time points were decided based on the pharmacokinetic parameters of 
Griseofulvin in past successful global BE study 15 and the pharmacokinetic data available
in SPC6. The last sampling time point was selected as 96 hours (> 3 half-lives)
considering the elimination half-life of around 9.5 hrs – 21 hours. The study is planned in 
fed condition as the SPC6, 15 of griseofulvin recommends it‟s intake with food. BE study
conforms to CDSCO and/or other global regulatory guidelines. 
4.3. 
Justification for Dose 
Griseofulvin is indicated in the treatment of fungal infections of the skin, scalp, hair or 
nails caused by Microsporum spp., Trichophyton spp., Epidermophyton spp., where 
topical therapy is considered inappropriate or has failed. 
Approved dose of Griseofulvin in adults (greater than or equal to 50 kg) is 500 to 1,000 
mg daily, but not less than 10 mg/kg bodyweight daily. A single daily dose is often 
satisfactory, but divided doses may be more effective in patients who respond poorly. 
Griseofulvin is recommended with 500 mg twice a day dose to manage the 
dermatophytosis in the current scenario. Griseofulvin 1000 mg/ day dose is needed for 
the treatment of infections that are more difficult to eradicate, such as tinea pedis. Hence, 
 
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Griseofulvin 500 mg tablet twice a day dose will be useful for patients requiring 1000 mg 
daily dose. The test product (T1) is a tablet containing 500 mg of Griseofulvin and it will 
be compared with the reference product (Griseofulvin 500 mg tablet) to demonstrate bio-
equivalence. The safety of Griseofulvin Tablets, 500 mg when given as a single dose, in 
healthy volunteers is established through different studies.  As per the literature15 a single
oral dose of 500 mg results in quantifiable levels of Griseofulvin. 
The test product T2 containing Griseofulvin 250 mg is indicated in patients requiring 250 
mg Griseofulvin tablet twice a day (500 mg daily dose). The present study involves 
administration of test product T2 containing 250 mg Griseofulvin to evaluate it‟s dose 
proportionality with 500 mg tablet.   
Both 250mg and 500mg are approved doses in India, and Australia. 
The dosing of each treatment will be done under fed condition based on the 
recommendation given in the SPC6, 15 to take the drug after meal, to increase the rate and
extent of absorption. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
periods of the study including post study evaluation. 
The end of the study is defined as the date of last scheduled procedure shown in the 
Schedule of Activities. 
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1.
Participant must be 18 to 45 years of age inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics 
2.
Participants who are healthy as determined by the investigator or medically qualified
designee on a medical evaluation including medical baseline history, physical
 
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examination and vital sign examination (blood pressure, pulse rate, respiration rate 
and body temperature).  
3.
Participants with clinically acceptable findings as determined by haematology,
biochemistry, urinalysis, 12 lead ECG.
4.
Participant‟s willingness to follow the protocol requirements especially abstaining
from xanthine containing food or beverages (chocolates, tea, coffee or cola drinks) or
grapefruit or grapefruit juice, any alcoholic products, the use of cigarettes and the use
of tobacco products from 48.00 hours before the start of dosing until after collection
of the final pharmacokinetic (PK) sample and adherence to food, fluid and posture
restrictions.
5.
Participants with  no history of significant alcoholism (Volunteers who do not have
habit  of  heavy drinking which is defined as regular intake of more than 2 units of
alcohol per day for male and 1 unit for female {I unit= 150 ml of wine or 360 ml of
beer or 45ml of 40% of alcohol}).
6.
Participants with no history of drug abuse (benzodiazepines and barbiturates) for the
last one month and other illegal drugs (Appendix 2) for the last 06 months.
7.
Participants who are non-smokers and ex-smokers will be included. “Ex-smokers are
someone who completely stopped smoking for at least 3 months.”
Weight 
8.
Body mass index (BMI) within the range 18.5-30 kg/m2 (inclusive) and weight ≥ 50
kg.
Sex 
9.
Healthy Male and non-pregnant female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a.
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
treatment period and for at least six months after the last dose of study treatment:  

Refrain from donating sperm as well as agree to use contraception/barrier as
detailed below
o
Agree to use a male condom and should also be advised for a female
partner to use a highly effective method of contraception as a condom
may break or leak when having sexual intercourse with a woman of
childbearing potential who is not currently pregnant
o
Agree to use male condom when engaging in any activity that allows
for passage of ejaculate to another person
 
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b. Female Participants:

A female participant is eligible to participate if she is not pregnant and intending to
become pregnant or breastfeeding, and at least one of the following conditions
applies:
o
Is not a woman of childbearing potential (WOCBP)
OR
o
Is a WOCBP and using a contraceptive method that is highly effective, with a
failure rate of <1%, as described in Appendix 4 during the treatment period
and for at least 1 month after the last dose of study treatment. The investigator
should evaluate the effectiveness of the contraceptive method in relationship
to the first dose of study treatment.
o
A WOCBP must have a negative highly sensitive [(Appendix 2)] pregnancy test
(serum as required by local regulations) within 1 day before each dose of study
treatment (The participant must be excluded from participation if the serum
pregnancy result is positive).

Additional requirements for pregnancy testing during and after study treatment are
located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and
recent sexual activity to decrease the risk for inclusion of a woman with an early
undetected pregnancy
Informed Consent 
10. Capable of giving signed informed consent as described in Appendix 1 which
includes compliance with the requirements and restrictions listed in the informed
consent form (ICF) and in this protocol.
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.
Known history of hypersensitivity to Griseofulvin.
2.
Participants who have taken prescription medications or over-the-counter products
(including vitamins, minerals and/or herbal supplements) within 14 days prior to
administration of IMP.
3.
Any medical or surgical conditions, which might significantly interfere with the
functioning of gastrointestinal tract, blood–forming organs etc.
 
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4.
History of cardiovascular, renal, hepatic, ophthalmic, pulmonary, neurological,
metabolic, haematological, gastrointestinal, endocrine, immunological or psychiatric
diseases.
5.
History of malignancy (including skin cancers) or other serious diseases.
6.
History of porphyria.
7.
Known history of SLE (Systemic lupus erythematosus) in the exclusion criteria.
Prior/Concomitant Therapy 
8.
Participants consuming aspirin, oral contraceptive pills, phenobarbital, and warfarin
having potential to trigger drug interactions with griseofulvin for any ailment in the
previous 28 days, prior to dosing day.
Prior/Concurrent Clinical Study Experience 
9.
Participation in a clinical drug study or bioequivalence study 90 days prior to period
I dosing of the present study.
Diagnostic assessments 
10. Participants with positive HIV tests, HBsAg or Hepatitis-C tests.
11. Found positive in breath alcohol test.
12. Found positive in urine test for drug abuse.
Other Exclusions 
13. Blood donation 90 days prior to period I dosing of the present study.
14. History of problem in swallowing pills.
15. Any contraindication to blood sampling i.e. keloid formation.
16. Sensitivity to heparin or heparin-induced thrombocytopenia.
17. Premenarchal female subjects
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 

Refrain from consumption of grapefruit or grapefruit juice, pomelos, exotic citrus
fruits, grapefruit hybrids, or fruit juices from 48.00 hours before the start of dosing
until after collection of the final pharmacokinetic (PK) sample.

In each study period, all participants will be required to fast overnight for at least
10.00 hours prior to receiving high-fat and high-calorie breakfast. After dosing the
participants will not be allowed food for at least 04.00 hours. Meal timings are
summarized in the SoA.
 
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
On dosing study days, after an overnight fast of 10.00 hours, all participants will be
given the same high-fat and high-calorie breakfast, 30 min prior to drug
administration. Participants should eat the high-fat and high-calorie breakfast
completely within 25 minutes.

No water is allowed for 01.00 hour before the start of dosing until 01.00 hour after
dosing except 240 ± 2 mL of water administered to the participants for dosing of
study treatments. Water is allowed ad libitum at all other times.
5.3.2. 
Caffeine, Alcohol, and Tobacco 

During each dosing session, participants will abstain from ingesting caffeine- or
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48.00
hours before the start of dosing until after collection of the final pharmacokinetic
(PK) sample.

During each dosing session, participants will abstain from alcohol for 48.00 hours
before the start of dosing until after collection of the final PK sample.

Use of tobacco products will not be allowed for 48.00 hours before the start of
dosing until after collection of the final pharmacokinetic (PK) sample.
5.3.3. 
Activity 

Participants will abstain from strenuous exercise from the time of their check-in
activity and throughout the stay at clinical facility. Participants may participate in
light recreational activities during studies (e.g., watching television, reading).

Participants will be advised to avoid exposure to intense natural or artificial sunlight
until completion of 5 days post last dose.
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations 
and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.  
 
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6.
STUDY TREATMENT
Study treatment is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study treatment (s) Administered 
Treatment Code 
T1 
 T2 
R 
Treatment Name 
Griseofulvin Tablets, 
500 mg 
Griseofulvin 
Tablets, 250 mg 
Griseofulvin 
Tablets, 500 mg 
(Grisovin 
Aspen 
Pharma Pty Ltd, 
Australia) 
Type 
Test Drug 
Test Drug 
Reference Drug 
Dose Formulation 
tablet 
tablet 
tablet 
Unit Dose 
Strength(s) 
500 mg 
250 mg 
500 mg 
Dosage Level(s) 
1 tablet 
1 tablet 
1 tablet 
Route of 
Administration 
oral 
oral 
oral 
Use 
experimental 
experimental 
 active-comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
Provided 
by 
the 
Sponsor 
Provided by the 
Sponsor 
Provided by the 
Sponsor 
Packaging and 
Labeling 
Study treatment will 
be 
provided 
in 
container. 
Each 
container 
will 
be 
labeled as required 
per 
country 
requirement. 
Study 
treatment 
will be provided in 
container. 
Each 
container will be 
labeled as required 
per 
country 
requirement. 
Study 
treatment 
will be provided in 
container. 
Each 
container will be 
labeled as required 
per 
country 
requirement. 
 
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6.2. 
Preparation/Handling/Storage/Accountability 
1.
The investigator or designee must confirm appropriate temperature conditions have
been maintained during transit for all study treatment received and any discrepancies
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only
authorized site staff may supply or administer study treatment. All study treatments
must be stored in a secure, environmentally controlled, and monitored (manual or
automated) area in accordance with the labeled storage conditions with access
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable)
is responsible for study treatment accountability, reconciliation, and record
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment
are provided in the CRO‟s Standard Operating Procedure.

Under normal conditions of handling and administration, study treatment is not
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational
hazards and recommended handling precautions either will be provided to the
investigator, where this is required by local laws, or is available upon request from
GSK.
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; potential bias will be reduced by the following steps: The 
randomization for this study will be generated by PBS personnel using the PROC PLAN 
on statistical software SAS® 9.2 or a higher version at CRO. The handling of
randomization will be done as per the CRO‟s Standard Operating Procedure. 
The analyst from bioanalytical facility will be blinded to the sequence of administration 
of Test and Reference product to the individual participant. 
6.4. 
Study treatment Compliance 

When participants are dosed at the site, they will receive study treatment directly
from the investigator or designee, under medical supervision.  The date and time of
each dose administered in the clinic will be recorded in the source documents.  The
dose of study treatment and study participant identification will be confirmed at the
time of dosing by a member of the study site staff other than the person
administering the study treatment.  Study site personnel will examine each
participant‟s mouth to ensure that the study treatment was ingested.

Record of dosing for individual participant will be maintained in the CRF.
 
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6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, minerals and/or herbal supplements) that the participant is receiving at the time 
of enrolment or receives during the study must be recorded along with: 

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 14 days before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study.  
In case of any illness requiring unacceptable medication, Paracetamol/Acetaminophen/ 
Diclofenac is permitted for use any time during the study as per discretion of investigator 
in consultation with the Medical Monitor. Other concomitant medication may be 
considered on a case-by-case basis by the investigator in consultation with the Medical 
Monitor if required. 
6.6. 
Dose Modification 
Refer to Section 4.3 for selection of each participant's dose of study. 
6.7. 
Treatment after the End of the Study 
As this is the single dose bioequivalence study to be conducted in healthy participants, no 
treatment at the end of study will be provided. 
7.
DISCONTINUATION OF STUDY TREATMENT AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Treatment
It may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment in subsequent study period only if the participant is 
withdrawn from the study due to any adverse event, serious adverse event or non-
compliance to the protocol. Drop-outs will not be replaced. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
 
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For all participants, ALT will be done before check-in for each study period. 
Discontinuation of study treatment for abnormal liver tests is required when the 
participant shows ALT ≥ 3xULN. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 

A participant may withdraw from the study at any time at his/her own request or
may be withdrawn at any time at the discretion of the investigator for safety,
behavioral, compliance or administrative reasons. This is expected to be
uncommon.

If participant is found positive for breath alcohol test in any ambulatory visit,
then the ambulatory sample of that particular visit will not be collected.
However, he/she may be requested to come for subsequent ambulatory samples
in same study period, if continuation in the study is not expected to have any
significant impact on the safety or PK outcome in the judgement of Investigator.

The decision to withdraw the subject if suffering from vomiting/diarrhoea (3 or
more consecutive watery stools) at or before two times of median Tmax (8 hours)
will be taken by the Investigator considering the nature and amount of vomitus,
likely/anticipated impact on the study outcome and the participants‟ health
status.

If participant is dropped out due to personal reasons in a given period, he can be
continued in subsequent periods if the PK data generated through such
participation can be used for statistical analysis.

At the time of discontinuing from the study, if possible, an early discontinuation
visit should be conducted, as shown in the SoA. See SoA for data to be collected
at the time of study discontinuation and follow-up and for any further
evaluations that need to be completed.

The participant will be permanently discontinued both from the study treatment
and from the study at that time.

If the participant withdraws consent for disclosure of future information, the
sponsor may retain and continue to use any data collected before such a
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any
samples taken and not tested, and the investigator must document this in the site
study records.
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
 
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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 

The site must attempt to contact the participant and reschedule the missed visit
as soon as possible and counsel the participant on the importance of maintaining
the assigned visit schedule and ascertain whether or not the participant wishes to
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee
must make every effort to regain contact with the participant (where possible, 3
telephone calls and, if necessary, a certified letter to the participant‟s last known
mailing address or local equivalent methods). These contact attempts should be
documented in the participant‟s medical record.

Should the participant continue to be unreachable, he/she will be considered to
have withdrawn from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Protocol waivers or exemptions are not allowed

Immediate safety concerns should be discussed with the sponsor immediately upon
occurrence or awareness to determine if the participant should continue or
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening
log to record details of all participants screened and to confirm eligibility or record
reasons for screening failure, as applicable.

Procedures conducted as part of the participant‟s routine clinical management (e.g.,
blood count) and obtained before signing of ICF may be utilized for screening or
baseline purposes provided the procedure met the protocol-specified criteria and was
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of
the study will not exceed 367.4 mL for male participants and 371.4 mL for female
participants.

Repeat or unscheduled samples may be taken for safety reasons or for technical
issues with the samples.
8.1. 
Efficacy Assessments 
No efficacy assessment will be conducted in this Bioequivalence study. 
 
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
The participants will be monitored for occurrence of adverse events and serious adverse 
events throughout the study. Safety evaluation will be done on the basis of outcomes of 
physical examination, vital signs measurement and clinical laboratory results. The 
activities will be performed during each study period and during post study evaluation as 
given in the SoA. 
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. 
Post study evaluation will be done at the time of collection of last PK sample in last study 
period. Physical examination and measurement of vital signs (blood pressure, pulse rate, 
respiration rate and body temperature) performed at the time of check-out will be 
considered for post-study evaluation if the timing of post study evaluation and check-out 
coincides. 
If any participant fails to complete the study or is discontinued from the study, the post-
study evaluation will be done either on the day of discontinuation or before/at the end of 
study. If the post study evaluation is not completed within this time frame due to any 
reason, the same can be attempted at later stage at the discretion of Principal Investigator. 
The reason for not completing the study will be specified in the respective CRF and the 
clinical report. 
The participants 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. 
8.2.1. 
Physical Examinations 

A complete physical examination will include, at a minimum, assessments of the
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height
and weight will also be measured and recorded.

Demographic information will include participant registration number, initials,
date of birth, race, age, gender, height, weight and Body Mass Index (BMI) of
the participants.

Investigators should pay special attention to clinical signs related to previous
serious illnesses.
 
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8.2.2. 
Vital Signs 

Blood pressure, pulse rate, respiration rate and body temperature will be 
assessed as outlined in the SoA (see Section 1.3).
8.2.3. 
Electrocardiograms 

12-lead ECG will be obtained as outlined in the SoA (see Section 1.3).
8.2.4. 
Clinical Safety Laboratory Assessments 

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and
to the SoA for the timing and frequency.

The investigator must review the laboratory report, document this review, and
record any clinically relevant changes occurring during the study in the AE
section of the CRF. The laboratory reports must be filed with the source
documents. Clinically significant abnormal laboratory findings are those which
are not associated with the underlying disease, unless judged by the investigator
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal
during participation in the study or within 5 days after the last dose of study
treatment should be repeated until the values return to normal or baseline or are
no longer considered significantly abnormal by the investigator or medical
monitor.

If such values do not return to normal/baseline within a period of time judged
reasonable by the investigator, the etiology should be identified and the sponsor
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be
conducted in accordance with the laboratory manual and the SoA.
8.2.5. 
Suicidal Ideation and Behaviour Risk Monitoring 
Not Applicable. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 7).  
 
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8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 1.3).

Medical occurrences after obtaining informed consent but before the initiation of 
study treatment will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours of occurrence of SAE, as 
indicated in Appendix 3. The investigator will submit any follow up information 
to the sponsor within 24 hours of occurrence.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the 
sponsor.
8.3.2. 
Method of Detecting AEs and SAEs 

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred
method to inquire about AE occurrence.
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow up with 
each participant at subsequent visits/contacts. All SAEs will be followed up until the 
event is resolved, stabilized, otherwise explained, or the participant is lost to follow-up 
(as defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Within 24 hours of SAE occurrence (both Initial and Follow up information), the
Investigator should complete a soft copy of the Table 5 format of the New Drugs
& Clinical Trial Rules, 2019 with details of the SAE (as required by the HA) and
Forward the completed Table 5 scan copy to the Sponsor, HA and Ethics
Committee.

Within 14 calendar days of SAE occurrence, the Investigator should provide
causality assessment to the HA, Ethics Committee and Head of Institution.
 
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
Within 14 calendar days of Sponsor (GSK) awareness of SAE, the Sponsor
forwards the Sponsor causality via completed Final Table 5 to the Chairman of
Ethics Committee, Head of Institution and to the HA (along with other relevant
documents related to submission to the HA).
8.3.5. 
Pregnancy 

Details of all pregnancies in female participants and, female partners of male
participants will be collected after the start of study treatment and until 6 months
after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs and should be
reported within 24 hours of occurrence (please see details provided in Appendix 3).
8.4. 
Treatment of Overdose 
For this study, any dose of Griseofulvin Tablets > 500 mg, within a 24-hour time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. A detailed description of 
overdose of Griseofulvin Tablets is provided in the Summary of Product Characteristics 
(6).
In the event of an overdose, the investigator should: 
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until
Griseofulvin can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis within 5 days from the date of the last dose
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
8.5. 
Pharmacokinetics 
Whole blood samples of approximately 5 mL will be collected for measurement of 
plasma concentrations of Griseofulvin as specified in the SoA.  
 
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An intravenous cannula will be inserted into the participant‟s arm for the collection of the 
blood samples before the pre-dose blood sample and up to 24.00 hrs post-dose. If 
difficulties occur in blood withdrawal or if the participant 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. 
Before every blood sample collection, 0.2 mL of blood present in the intravenous cannula 
will be discarded during the use of the intravenous cannula except for the ambulatory 
sample. Also after every blood sample collection, 0.2 mL of heparinised saline (by 
mixing 1 mL of 5000 IU/5mL of heparin with 500 mL of normal saline) will be injected 
into the intravenous cannula. 
Twenty-Two (22) blood samples will be collected in Na-Heparin vacutainers at pre-dose 
(collected within 01.00 hour prior to dosing), 00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 
03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 48.00, 
72.00 and 96.00 hours post dose. 
Note: The actual time of blood collection (24 hour clock) will be considered for 
calculation of PK parameters. Duration of 2 minutes is required for the completion of 
procedure of blood sample collection. Hence, the reason for deviation up to 2 minutes for 
the blood sample collection activity need not be documented. However, the reason for 
delay beyond 2 minutes will be documented in the case record form and/or other 
document. 
Blood samples after 24 hrs will be collected on ambulatory basis through direct vein 
puncture. The actual end-point time of collection of each blood sample will be recorded 
in the CRF. 
Ambulatory blood sample will be collected up to 04.00 hrs from the scheduled time of 
blood sample collection. If the participant reports for blood sample collection beyond 
04.00 hrs, the blood sample will not be collected, and the participant will be requested to 
come for the next ambulatory sample (if any). 
Approximate blood loss during the study: 
Males 
Females   
Total PK blood samples (66 x 5 mL) 
: 
330 mL         330 mL 
Pre study screening  
: 
Upto 10 mL Upto10 mL 
Post study evaluation 
: 
Upto 10 mL Upto 10 mL 
Discarded heparinised blood (57 x 0.2 mL) 
: 
11.4 mL 
11.4 mL 
*For ALT test (before check-in for each
: 
6 mL 
6 mL 
 
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2019N413557_00 
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Set# 02 (back-up aliquot) will be forwarded to the same analytical laboratory only after 
confirmation of receipt of Set# 01 by the analytical laboratory, if necessary. 
A validated LC-MS/MS analytical methodology will be used for the determination of 
Griseofulvin from the human plasma samples. Validation of the methodology will be 
carried out in accordance with applicable guidelines and the applicable SOP of analytical 
facility of Accutest Research Laboratories (I) Pvt. Ltd which are designed in accordance 
with the regulatory guidelines such as USFDA, EMEA, DCGI etc. 
The following parameters (as applicable for BE demonstration and for dose 
proportionality) will be calculated for each participant-formulation combination using the 
non-compartmental model by using statistical package SAS® 9.2 or higher version:
All concentration values below the limit of quantification (BLQ) will be set to zero for 
the estimation of pharmacokinetic parameters. 
If the pre-dose value is >5 percent of Cmax, the respective period of that subject will be 
dropped from all PK evaluations and statistical evaluations 
The pharmacokinetic samples of subjects dropped out or withdrawn due to vomiting / 
diarrhoea or any other reason will not be analyzed for the respective study period. The 
samples of subjects completing at least 2 periods of the study will be subjected to 
statistical analysis. 
Depending upon availability of data, the subject will be either included in bioequivalence 
evaluation or dose proportionality evaluation. 
Primary parameters 
Cmax 
Maximum observed drug concentration during the study. 
AUC0-t 
Area under the plasma concentration - time curve measured to the last 
quantifiable concentration, using the linear trapezoidal rule. 
AUC0-inf 
AUC0-t plus additional area extrapolated to infinity, calculated using the 
formula AUC0-t + Ct/Kel, where Ct is the last measurable drug 
concentration and Kel  is the elimination rate constant. 
Secondary parameters 
Tmax 
Time to observe maximum drug concentration. If the maximum value 
occurs at more than 1 time point, Tmax is defined as the first time point 
with this value. 
AUC0-t
/AUC0-inf 
Ratio of AUC0-t and AUC0-inf 
Residual 
area 
Extrapolated area (AUC0-inf - AUC0-t)/ AUC0-inf 
 
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8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Not Applicable. 
8.10. 
[Health Economics] OR [Medical Resource Utilization and 
Health Economics] 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
Null Hypothesis Testing 
For BE Demonstration (T1 vs. R) 
Null hypothesis H0 and alternative hypothesis H1 can be written in multiplicative form: 
H0: mtest 1 / mref < L or mtest 1 / mref > U 
H1: L ≤ mtest 1 / mref ≤ U 
Where L (Lower Limit) = 80.00% and U (Upper Limit) = 125.00%, 
mtest 1= geometric least-squares means for test product (Griseofulvin 500mg tablets) 
mref = geometric least-squares means for reference product (Griseofulvin tablets, 500 mg 
(Grisovin)) 
The type I error will be set to α = 5% and therefore 90% (two-tails) confidence intervals 
will be provided together with indication whether the null hypothesis of non-equivalence 
for appropriate parameter can be rejected. 
For For dose proportionality (T2 vs. T1) 
Null hypothesis H0 and alternative hypothesis H1 can be written in multiplicative form: 
H0: mtest 2 / mtest 1 < L or mtest 2 / mtest 1> U 
H1: L ≤ mtest 2 / mtest 1 ≤ U 
Where L=80.00% and U=125.00%, 
mtest 1= geometric least-squares means for test product (Griseofulvin 500 mg tablets) 
mtest 2 = geometric least-squares means for reference product (Griseofulvin 250 mg 
tablets) 
The type I error will be set to α = 5% and therefore 90% (two-tails) confidence intervals 
will be provided together with indication whether the null hypothesis of non-equivalence 
for appropriate parameter can be rejected. 
 
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Step 1: For BE Demonstration (T1 vs. R): 
PROC MIXED procedure will be used for analysis of variance and the estimation of least 
square mean differences (Test (T1) - Reference (R)) of the test (T1) and reference 
formulations on the log-transformed pharmacokinetic parameters Cmax, AUC0-t and 
AUC0-inf. The corresponding standard errors of the differences will also be computed. 
Based on these parameters, the 90% confidence intervals will be constructed for the least 
square mean differences of log-transformed parameters Cmax, AUC0-t and AUC0-inf. The 
antilog (or exponential) of the limits obtained from the log-transformed data will give the 
90% confidence interval for the ratio of geometric means of test (T1) and reference (R) 
products. 
If the 90% confidence interval of geometric mean ratio of Cmax, AUC0-t and AUC0-inf 
between test (T1) and reference (R) products falls within the range of 80.00% to 125.00% 
for Griseofulvin, the null hypothesis will be rejected. In this case the test product (T1) 
will be concluded as bioequivalent to the reference product R.  
If bioequivalence is demonstrated between the Test product (T1) and reference product 
(R), the following step II will be followed.  
Step 2: For dose proportionality (T2 vs. T1): 
Dose normalization will be done for test product T2 for AUC0-t and Cmax parameter by 
multiplying with the correction factor 2. 
PROC MIXED procedure will be used for analysis of variance and the estimation of least 
square mean differences (Test (T2) - Test (T1)) of the test (T2) and test (T1) products on 
the log-transformed pharmacokinetic parameter AUC0-t and Cmax. The corresponding 
standard errors of the differences will also be computed. Based on these parameters, the 
90% confidence intervals will be constructed for the least square mean differences of log-
transformed parameter AUC0-t and Cmax. The antilog (or exponential) of the limits 
obtained from the log-transformed data will give the 90% confidence interval for the ratio 
of geometric means of test (T2) and test (T1) products. 
Null hypothesis will be rejected if the 90% confidence interval of geometric mean ratio of 
AUC0-t and Cmax between test (T2) and test (T1) products falls within the range of 
80.00% to 125.00% for Griseofulvin. 
9.2. 
Sample Size Determination 
*Intra subject variability of 21% was chosen as clinically meaningful estimate based on 
the Sensitivity analysis on the variability estimates of 17% performed using 95th
percentile approach. 8
A sample size of 27 participants (adjusted for 9 subjects per sequence) without dropouts 
will be appropriate to provide 90% power for 90% confidence interval for the ratio of 
 
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Test to Reference for log-transformed Cmax and AUC to lie within the acceptance region 
of bioequivalence 80% to 125%. This estimate is based on the ratio of Test product and 
Reference product is 0.95 and intra subject variability of 21% of Griseofulvin. 
A sample size of 36 subjects are proposed for this 3-way cross-over study considering the 
dropouts and withdrawal of participants. 
9.3. 
Populations for Analyses 
Three (3) populations sets are defined for analysis purposes. 
Safety Analysis Set 
The safety population will include all randomized participants who receive at least one 
dose of study medication. The safety population will be used for all analyses of safety 
data. Individual pharmacokinetic parameters and its descriptive statistics will be 
presented. 
BE Analysis Set 
The data of subjects completing at least 2 periods with 500mg test and 500mg reference 
treatments of the study will be subjected to statistical analysis. 
Dose Proportionality Analysis Set 
The data of subjects completing at least 2 periods with 500mg test and 250mg test 
treatments will be subjected to dose proportionality analysis. 
The following populations are defined: 
Population 
Description 
Enrolled 
All participants who signed the ICF 
Randomized 
All participants assigned to study treatment. 
BE Analysis Set 
The data of subjects, completing at least 2 periods with 
500mg test and 500mg reference treatments of the study will 
be subjected to statistical analysis. 
Safety Analysis Set 
The safety population will include all randomized participants 
who receive at least one dose of study medication. The safety 
population will be used for all analyses of safety data. 
Individual pharmacokinetic parameters and its descriptive 
statistics will be presented 
Dose 
Proportionality The data of subjects completing at least 2 periods with 500mg 
 
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Analysis Set 
test and 250mg test treatments will be subjected  to dose 
proportionality analysis 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to study initiation and it will include a 
more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.4.1. 
Analysis of Variance 
Step 1: For BE Demonstration (T1 vs. R): 
ANOVA will be performed using PROC MIXED on log-transformed  pharmacokinetics 
parameters Cmax, AUC0-t and AUC0-inf at α level of 0.05.  
The analysis of variance model will include sequences, period and treatment as fixed 
factors and participants nested within sequence as random factor [i.e. Model LCmax or 
LAUC0-t or LAUC0-inf = sequence period treatment (fixed factors) and random: 
Participant (Sequence) (random factor)]. 
A separate ANOVA model will be used to analyze each of the parameters. All main 
effects will be tested against the residual error (mean square error) from the ANOVA 
model as the error term. 
Each analysis of variance will also include calculation of least-square means, adjusted 
differences between formulation means and the standard error associated with these 
differences. 
Step 2: For dose proportionality (T2 vs. T1): 
ANOVA will be performed using PROC MIXED on log-transformed pharmacokinetics 
parameter AUC0-t and Cmax at the α level of 0.05.  
The analysis of variance model will include sequences, period and treatment as fixed 
factors and participants nested within sequence as random factor [i.e. Model LAUC0-t or 
LCmax = sequence period treatment (fixed factors) and random: Participant (Sequence) 
(random factor)]. 
A separate ANOVA model will be used to analyze each of the parameters. All main 
effects will be tested against the residual error (mean square error) from the ANOVA 
model as the error term. 
Each analysis of variance will also include calculation of least-square means, adjusted 
differences between formulation means and the standard error associated with these 
differences. 
 
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9.4.2. 
Confidence Interval 
Consistent with the two one-sided test for bioequivalence, 90% confidence intervals will 
be constructed for the difference (Test (T1) – Reference (R) or Test (T2) - Test (T1) ) of 
least square means of the log-transformed Cmax, AUC0-t and AUC0-inf for BE 
demonstration and of the log-transformed AUC0-t and Cmax for dose proportionality. The 
antilog (or exponential) of these limits will give the 90% confidence interval for the ratio 
of geometric least square means of the test (T1) and reference (R) formulations or test 
(T2) and test (1) formulations. 
9.4.3. 
Acceptance Criteria for Bioequivalence 
Bioequivalence will be concluded if: 
The 90% confidence interval of geometric mean ratio of log-transformed Cmax, AUC0-t 
and AUC0-inf between test (T1) and reference (R) products fall within the range of 
80.00% to 125.00% for Griseofulvin. 
Dose proportionality will be concluded if: 
The 90% confidence interval of geometric mean ratio of log-transformed AUC0-t and 
Cmax between test (T2) and test (T1) products falls within the range of 80.00% to 
125.00% for Griseofulvin. 
9.4.4. 
Accountability Procedure 
9.4.4.1. 
Treatment of Missing Values 
Missing sample values (MSV) or non-reportable values (NRV), of the plasma 
concentration data, will be represented as MSV and NRV in the plasma concentration 
tables and reasons for their missing will be documented. Any BLQ value occurring 
between two measurable concentration values will also be treated as missing sample 
(MS).  These missing values will be treated as „missing values‟ for Pharmacokinetic and 
statistical analysis. All the procedures will be performed in accordance with current 
version of SOP for „Calculation of Pharmacokinetic Parameters‟. 
For participants with missing or non-reportable concentrations for three or more of the 
last samples, only the Cmax and Tmax will be presented and included in the statistical 
analysis. Other PK parameters will not be reported.  
Data from the participants with missing concentrations values (missed blood draws, lost 
samples, samples unable to be quantified) may be used if pharmacokinetic parameters 
can be estimated using the remaining data points. Otherwise, concentration data from 
these participants will be excluded from the final analysis. 
 
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9.4.4.2. 
Missing samples 
Missing samples can be due to withdrawal of participant and accidental spillage of 
samples as mentioned in current version of SOP for „Missing Sample‟. 
9.4.4.3. 
Treatment of outliers 
Before the results of the bioequivalence analysis are summarized into confidence 
intervals, the available untransformed Cmax, AUC0-t and AUC0-inf data for BE 
demonstration and AUC0-t and Cmax data for dose proportionality will be tested for 
possible outliers based on studentized residuals. Participants identified as outliers will be 
removed regardless of whether results meet the standard 
Values that meet both of the following criteria will be considered outliers: 
• Studentized residual value larger than 3; and
• Observation outside of the range [Q1 – 3 x IQR; Q3 + 3 x IQR], where Q1, Q3 and IQR
are respectively the 1st quartile, the 3rd quartile and the inter-quartile range of the
distribution of all observations (i.e. regardless of the formulation).
Data from participants who meet both criteria for Cmax, AUC0-t and AUC0-inf data for BE 
demonstration and AUC0-t and Cmax data for dose proportionality will be excluded from 
the statistical analysis for the outlying period. 
No more than 5% of the participants may be considered outliers. If greater than 5% of the 
participants are considered outliers, no data will be removed from the statistical analysis. 
A valid clinical or physiological reason will be explored for such an outlier, if found, and 
will be reported if identified by the Principal Investigator of the study (in accordance with 
current SOP of statistical outlier).  
However, to avoid the biasness in the results, the statistical analysis will be performed on 
both the data sets i.e. including as well as excluding the outliers if the outlier is justified 
clinically as well. 
9.4.5. 
Treatment of Time Point Deviation 
Sampling time deviations will be considered during the calculation of pharmacokinetic 
parameters. However, graphical summary for mean data will be presented using nominal 
sampling times. Graphical summaries for individual subjects will be presented using 
actual sampling times. 
9.4.6. 
Safety Analyses 
All safety analyses will be made on the Safety Population. Safety data will be presented 
in tabular and/or graphical format and summarized descriptively.  
 
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Interim Analyses 
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9.5. 
Not Applicable. 
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
 
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by
the investigator and reviewed and approved by the IRB/IEC before the study is
initiated.

Any amendments to the protocol will require IEC/IRB approval before
implementation of changes made to the study design, except for changes
necessary to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC
annually or more frequently in accordance with the requirements, policies,
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European
regulation 536/2014 for clinical studies (if applicable), and all other
applicable local regulations
10.1.2. 
Financial Disclosure 
[Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
 
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10.1.3. 
Informed Consent Process 

The investigator or his/her representative will explain the nature of the study to
the participant or his/her legally authorized representative and answer all
questions regarding the study.

Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of
informed consent that meets the requirements of 21 CFR 50, local regulations,
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA)
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was
obtained before the participant was enrolled in the study and the date the written
consent was obtained. The authorized person obtaining the informed consent
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s)
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant‟s
legally authorized representative.
GSK (alone or working with others) may use participant‟s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about Griseofulvin Tablets or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the Griseofulvin 
Tablets approved for medical use or approved for payment coverage.  
10.1.4. 
Data Protection 

Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier
only; participant names or any information which would make the participant
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be
used by the sponsor in accordance with local data protection law. The level of
disclosure must also be explained to the participant who will be required to give
consent for their data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be examined
by Clinical Quality Assurance auditors or other authorized personnel appointed
by the sponsor, by appropriate IRB/IEC members, and by inspectors from
regulatory authorities.
 
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10.1.5. 
Dissemination of Clinical Study Data 

Where required by applicable regulatory requirements, an investigator signatory
will be identified for the approval of the clinical study report.  The investigator
will be provided reasonable access to statistical tables, figures, and relevant
reports and will have the opportunity to review the complete study results at a
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study
results. The investigator is encouraged to share the summary results with the
study participants, as appropriate.
10.1.6. 
Data Quality Assurance 

All participant data relating to the study will be recorded on printed or electronic
CRF unless transmitted to the sponsor or designee electronically (e.g.,
laboratory data). The investigator is responsible for verifying that data entries
are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review,
and regulatory agency inspections and provide direct access to source data
documents.

The sponsor or designee is responsible for the data management of this study
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that
data entered into the CRF by authorized site personnel are accurate, complete,
and verifiable from source documents; that the safety and rights of participants
are being protected; and that the study is being conducted in accordance with the
currently approved protocol and any other study agreements, ICH GCP, and all
applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this
study must be retained by the investigator for 25 years from the issue of the final
Clinical Study Report (CSR)/ equivalent summary unless local regulations or
institutional policies require a longer retention period. No records may be
destroyed during the retention period without the written approval of the
sponsor. No records may be transferred to another location or party without
written notification to the sponsor.
 
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10.1.7. 
Source Documents 

Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected. Source documents are filed at the
investigator‟s site.

Data reported on the CRF or entered in the eCRF that are transcribed from
source documents must be consistent with the source documents or the
discrepancies must be explained. The investigator may need to request previous
medical records or transfer records, depending on the study. Also, current
medical records must be available.
10.1.8. 
Study and Site Start and Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 

Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 

The results of this study may be published or presented at scientific meetings. If
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to
the sponsor before submission. This allows the sponsor to protect proprietary
information and to provide comments.

The sponsor will comply with the requirements for publication of study results.
In accordance with standard editorial and ethical practice, the sponsor will
generally support publication of multicenter studies only in their entirety and not
as individual site data. In this case, a coordinating investigator will be
designated by mutual agreement.
 
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
Authorship will be determined by mutual agreement and in line with
International Committee of Medical Journal Editors authorship requirements.
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 

The tests detailed in Table 1 will be performed by the local laboratory of CRO.

Protocol-specific requirements for inclusion or exclusion of participants are
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined
necessary by the investigator or required by local regulations.

Pregnancy Testing Refer to Section 5.1 Inclusion Criteria for screening
pregnancy criteria.

Pregnancy testing serum (Serum (β) Beta- hCG) should be conducted before
check-in for each study period during treatment

Pregnancy testing serum should be conducted at the end of relevant systemic
exposure.

Additional serum pregnancy tests may be performed, as determined necessary
by the investigator or required by local regulation, to establish the absence of
pregnancy at any time during the participant's participation in the study.
Table 1 
Protocol-Required Safety Laboratory Assessments 
Test Description 
Reference range 
Clinically 
Acceptable 
Limit 
HEMATOLOGY 
Haemoglobin 
12.5 - 18.0 g/dL - Male 
11.5 – 16.0 g/dL - Female# 
12.3 – 18.0  g/dL – Male 
11.0 – 16.0 g/dL – Female# 
Erythrocyte Count 
4.5 - 5.9 million/cmm - Male 
4.0 - 5.1 million/cmm - 
Female# 
4.0 – 7.1 million/cmm - 
Male 
3.6 - 5.6 million/cmm - 
Female# 
PCV (Packed Cell Volume) 
41.5 - 50.4% - Male 
35.9 - 44.6% - Female# 
To 
be 
correlated 
with 
hemoglobin value 
MCV (Mean Corpuscular Volume) 
80 - 96 μm3 
MCH (Mean Corpuscular Haemoglobin) 
27.5 - 33.2 pg 
MCHC (Mean Corpuscular Haemoglobin-
Concentration) 
33.4 - 35.5g/dL 
WBC Count 
4400 - 11000 /cmm 
3960-12100 /cmm 
 
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(Contd…) 
Test Description 
Reference range 
Clinically 
Acceptable 
Limit 
Differential Count 
Neutrophils 
40 - 80 % 
36 - 88  % 
Eosinophils 
0 - 7 % 
upto 14 % 
Test Description 
Reference range 
Clinically 
Acceptable 
Limit 
Basophils 
0 - 2 % 
0 - 2 % 
Lymphocytes 
20 - 40 % 
18 - 44 % 
Monocytes 
2 - 10 % 
2 - 10 % 
Platelet Count 
150 - 450 x 1000/cmm 
135 - 495 x 1000/cmm 
BIOCHEMISTRY 
Blood urea 
Upto 50 mg/dL 
Upto 55 mg/dL 
Blood Glucose (Random) 
70 to 130 mg/dL 
63 to 140 mg/dL 
Blood Urea Nitrogen 
Upto 23.3 mg/dL 
Upto 25.0 mg/dL 
Serum Creatinine 
0.7 - 1.2 mg/dL - Male 
0.5 - 0.9 mg/dL - Female# 
0.6 - 1.3 mg/dL - Male 
0.4 - 1.0 mg/dL - Female# 
Serum Bilirubin – Total 
0.0 to 1.0 mg/dL 
0.0 - 1.47 mg/dL 
Serum Bilirubin – Direct 
0.0 to 0.2 mg/dL 
0.0 -  0.3 mg/dL 
Serum Bilirubin – Indirect 
0.1 to 1.0 mg/dL 
0.0 – 1.5 mg/dL 
SGOT (ASAT) 
Upto 38 U/L - Male 
Upto 32 U/L - Female# 
Upto 70 U/L - Male 
Upto 50 U/L - Female# 
SGPT (ALAT/ALT) 
Upto 41 U/L - Male 
Upto 31 U/L - Female# 
Upto 72 U/L - Male 
Upto 50 U/L - Female# 
S.Alkaline Phosphatase
40 to 129 U/L - Male 
35 to 104 U/L - Female# 
36 to 141 U/L - Male 
35 to 120 U/L - Female# 
 
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(Contd…) 
Infectious Disease Screening 
HIV-1 & HIV-2 Antibodies 
Reactive / Non-Reactive 
Non-Reactive 
Hepatitis B 
Reactive / Non-Reactive 
Non-Reactive 
HCV Antibodies 
Reactive / Non-Reactive 
Non-Reactive 
Test Description 
Reference range 
Clinically Acceptable Limit 
Serum (β) Beta- hCG Test # 
Serum (β) Beta- hCG (Human Chorionic 
Gonadotropin) level (For Female) 
Positive / Negative 
Negative 
Urinalysis 
Physical Examination: 
Colour 
--- 
--- 
Reaction (pH) 
5.0 to 9.0 
--- 
Specific gravity 
1.000 to 1.030 
--- 
Transparency 
--- 
--- 
Volume 
--- 
--- 
Chemical Examination: 
Protein 
Negative 
Trace (+) 
Glucose 
Negative 
Trace (+) 
Ketone bodies 
Negative 
Trace (+) 
Occult blood 
Negative 
Trace (+) 
Urobilinogen 
0.2 to 1.0 Ehrlich unit/dL 
0.2 to 1.0 Ehrlich unit/dL 
Bilirubin (Bile salt / bile pigment) 
Negative 
Trace (+) 
Test Description 
Reference range 
Clinically 
Acceptable 
Limit 
 
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(Contd…) 
Microscopic Examination 
Leucocytes 
0-10 /hpf
0-10 /hpf
Red Blood Cells 
0-10 /hpf
0-10 /hpf
Epithelial Cells 
0-10 /hpf
0-10 /hpf
Casts 
Absent 
(+) 
Crystals 
Absent 
(+) 
Bacteria 
Absent 
Absent 
Urine Examination For Drug of Abuse 
Test Description 
Reference range 
Benzodiazepines 
Negative = Below 300 ng/mL 
Marijuana 
Negative = Below 50 ng/mL 
Barbiturates 
Negative = Below 300 ng/mL 
Cocaine 
Negative = Below 300 ng/mL 
Morphine 
Negative = Below 300 ng/mL 
Amphetamine 
Negative = Below 1000 ng/mL 
*Urine 
microscopy 
will 
be 
done 
only 
if 
dipstick 
found 
positive 
for
protein/leukocytes/blood. 
# If applicable. 
Note: 
1. If laboratory values are within normal range, it will be classified as Normal (N).
2. If laboratory values are outside normal range, but within acceptable range, it will
be classified as Not Clinically Significant (NCS).
Test Description 
Reference range 
Clinically 
Acceptable 
Limit 
 
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3. If any parameter is outside acceptable range without any associated clinical
sign/symptom(s), it will be considered as Not Clinically Significant (NCS) at the
discretion of medical personnel.
4. If any parameter is outside acceptable range and associated with clinical
sign/symptom(s), it will be considered as Clinically Significant (CS) and will be
documented as an AE accordingly.
5. If a value reflects or is indicative of any organ dysfunction (through a marked
abnormal laboratory parameter), it will be considered as Clinically Significant
(CS) and will be documented as an AE even in the absence of subject‟s clinical
sign/symptom(s) and will be documented accordingly.
6. Reference may change as per manufacturer‟s kit reference. 18
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 

An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of a study treatment, whether or not considered related to the
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)
or other safety assessments (e.g., ECG, radiological scans, vital signs
measurements), including those that worsen from baseline, considered clinically
significant in the medical and scientific judgment of the investigator (i.e., not related
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
treatment or a concomitant medication. Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant‟s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the
participant‟s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that
leads to the procedure is the AE.
 
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
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present
or detected at the start of the study that do not worsen.
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 

In general, hospitalization signifies that the participant has been detained (usually
involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the
physician‟s office or outpatient setting. Complications that occur during
hospitalization are AE. If a complication prolongs hospitalization or fulfills any
other serious criteria, the event is serious. When in doubt as to whether
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not
worsen from baseline is not considered an AE.
Results in persistent or significant disability/incapacity 

The term disability means a substantial disruption of a person‟s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect 
Other situations: 

Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that may
 
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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical treatment to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 

Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency
or drug abuse.
10.3.3. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 

When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports)
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant‟s
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are
requested by GSK. In this case, all participant identifiers, with the exception of the
participant number, will be redacted on the copies of the medical records before
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  

Mild: An event that is easily tolerated by the participant, causing minimal discomfort
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as
severe should not be confused with an SAE. Severe is a category utilized for rating
the intensity of an event; and both AE and SAE can be assessed as severe.

An event is defined as „serious‟ when it meets at least 1 of the predefined outcomes
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Other measures to evaluate AE and SAE may be utilized (e.g. National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). 
Assessment of Causality 

The investigator is obligated to assess the relationship between study treatment and
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other
risk factors, as well as the temporal relationship of the event to study treatment
administration will be considered and investigated.

The investigator will also consult the Investigator‟s Brochure (IB) and/or Product
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has
minimal information to include in the initial report to GSK. However, it is very
important that the investigator always make an assessment of causality for
every event before the initial transmission of the SAE data completed in the SAE
Sections of the paper CRF (for entry in the GSK Argus Safety database) and the
Table 5 format to GSK (for submission to the HA) within 24 hours of occurrence of
the event. The investigator may change his/her opinion of causality in light of
follow-up information and send an SAE follow-up report (completed in the SAE
sections of the paper CRF and the Table 5 format) with the updated causality
assessment to GSK within 24 hours of awareness of the new information.

The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
Follow-up of AE and SAE 

The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by GSK to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may
include additional laboratory tests or investigations, histopathological examinations,
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem
findings including histopathology, within 24 hours of awareness of this information.

New or updated information will be recorded in the originally completed CRF.
 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel‟s: review of the 
participant‟s medical records, medical examination, or medical history interview. 
2.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an
alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal
range may be used to confirm a postmenopausal state in women not
using hormonal contraception or hormonal replacement therapy (HRT).
However, in the absence of 12 months of amenorrhea, confirmation with
more than one FSH measurement (>40 mIU/mL) is required.

Females on HRT and whose menopausal status is in doubt will be required to
use one of the non-estrogen hormonal highly effective contraception methods
if they wish to continue their HRT during the study. Otherwise, they must
discontinue HRT to allow confirmation of postmenopausal status before
study enrolment.
10.4.2. 
Contraception Guidance: 
 
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
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year
when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner additionally following contraceptive barrier methods such as condoms
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when
used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit
ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction) 
10.4.3. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 

Investigator will attempt to collect pregnancy information on any male participant‟s
female partner of a male study participant who becomes pregnant while participating
in this study. This applies only to male participants who receive Griseofulvin
Tablets.

After obtaining the necessary signed informed consent from the pregnant female
partner directly, the investigator will record pregnancy information on the
appropriate form and submit it to GSK within 24 hours of learning of the partner‟s
pregnancy.

The female partner will also be followed to determine the outcome of the pregnancy.
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal
status (presence or absence of anomalies) or indication for procedure.
Female Participants who become pregnant 

Investigator will collect pregnancy information on any female participant, who
becomes pregnant while participating in this study.

The initial information will be recorded on the appropriate form and submitted to
GSK within 24 hours of learning of a participant's pregnancy.
 
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
Participant will be followed to determine the outcome of the pregnancy. The
investigator will collect follow up information on participant and neonate, which will
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8
weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy for medical reasons will be
reported as an AE or SAE.

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will
be reported as such.

Any SAE occurring as a result of a post-study pregnancy which is considered
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 3. While the investigator is not obligated to actively seek
this information in former study participants, he or she may learn of an SAE through
spontaneous reporting.
Any female participant who becomes pregnant while participating  

will be withdrawn from the study
 
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10.5. 
Appendix 5: Country-specific requirements 
This study will be conducted in compliance with the protocol approved by the Ethical 
Committee (EC) and according to the current version of the Declaration of Helsinki, the 
current ICH GCP, New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E) and CDSCO 
Bioequivalence study guidelines as well National Laws and Regulations, all relevant SOPs 
required for the conduct of this study. 
 
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10.6. 
Appendix 6: Abbreviations and Trademarks 
Abbreviations 
AE(s) 
Adverse Event(s)   
ANOVA 
Analysis of Variance 
ALAT 
Alanine (Amino)Transaminase 
ALT 
Alanine aminotransferase 
ARL 
Accutest Research Laboratories (I) Pvt. Ltd.  
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 
BE 
Bioequivalence 
β-hCG 
Serum Beta Human Chorionic Gonadotropin level  
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
CDSCO 
 Central Drugs Standard Control Organisation 
Cmax 
Maximum Observed Drug Concentration In Plasma 
cmm 
Cubic Millimeter 
CONSORT 
Consolidated Standards of Reporting Trials  
CSR 
Clinical Study Report 
CRF 
Case Report Form  
DCGI 
Drug Controller General of India 
dL 
Deciliter 
ECG 
Electrocardiogram  
EC 
Ethics Committee 
EMEA 
European Medicines Agency 
FSH 
Follicle stimulating hormone 
g 
Grams 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline  
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immuno Deficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
hpf 
High power field 
hrs 
Hours 
HRT 
Hormonal Replacement Therapy 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
Kel 
Elimination Rate Constant 
kg 
Kilogram(s) 
L 
Liter 
LC-MS/MS 
Liquid Chromatography-Mass Spectrometer/Mass Spectrometer 
mg 
Milligram 
mIU 
Milli-International Units 
 
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mL 
Milliliter 
µm 
Micrometer 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MS 
Missing Sample 
MSDS 
Material Safety Data Sheet 
MSV 
Missing Sample Values 
Na-Heparin 
Sodium- Heparin 
no. 
Number 
NRV 
Not-reportable Value 
OTC 
Over The Counter 
PCV 
Packed Cell Volume 
pg 
Picogram 
PK 
Pharmacokinetic 
QTc 
Corrected QT interval  
SAE(s) 
Serious Adverse Event(s) 
SAS 
Statistical Analysis System 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SLE 
Systemic lupus erythematosus 
SOA 
Schedule of Activities  
SOP(s) 
Standard Operating Procedure(s) 
SRM 
Study Reference Manual  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2 
Terminal Half-Life 
Tmax 
Time To Observe Maximum Drug Concentration In Plasma 
ULN 
Upper limit of normal 
U/L 
Units per liter 
USFDA 
United States Food and Drug Administration 
vs. 
Versus 
WBC 
White Blood Cell  
WOCBP 
Woman of Childbearing Potential 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
SAS 
 
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11.
REFERENCES
1. Generating randomization schedule using SAS® Programming, Chunqin Deng and
Julia Graz. PPD, Inc, Research Triangle Park, North Carolina, available on
Website: - http://www2.sas.com/proceedings/sugi27/p267-27.pdf.
2. ICH HARMONISED GUIDELINE, INTEGRATED ADDENDUM TO ICH
E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2) 9 November
2016
3. Ministry of Health and Family Welfare (Department of Health), Notification,
New Delhi, the 30th January, 2013.
4. New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E)
5. National Ethical Guidelines For Biomedical And Health Research Involving
Human Participants, Indian Council Of Medical Research 2017
6. Summary of Product Characteristics Griseofulvin 500mg Tablets DATE OF
FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28th June
2005
7. Product Information GRISOVIN Aspen Pharma Pty Ltd, 34-36 Chandos Street,
St. Leonards NSW 2065, Australia, Date of most recent amendment: 20 January
2015
8. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con08818
9.pdf
9. Rajagopalan et al. Expert Consensus on The Management of Dermatophytosis in
India (ECTODERM India) BMC Dermatology (2018) 18:6
10. Rengasamy M, Chellam J, Ganapati S. Systemic therapy of dermatophytosis:
Practical and systematic approach. Clin Dermatol Rev 2017;1:S19-23
11. Grisovin 
FP 
prescribing 
information.
Available 
at:http://india-
pharma.gsk.com/en-in/products/prescribing-information/
12. GRISEOFULVIN. 
Available 
at:
https://monographs.iarc.fr/wp-
content/uploads/2018/06/mono79-12.pdf. Accessed on 30th June 2018
13. Toh MR, et al. Association between number of doses per day, number
ofmedications andpatient's non-compliance, and frequency of readmissions in a
multi-ethnicAsian population. Preventive Medicine Reports 1 (2014) 43–47
 
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14. Guidelines on the investigation of bioequivalence. Committee for Medicinal
Products for Human Use. (CHMP). European Medicines Agency, Doc ref:
CPMP/QWP/EWP/1401/98 Rev. 1, Rev.20, Jan 2010.
15. Public assessment report of Griseofilvon 500mg Tablets; UK/H/1773/001/DC;
UK licence no: PL 20117/0109; Morningside healthcare Limited.
16. WHO Technical Report Series, No. 937, 2006; Annex 8 Proposal to waive in vivo
bioequivalence requirements for WHO Model List of Essential Medicines
immediate-release, solid oral dosage forms
17. IARC MONOGRAPHS VOLUME 79, GRISEOFULVIN, 291-315.
18. Clinical Laboratory References:
a.
Todd. Sanford. Davidson. Clinical Diagnosis and Management by Laboratory
Methods, 20th Edition. W.B. Saunders Company, Philadelphia, U.S.A.
b. Dacie & Lewis Practical Haematology, S. Mitchell Lewis, Barbara J. Bain,
Imelda Bates, Churchill Livingstone, 9th Edition, 2001, U.K.
c.
Textbook of Medical Laboratory Technology, Praful B. Godkar, Darshan P.
Godkar, 2nd edition, 2003.
d. According to manufacturer‟s kit reference.
e.
Internal Laboratory Reference.
f.
Health Status of Indian Population - Current Scenario JAPI • VOL. 52 • MAY
2004.
 
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SAP_000.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
212504 
1
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for an open label, randomized, 
balanced, three treatment, three period, three sequence, single 
dose, crossover study to evaluate thebioequivalence of test 
Griseofulvin tablets, 500 mg versus reference Griseofulvin 
tablets, 500 mg as well as dose proportionality of test 
Griseofulvin tablets, 250 mg and 500 mg, in healthy, adult 
participants under fed conditions 
Compound Number  : CCI44 
Clinical 
Study 
Identifier 
: 212504 
Effective Date 
: [19-MAR-2020] 
Description: 

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report for Protocol No. 212504.

This RAP is intended to describe the safety, tolerability, and pharmacokinetic
(PK)analyses required for the study.

This RAP will be provided to the study team members to convey the content of
theStatistical Analysis Complete (SAC) deliverable.
RAP Author(s): 
Author
Date
Lead
 
SAS programmer (PBS), Accutest 
19-MAR-20
,  
Biostatistician (PBS), Accutest 
19-MAR-20
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
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RAP Team Reviews: 
RAP Team Review Confirmations 
(Method: E-mail) 
Reviewer  
Date 
 
19-MAR-20
Study Accountable Person (SAP) 
 
19-MAR-20
Regulatory Executive Senior, Clinical Pharmacology 
 
19-MAR-20
Manager- Statistics (Clinical Statistics & Clinical Programming) 
 
19-MAR-20
Senior Clinical Data Scientist (Data Management) 
 
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TABLE OF CONTENTS 
PAGE 
1.
INTRODUCTION ...................................................................................................... 5 
2.
SUMMARY OF KEY PROTOCOL INFORMATION .................. ................................5 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ........................... 5 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) ........................................ 5 
2.3. 
Study Design ................................................................................................. 6 
2.4. 
Statistical Hypotheses/ Statistical Analyses .................................................. 7 
3.
PLANNED ANALYSES ............................................................................................. 9 
3.1. 
Final Analyses ............................................................................................... 9 
4.
ANALYSIS POPULATIONS .................................................................................... 10 
4.1. 
Protocol Deviations ..................................................................................... 11 
5.
CONSIDERATIONS 
FOR 
DATA 
ANALYSESAND 
DATA 
HANDLING
CONVENTIONS ...................................................................................................... 12 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 12 
5.2. 
Other Considerations for Data Analyses and Data Handling Conventions . 13 
6.
STUDY POPULATIONANALYSES ........................................................................ .14 
6.1. 
Overview of Planned Study Population Analyses ...................................... .14 
6..2   Subjects's Disposition...................................................................................14 
6.3    Protocol Deviations.....................................................................................14 
6.4. Demographic and Baseline Characteristics................................................. 14 
6.4.1    Demographic Characteristics 
6.4.2    Substance Use............................................................................14 
6.4.3    Medical Conditions.......................................................................15 
6.5.     Concomitant Medications.........................................................................15 
7. 
SAFETY ANALYSIS ............................................................................................... 16 
7.1. 
Clinical Laboratory Analyses ....................................................................... 16 
7.2. 
Other Safety Analyses ................................................................................. 16 
8. 
PHARMACOKINETIC ANALYSIS .......................................................................... 17 
8.1. 
Primary Pharmacokinetic Analyses ............................................................. 17 
8.1.1. 
Endpoint / Variables ..................................................................... 17 
8.1.1.1. 
Drug Concentration Measures ................................... 17 
8.1.1.2. 
Derived Pharmacokinetic Parameters ........................ 17 
8.1.2. 
Summary Measure ....................................................................... 17 
8.1.3. 
Population of Interest ................................................................... 18 
8.1.4. 
Statistical Analyses / Methods ..................................................... 18 
8.1.4.1. 
Statistical Methodology Specification ......................... 18 
9.
REFERENCES ....................................................................................................... 20 
10. APPENDICES ......................................................................................................... 21 
10.1. 
Appendix 1: Schedule of Activities .............................................................. 22 
10.1.1. 
Protocol Defined Schedule of Events .......................................... 22 
10.2. 
Appendix 2: Study Phases and Treatment EmergentAdverse...................29 
 
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10.2.1. 
Study Phases for Treatment Emergent Adverse Events and 
Concomitant Medication ............................................................... 29 
10.3. 
Appendix 3: Data Display Standards& Handling Conventions ....................30 
10.3.1. 
Reporting Process ........................................................................ 30 
10.3.2. 
Reporting Standards ..................................................................... 30 
10.3.3. 
Reporting Standards for Pharmacokinetic .................................... 30 
10.4. 
Appendix 4: Derived and Transformed Data................................................32 
10.4.1. 
Pharmacokinetic ........................................................................... 32 
10.5. 
Appendix 5: Reporting Standards for Missing Data..................................... 33 
10.5.1. 
Premature Withdrawals ................................................................. 33 
10.5.2. 
Handling of Missing Data .............................................................. 33 
10.5.2.1.  Handling of Missing and Partial Dates ........................ 33 
10.6. 
Appendix 6: Values of Potential Clinical Importance....................................35 
10.6.1. 
Laboratory Values ......................................................................... 35 
10.6.2. 
ECG .............................................................................................. 36 
10.6.3. 
Vital Signs ..................................................................................... 35 
10.7. 
Appendix 7: Abbreviations & Trade Marks...................................................36 
10.7.1. 
Abbreviations ................................................................................ 36 
10.7.2. 
Trademarks ................................................................................... 37 
10.8. 
Appendix 8: List of Data Displays.................................................................39 
10.8.1. 
Study PopulationTables ................................................................ 38 
10.8.2. 
Pharmacokinetic Tables ................................................................ 39 
10.8.3. 
Pharmacokinetic Figures .............................................................. 40 
10.8.4. 
ICH & Non- ICH Listings ............................................................... 43 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2019N413557_00 
07-Oct-2019
Original 
All decisions regarding final analysis, as defined in this RAP document, have been made 
prior to Database Freeze (DBF) of the study data. 
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis specified 
in the protocol [(Dated: 11-DEC-2019)]. 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Endpoints 
Primary 
Primary 

To determine whether the Test Product
(T1):GriseofulvinTablets, 
500 
mg 
is
bioequivalent 
to 
Reference 
Product
(R):GriseofulvinTablets, 
500 
mg 
(Grisovin) in healthy participants.

To evaluate the dose proportionality across
the dose range of 250 mg to 500 mg after
single dose administration of Test Product
(T2):GriseofulvinTablets, 250 mg and Test
Product (T1):GriseofulvinTablets, 500 mg
in healthy participants.

Cmax, AUC0-t and AUC0-inf for
griseofulvin

AUC0-tand Cmax
Secondary 
Secondary  

To monitor the safety and tolerability of a
single oral dose of Test Product (T1):
Griseofulvin Tablets, 500 mg; Test Product
(T2): 
Griseofulvin
Tablets,
250 mgandReference
Product
(R):Griseofulvin 
Tablets, 
500 
mg 
(Grisovin). 

Safety and tolerability as measured
by adverse events, vital signs and
clinical laboratory measurements
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
T1 = GriseofulvinTablets, 500 mg Test Product 
T2 = GriseofulvinTablets, 250 mg Test Product 
R = GriseofulvinTablets, 500 mg (Grisovin) Reference 
DesignFeatures 

This is an open label, randomized, balanced, three treatment, three
period, three sequence, single dose, crossover study to evaluate
thebioequivalence of test Griseofulvin tablets, 500 mg versus
reference Griseofulvin tablets, 500 mg as well as dose
proportionality of test Griseofulvin tablets, 250 mg and 500 mg, in
healthy, adult participants under fed conditions. This study includes
a screening period (within 21 days prior to dosing of period-I) and
three open-label treatment periods. Participants will be followed up 5
days after last dosing.

Each participant will receive all 3 treatments according to their
assignment to one of 3 treatment sequences (T1T2R, T2RT1 or
RT1T2).
Dosing 

In each period, single oral dose [Test Product (T1): 1 x 500 mg
Tablet or Test Product (T2): 1 x 250 mg Tablet or Reference Product
(R): 1 x 500 mg Tablet] of the study treatments will be administered
to the participants as per randomization with 240 ± 2 mL of water at
ambient temperature under fed condition.
Time & Events 

[Refer to Appendix 1: Schedule of Activities]
Treatment 
Assignment 

The whole study will be divided into three periods. For each period,
eligible participants will be randomized to either T1T2R, T2RT1 or
RT1T2 treatment sequence according to 1:1:1 ratio.
 
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Overview of Study Design and Key Features 
Interim 
Analysis 

No interim analysis is planned.
2.4. 
Statistical Hypotheses/ Statistical Analyses 
Null Hypothesis Testing 
For BE Demonstration (T1 vs. R) 
Null hypothesis H0 and alternative hypothesis H1 can be written in multiplicative form: 
H0: mtest 1 / mref< L or mtest 1 / mref> U 
H1: L ≤ mtest 1 / mref ≤ U 
Where L (Lower Limit) = 80.00% and U (Upper Limit) = 125.00%, 
mtest 1= geometric least-squares means for test product (Griseofulvin 500mg tablets) 
mref= geometric least-squares means for reference product (Griseofulvin tablets, 500 mg 
(Grisovin)) 
The type I error will be set to α = 0.05 and therefore 90% (two-tails) confidence intervals 
will be provided together with indication whether the null hypothesis of non-equivalence 
for appropriate parameter can be rejected. 
For dose proportionality (T2 vs. T1) 
Null hypothesis H0 and alternative hypothesis H1 can be written in multiplicative form: 
H0: mtest 2 / mtest 1< L or mtest 2 / mtest 1> U 
H1: L ≤ mtest 2 / mtest 1 ≤ U 
Where L=80.00% and U=125.00%, 
mtest 1= geometric least-squares means for test product (Griseofulvin 500 mg tablets) 
mtest 2= geometric least-squares means for reference product (Griseofulvin 250 mg tablets) 
The type I error will be set to α = 0.05 and therefore 90% (two-tails) confidence intervals 
will be provided together with indication whether the null hypothesis of non-equivalence 
for appropriate parameter can be rejected. 
Step 1: For BE Demonstration (T1 vs. R): 
PROC MIXED procedure will be used for analysis of variance and the estimation of least 
square mean differences (Test (T1) - Reference (R)) of the test (T1) and reference 
formulations on the log-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-
inf.The corresponding standard errors of the differences will also be computed. Based on 
these parameters, the 90% confidence intervals will be constructed for the least square 
mean differences of log-transformed parameters Cmax, AUC0-t and AUC0-inf. The antilog (or 
exponential) of the limits obtained from the log-transformed data will give the 90% 
confidence interval for the ratio of geometric means of test (T1) and reference (R) 
products. 
 
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If the 90% confidence interval of geometric mean ratio of Cmax, AUC0-t and AUC0-inf 
between test (T1) and reference (R) products falls within the range of 80.00% to 125.00% 
for Griseofulvin, the null hypothesis will be rejected. In this case the test product (T1) will 
be concluded as bioequivalent to the reference product R. 
If bioequivalence is demonstrated between the Test product (T1) and reference product 
(R), the following step II will be followed.  
Step 2: For dose proportionality (T2 vs. T1): 
Dose normalization will be done for test product T2 for AUC0-tand Cmax parameter by 
multiplying with the correction factor 2. 
PROC MIXED procedure will be used for analysis of variance and the estimation of least 
square mean differences (Test (T2) - Test (T1)) of the test (T2) and test (T1) products on 
the log-transformed pharmacokinetic parameter AUC0-t and Cmax.The corresponding 
standard errors of the differences will also be computed. Based on these parameters, the 
90% confidence intervals will be constructed for the least square mean differences of log-
transformed parameter AUC0-t and Cmax. The antilog (or exponential) of the limits obtained 
from the log-transformed data will give the 90% confidence interval for the ratio of 
geometric means of test (T2) and test (T1) products. 
Null hypothesis will be rejected if the 90% confidence interval of geometric mean ratio of 
AUC0-t and Cmax between test (T2) and test (T1) products falls within the range of 80.00% 
to 125.00% for Griseofulvin. 
 
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3.
PLANNED ANALYSES
3.1. 
Final Analyses
The final planned primary analyses will be performed after the completion of the following 
sequential steps: 
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database
release (DBR) and database freeze (DBF) (both the CRF data and PK data) has been
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4.
ANALYSIS POPULATIONS
Population 
Definition / Criteria 
Analyses Evaluated 
Enrolled 
All participants who signed the 
ICF  
Screen Failure 
Randomized 
All participants assigned to study 
treatment. 
Study Population 
BE Analysis Set 
The data of subjects, completing 
at least 2 periods with 500mg test 
and 500mg reference treatments 
of the study will be subjected to 
statistical analysis. 
PK 
Safety 
Analysis 
Set 
The safety population will include 
all randomized participants who 
receive at least one dose of study 
medication. The safety population 
will be used for all analyses of 
safety 
data. 
Individual 
pharmacokinetic parameters and 
its descriptive statistics will be 
presented 
Study completion 
Dose 
Proportionality 
Analysis Set 
The data of subjects completing at 
least 2 periods with 500mg test 
and 250mg test treatments will be 
subjected 
 
to 
dose 
proportionality analysis 
PK 
 
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4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be summarised 
and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
and will be documented in the Deviation form. 
o Data will be reviewed prior to freezing the database to ensure all important
deviations are captured and categorised on the protocol deviations dataset.
o This dataset will be the basis for the summaries and listings of protocol deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion page 
of the CRF. 
 
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5.
CONSIDERATIONS FOR DATA ANALYSESAND DATA
HANDLING CONVENTIONS
5.1. 
Study Treatment & Sub-group Display Descriptors
Treatment Code 
T1 
 T2
R
Treatment Name 
Griseofulvin Tablets, 
500 mg 
GriseofulvinTablets, 
250 mg 
GriseofulvinTablets, 
500 mg (Grisovin 
Aspen Pharma Pty 
Ltd, Australia) 
Type  
Test Drug 
Test Drug 
Reference Drug 
Dose Formulation 
tablet
tablet
tablet
Unit
Dose 
Strength(s) 
500 mg 
250 mg 
500 mg 
Dosage Level(s) 
1 tablet 
1 tablet 
1 tablet 
Route
of 
Administration 
oral
oral
oral
Use 
experimental
experimental
 active-comparator
IMP and NIMP 
IMP
IMP
IMP
Sourcing 
Provided 
by 
the 
Sponsor  
Provided 
by 
the 
Sponsor 
Provided 
by 
the 
Sponsor 
Packaging 
and 
Labeling 
Study treatment will 
be 
provided 
in 
container. 
Each 
container 
will 
be 
labeled as required 
per
country 
requirement. 
Study treatment will 
be 
provided 
in 
container. 
Each 
container will be 
labeled as required 
per
country 
requirement. 
Study treatment will 
be 
provided 
in 
container. 
Each 
container will be 
labeled as required 
per 
country
requirement. 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1.
For BE Demonstration (T1 vs. R )
2.
For dose proportionality (T2 vs. T1)
 
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5.2. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
10.1 
Appendix1: Schedule of Activities 
10.2 
Appendix 2: Study Phases and Treatment Emergent Adverse Events 
10.3 
Appendix 3: Data Display Standards & Handling Conventions 
10.4 
Appendix 4: Derived and Transformed Data 
10.5 
Appendix 5: Reporting Standards for Missing Data 
10.6 
Appendix 6: Values of Potential Clinical Importance 
10.7 
Appendix 7: Abbreviations & Trade Marks 
10.8 
Appendix 8 :List of Data Display 
 
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6.
STUDY POPULATIONANALYSES
6.1. Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” population. Screen failures will be 
listed based on the “All participants” population.  
Study population analyses including analyses of subject’s disposition, protocol deviations, 
demographic and baseline characteristics and prior and concomitant medications will be based 
on GSK Core Data Standards. Details of planned study population data displays will be 
presented in Appendix 7: List of Data Displays of Full RAP.  
6.2. Subject’s Disposition 
The number and percentage of subjects who completed the study as well as subjects who 
withdrew prematurely from the study will be summarized by completion status and reason for 
withdrawal. A listing of the subjects who withdrew from the study prematurely will be 
provided.  
The number of subjects included in the safety population, and those included in the PK 
population will be summarized. Subjects who are excluded from the safety population and 
those who are excluded from PK population will be listed with the corresponding reason.  
Subject’s disposition summary will be displayed by “Total”.  
6.3. Protocol Deviations 
A listing of the inclusion/exclusion criteria deviation record for all subjects with deviations will 
be provided. Other deviations will be noted as applicable, including use of prohibited 
concomitant medications during the study, incorrect study drug administration, and any other 
deviations deemed to have the potential for notably influencing the study results. A summary 
of important protocol deviations and by-subject listing of important protocol deviations will be 
provided.  
The summary will be displayed by “Total”.  
6.4. Demographic and Baseline Characteristics 
6.4.1. Demographic characteristics  
Demographic characteristics listed below will be summarized either with descriptive statistics 
for continuous variables or with frequencies and percentages for categorical variables. A by-
subject listing of these characteristics will be provided.  

Continuous variables: Age, Height, Weight, and Body mass index (BMI)

Categorical Variables: Sex, Ethnicity and Geographic Ancestry
The summary will be displayed by “Total” for demographic characteristics. 
6.4.2. Substance Use 
Substance use, including smoking, alcohol consumption and drug abuse, will be summarized 
and listed.  
The summary will be displayed by “Total”.  
 
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6.4.3. Medical Conditions 
The reported adverse event or serious adverse event will be recorded in CRF. A collective data 
of incidence of adverse events will be provided in the clinical study report.  
6.5. Concomitant Medications 
The details of concomitant medication prescribed and used will be referred from CRF. The list 
of concomitant medication/ drugs will be provided in the clinical study report.  
 
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7.
SAFETY ANALYSES
The safety analyses will be based on the safety population, unless otherwise specified. 
Descriptive statistics will be used to assess safety and tolerability objectives. No formal 
tatistical analyses of safety data are planned. Data will be summarized and listed according 
to Accutest Data Standards and statistical principles. 
7.1. 
Adverse Events Analyses 
Adverse events analysesincluding the analysis of adverse events (AEs), Serious adverse 
events (SAEs) and other significant AEs will be based on Accutest Data Standards. 
7.2. 
Clinical Laboratory Analyses 
 The analysis of laboratory safety test results will be based on GSK Core Data Standards, 
unless otherwise specified. The details of these are presented in Appendix 1: Schedule of 
Activities.
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
ased onGSKCoreDataStandards, unless otherwise specified. The details of the planned 
displays are presented inAppendix: List of Data Displays. 
 
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8.
PHARMACOKINETIC ANALYSES
8.1. 
Primary Pharmacokinetic Analyses
8.1.1. 
Endpoint / Variables
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix : Data Display Standards & Handling Conventions (Section 10.3.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of SAS 
version 9.4.All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from concentration-
time data, as data permits. 
Parameter 
Parameter Description 
Cmax 
Maximum observed drug concentration during the study. 
AUC0-t 
Area under the plasma concentration - time curve measured to the last 
quantifiable concentration, using the linear trapezoidal rule. 
AUC0-inf
AUC0-t plus additional area extrapolated to infinity, calculated using the formula 
AUC0-t + Ct/Kel, where Ct is the last measurable drug concentration and Kelis the 
elimination rate constant. 
Tmax 
Time to observe maximum drug concentration. If the maximum value occurs at 
more than 1 time point, Tmax is defined as the first time point with this value. 
AUC0-t /AUC0-inf Ratio of AUC0-t and AUC0-inf 
Residual area 
Extrapolated area (AUC0-inf - AUC0-t)/ AUC0-inf 
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 square regression. 
t1/2 
Terminal half-life as determined by quotient 0.693/Kel 
Vd 
Fluid volume that would require to contain the whole drug in the body at the 
same conc. found in the plasma is given by formula, Dose / (Kel x AUC0-inf) 
CL 
Clearance of a given individual in the measure of his body capacity to eliminate 
a drug and is given by formula Dose / AUC0-inf 
NOTES: 

Additional parameters may be included as required.

The pharmacokinetic parameters will not be calculated in case of inconclusive concentration time profile (e.g. lack
of sufficient measurable concentrations).

No value of Kel, Residual area, AUC0-t/AUC0-inf, AUC0-inf,Vd, CL and t1/2 will be reported for cases that do not
exhibit a terminal log-linear phase in the concentration versus time profile
8.1.2. 
Summary Measure 
Parameters Cmax, AUC0-t and AUC0-inf will be applicable for BE demonstration and 
Parameters Cmax, and AUC0-tfor dose proportionality. These parameters will be calculated 
for each participant-formulation combination using the non-compartmental model by using 
statistical package SAS® 9.4 
 
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8.1.3. 
Population of Interest 
The primary pharmacokinetic analyses will be based on theBE Analysis Setpopulation, 
unless otherwise specified. 
8.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix: List of Data Displaysand will be 
based on AccutestData Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
8.1.4.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient data 
is available (i.e. if participants have well defined plasma profiles). 
Endpoint / Variables 
Primary end points for BE Demonstration (T1 vs. R): Cmax, AUC0-t and AUC0-inf 
Primary end points for dose proportionality (T2 vs. T1) :Cmax, AUC0-t 
Model Specification 
ANOVA will be performed on Log-transformed Cmax, AUC0-t and AUC0-inf  using 
Proc Mixed Model. 
Model LCmax or LAUC0-t or LAUC0-inf = sequence period treatment (fixed factors) and 
random: Participant (Sequence) (random factor)] 
Model Checking & Diagnostics 
A separate ANOVA model will be used to analyze each of the parameters. All main effects 
will be tested against the residual error (mean square error) from the ANOVA model as the 
error term. Each analysis of variance will also include calculation of least-square means, 
adjusted differences between formulation means and the standard error associated with 
these differences. 
•
For the Proc Mixed Model, model assumptions will be checked, and appropriate
adjustments may be applied based on the data.
•
Distributional assumptions underlying the model used for analysis will be examined by
obtaining a normal probability plot of the residuals and a plot of the residuals versus
the fitted values (i.e. checking the normality assumption and constant variance
assumption of the model respectively) to gain confidence that the model assumptions
are reasonable.
•
Non-parametric analyses will be conducted on un-transformed parameter Tmax.
Model Results Presentation 
Bioequivalence will be concluded if: 
The 90% confidence interval of geometric mean ratio of log-transformed Cmax, AUC0-t and 
AUC0-inf between test (T1) and reference (R) products fall within the range of 80.00% to 
 
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125.00% for Griseofulvin. 
Dose proportionality will be concluded if: 
The 90% confidence interval of geometric mean ratio of log-transformedAUC0-t and Cmax 
between test (T2) and test (T1) products falls within the range of 80.00% to 125.00% for 
Griseofulvin. 
 
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9.
REFERENCES
1. Summary of Product Characteristics Griseofulvin 500mg Tablets DATE OF FIRST
AUTHORISATION/RENEWAL OF THE AUTHORISATION 28th June 2005
2. Product Information GRISOVIN Aspen Pharma Pty Ltd, 34-36 Chandos Street, St.
Leonards NSW 2065, Australia, Date of most recent amendment: 20 January 2015
3. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con088189.pdf
4. Rajagopalan et al. Expert Consensus on The Management of Dermatophytosis in India
(ECTODERM India) BMC Dermatology (2018) 18:6
5. Rengasamy M, Chellam J, Ganapati S. Systemic therapy of dermatophytosis: Practical
and systematic approach. ClinDermatol Rev 2017;1:S19-23
6. GRISEOFULVIN. 
Available 
at: 
https://monographs.iarc.fr/wp-
content/uploads/2018/06/mono79-12.pdf. Accessed on 30th June 2018 
7. Grisovin FP prescribing information. Available at:http://india-pharma.gsk.com/en-
in/products/prescribing-information/
8. Guidelines on the investigation of bioequivalence. Committee for Medicinal Products
for 
Human 
Use. 
(CHMP). 
European 
Medicines 
Agency, 
Doc 
ref:
CPMP/QWP/EWP/1401/98 Rev. 1, Rev.20, Jan 2010.
9. Public assessment report of Griseofilvon 500mg Tablets; UK/H/1773/001/DC; UK
licence no: PL 20117/0109; Morningside healthcare Limited.
10. WHO Technical Report Series, No. 937, 2006; Annex 8 Proposal to waive in vivo
bioequivalence requirements for WHO Model List of Essential Medicines immediate-
release, solid oral dosage forms
11. IARC MONOGRAPHS VOLUME 79, GRISEOFULVIN, 291-315.
Clinical Laboratory References:
a.
Todd. Sanford. Davidson. Clinical Diagnosis and Management by Laboratory
Methods, 20th Edition. W.B. Saunders Company, Philadelphia, U.S.A.
b. Dacie& Lewis Practical Haematology, S. Mitchell Lewis, Barbara J. Bain,
Imelda Bates, Churchill Livingstone, 9th Edition, 2001, U.K.
c.
Textbook of Medical Laboratory Technology, Praful B. Godkar, Darshan P.
Godkar, 2nd edition, 2003.
d. According to manufacturer’s kit reference.
e.
Internal Laboratory Reference.
f.
Health Status of Indian Population - Current Scenario JAPI • VOL. 52 • MAY
2004.
 
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10.
APPENDICES
 
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10.1. 
Appendix 1: Schedule of Activities 
10.1.1. 
Protocol Defined Schedule of Events 
Procedure 
Screening 
(within 
21 
days 
prior 
to 
dosing of 
period-I) 
First Period 
Washout [at 
least 7 days 
(not 
more 
than 14 days) 
between 
subsequent 
dosing] 
Day 6 
Check-in 
Day -1 
Dosing day 
Day 1 
Checkout 
day 
Day 2 
Ambulatory 
sample visit 
Day 
3 
Day 
4 
Day 
5 
Issue 
of 
Participant 
informed 
consent form 
X 
Breath Alcohol 
test a, c 
X 
X 
X 
X 
X 
Questionnaire 
about smoking 
c
X 
X 
X 
X 
Weight a 
X 
Height a 
X 
Medical 
/ 
clinical history 
a
X 
X 
Vital 
Signs 
measurement 
a,b, i
X 
X
X
X 
X 
X 
X
Physical 
examination a,b, 
i
X 
X 
X
12 Lead ECG a 
X 
Serologya 
X 
Haematologya, i 
X 
Biochemistry 
a, i
X 
 
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ALT (Alanine 
transaminase) 
test e 
X 
Urinalysis  a, i 
X 
Serum 
pregnancy test 
for female e 
X 
Urine 
examination 
for drugs of 
abuse  h 
X 
Admit 
to 
Clinical 
Research 
Center 
X
Meals d 
X
X
Study 
medication 
administration 
f
X
PK Samples g 
X 
X
X 
X 
X
Concomitant 
medication  
AE 
SAE 
 
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Procedure 
Second Period 
Washout 
[at 
least 
7 
days 
(not more than 
14 
days) 
between 
subsequent 
dosing] 
Day 13 
Check-in 
Day 7 
Dosing day 
Day 8 
Checkout 
day 
Day 9 
Ambulatory sample 
visit 
Day 
10 
Day 
11 
Day 
12 
Issue
of
Participant  
informed 
consent form 
Breath Alcohol 
test  a, c 
X 
X 
X 
X 
Questionnaire 
about 
smoking 
c
X 
X 
X 
X 
Weight a 
Height a 
Medical / clinical 
history a 
X 
Vital 
Signs 
measurement a,b, i 
X 
X 
X 
X 
X 
X 
Physical 
examination a,b, i 
X 
X 
12 Lead ECG  a 
Serology  a 
Haematology a, i 
Biochemistry  a, i 
ALT test e 
X 
Urinalysis  a, i 
Serum 
pregnancy 
test 
for female e 
X 
 
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Urine 
examination for 
drugs of abuse  h 
X 
Admit to Clinical 
Research Center 
X 
Meals d 
X 
X
Study 
medication 
administration  f 
X 
PK Samples g 
X 
X 
X 
X 
X 
Concomitant 
medication  
AE 
SAE 
 
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Procedure 
Third Period 
Post 
Study 
(Day 19) 
OR 
Early 
Discontinuation 
of Participant M
Check-in 
Day 14 
Dosing day 
Day 15 
Checkout 
day 
Day 16 
Ambulatory sample 
visit 
Day 
17 
Day 
18 
Day 
19 
Issue
of
Participant 
informed 
consent form 
Breath Alcohol 
test  a, c 
X 
X 
X 
X 
Questionnaire 
about smoking c 
X 
X 
X 
X 
Weight a 
Height  a 
Medical / clinical 
history a 
X 
Vital 
Signs 
measurement  
measurementa,b, i 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination  
measurementa,b, i 
X 
X 
X 
12 Lead ECG a 
Serologya 
Haematology a, i 
X 
Biochemistry  
a, i
X 
ALT test e 
X 
Urinalysis  a, i 
X 
Serum 
pregnancy 
test 
X 
X 
 
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Note: Additionally, any other assessment including laboratory test(s) will be done if judged necessary by the 
Principal Investigator (PI) or medical officer at any time during the course of study. 
a.
Breath alcohol test, demographic data (Weight, Height and BMI), medical / clinical history, physical
examination including vital signs, 12-lead Electrocardiogram (ECG), Haematology, biochemistry,
serology (HIV, Hepatitis B and C) and urinalysis will be performed at screening.
b.
Physical examination and vital signs examination (blood pressure, pulse rate, respiration rate and body
temperature) will be done at check-in and check-out of each study period.
Physical examination and vital examination can be started approximately 02.00 hours prior to the
scheduled time in each study period.
Intravenous cannula site will be observed by principal investigator/co-investigator /Sub-investigator
/medical officer for any swelling or thrombophlebitis.
Measurement of Vital signs (blood pressure, pulse rate, respiration rate and body temperature)will be
done at pre-dose and at 01.00, 03.00, 05.00, 08.00hrs ± 45 minutes of scheduled time in each study
period and at each ambulatory visits.
c.
Breath alcohol test and questionnaire about smoking (history of smoking) will be carried out before
check-in and before each ambulatory blood sample collection for each study period.
d.
 
Standardized meal will be given during check-in night. The check-in night dinner will be served in
a way to maintain at least 10.00 hours fasting before receiving high-fat and high-calories breakfast. 

On dosing day, standardized high-fat and high-calories breakfast will be given 30 minutes prior to
drug administration. Participants should eat the high-fat and high-calorie breakfast completely
within 25 minutes.

Participants will be given standardized meal at around 04.00, 09.00 and 13.00 hours post-dose.
e.
For all participants, ALT will be done before check-in for each study period. For female participants,
for female e 
Urine 
examination for 
drugs of abuse h 
X 
Admit
to
Clinical 
Research Center 
X 
Meals d 
X 
X
Study 
medication 
administration f 
X 
PK Samples  g 
X 
X 
X 
X 
X 
Concomitant 
medication  
AE 
SAE 
 
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serum pregnancy test (Serum (β) Beta- hCG) will be done before check-in for each study period. 
f.
Single oral dose of the either of two test product or reference product will be administered as per
randomization with 240 ± 2 mL of water at ambient temperature under fed condition.
g.
Total number of blood samples (5 mL per sample): 22 per period.
Sampling times: Pre-dose (collected within 01.00 hour prior to dosing) and at 00.50, 01.00, 01.50, 02.00,
02.50, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 10.00, 12.00, 24.00, 48.00,
72.00 and 96.00 hours post dose. The detailed description on blood sample collection is provided in
section 8.5 Pharmacokinetics.
Blood samples will be collected in Na-Heparin Vacutainer.
Blood samples after 24.00 hours will be collected on ambulatory basis.
h.
Urine examination for drugs of abuse test will be done on check-in Day for each study period.
i.
Physical examination, measurement of blood pressure, pulse rate, respiration rate and body temperature,
serum pregnancy test (Serum (β) Beta- hCG) (for female participants), Haematology, biochemistry and
urinalysis will done at post study or on early discontinuation of participant.
√indicates the occurrence, * indicates day starts from post-dose.
 
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10.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events 
10.2.1. 
Study Phases for Treatment Emergent Adverse Events and 
Concomitant Medication 
Subject. No. 
Study Period 
Age (years) 
Sex 
Adverse Event 
Date & Time of Onset 
Date & Time of Reporting 
Severity 
Seriousness 
Action Taken 
Outcome 
Causality assessment 
Likelihood 
Date & Time of Resolution 
Date &Time of Last Dose Administered 
Last  Investigational  Medicinal Product 
Administered 
Concomitant  Treatment 
 
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10.3. 
Appendix 3: Data Display Standards& Handling Conventions 
10.3.1. 
Reporting Process 
Software 

The currently supported versions of SAS software (Version 9.4) willbe used.
Analysis Datasets 

SDTM datasets will be created according toCDISC standards (SDTM IG Version 3.2].
Generation of RTF Files 

RTF files will not be generated.
Generation of xlm Files 

xlm files will not be generated.
10.3.2. 
Reporting Standards 
Planned and Actual Time 

Reporting for tables, figures and formal statistical analyses:

Sampling time deviations will be considered during the calculation of pharmacokinetic parameters.

Graphical summaries for individual subjects will be presented using actual sampling times.

Graphical summary for mean data will be presented using nominal sampling times

The impact of any major deviation from the planned assessment times and/or scheduled visit days on
the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings:

Planned and actual time relative to study drug dosing will be shown in .

Unscheduled or unplanned readings will be presented within the subject’slistings.
Unscheduled Visits 

Unscheduled visits will be included in subject visit domain.
Descriptive Summary Statistics 
Concentration Data 
Descriptive summary (mean, standard deviation, coefficient of variation, median, 
minimum and maximum) will be computed for each pharmacokinetic parameter for 
the test and reference products.  
Graphical Displays 
Graphical summary for mean data will be presented using nominal sampling times. 
10.3.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows 
Pharmacokinetic data will be calculated using the non-compartmental model by 
using statistical package SAS® 9.4. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Descriptive summary (mean, standard deviation, coefficient of variation, median, 
minimum and maximum) will be computed for each pharmacokinetic parameter for 
the test and reference products. 
Graphical summaries for individual subjects will be presented using actual sampling 
times 
Pharmacokinetic Parameter Derivation 
PK Parameter to be The following PK parameters will be derived by the Programmer: Cmax, AUC0-t, 
 
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Derived
by 
Programmer 
AUC0-inf, Tmax, AUC0-t /AUC0-inf, Residual area, Kel, t1/2, Vd, CL 
Pharmacokinetic Parameter Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
N, arithmetic mean, median, min, max, SD will be provided for untransformed data. 
For log-transformed data, geometric mean, 90% CI of geometric mean,  T/R ratio 
(%), mean square error (mse), , intra-subject variability, power of log-transformed 
data will be reported.   
Untransformed 
PK 
parameter 
tmax, AUC0-t /AUC0-inf, Residual area, Kel, t1/2, Vd, CL, Tlin, Lqct, 
 
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10.4. 
Appendix 4: Derived and Transformed Data 
10.4.1. 
Pharmacokinetic 
PK 

Plasma sample analysis will be carried out by Accutest Research Laboratories (I) Pvt Ltd.
Griseofulvin plasma concentrations will be determined using the currently validated
methodology. The actual sampling times, will be used in the PK calculations.

Griseofulvin plasma concentration-time data will be analyzed by non-compartmental
methods with SAS software version 9.4 and derived PK parameters will be summarized
and listed. Derived Pharmacokinetic parameters will be summarized by treatment group.
Mean, Median, Min, Max, SD for untransformed pharmacokinetic parameters

For log-transformed data, geometric mean, 90% CI of geometric mean,  T/R ratio (%),
mean square error (mse), , intra-subject variability, power of log-transformed data will be
reported.

Graphical summary for mean data will be presented using nominal sampling times.
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10.5. 
Appendix 5: Reporting Standards for Missing Data 
10.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
•
Subject study completion (i.e. as specified in the protocol) was defined as completion of
all phases of the study.

Withdrawn subjects will be notreplaced in the study.

All available data from participants who were withdrawn from the study will be listed
and all available planned data will be included in summary tables and figures, unless
otherwise specified.
10.5.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
Missing samples can be due to withdrawal of participant and accidental spillage of samples 
as mentioned in current version of SOP for ‘Missing Sample’. Missing sample values (MSV) 
or non-reportable values (NRV), of the plasma concentration data, will be represented as 
MSV and NRV in the plasma concentration tables and reasons for their missing will be 
documented. Any BLQ value occurring between two measurable concentration values will 
also be treated as missing sample (MS).  These missing values will be treated as ‘missing 
values’ for Pharmacokinetic and statistical analysis. All the procedures will be performed in 
accordance with current version of SOP for ‘Calculation of Pharmacokinetic Parameters’.For 
participants with missing or non-reportable concentrations for three or more of the last 
samples, only the Cmax and Tmax will be presented and included in the statistical analysis. 
Other PK parameters will not be reported. Data from the participants with missing 
concentrations values (missed blood draws, lost samples, samples unable to be quantified) 
may be used if pharmacokinetic parameters can be estimated using the remaining data 
points. Otherwise, concentration data from these participants will be excluded from the final 
analysis. 
Outliers 

Any participants excluded from the summaries and/or statistical analyses will be
documented along with the reason for exclusion in the clinical study report.
10.5.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 

Partial dates will be displayed as captured in case report forms of subjects

Imputed partial dates will not be used to derive study day, time to onset or duration
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., time
since diagnosis). In addition, imputed dates are not used for deriving the last contact
date in overall survival analysis dataset.
Adverse 
Events 

Imputations in the adverse events dataset are used for slotting events to the
appropriate study time periods and for sorting in data listings.

Partial dates for AE recorded in the CRF will be imputed using the following
conventions:
Missing start day 

If study treatment start date is missing (i.e. participant did not
start study treatment), then set start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year of study
 
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Element 
Reporting Detail 
treatment start date then 

If stop date contains a full date and stop date is
earlier than study treatment start date then set start
date= 1st of month.

Else set start date = study treatment start date.
o
Else set start date = 1st of month.
Missing start day 
and month 

If study treatment start date is missing (i.e. participant did not
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start date
then

If stop date contains a full date and stop date is
earlier than study treatment start date then set start
date = January 1.

Else set start date = study treatment start date.
o
Else set start date = January 1.
Missing stop day 
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 

Completely missing start or end dates will remain missing, with no imputation applied.
Concomitant 
Medications/
Medical 
History 

Partial dates for any concomitant medications recorded in the CRF will be imputed
using the following convention:
Missing start day 

If study treatment start date is missing (i.e. participant did not
start study treatment), then set start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year of study
treatment start date then

If stop date contains a full date and stop date is earlier
than study treatment start date then set start date= 1st
of month.

Else set start date = study treatment start date.
o
Else set start date = 1st of month.
Missing start day 
and month 

If study treatment start date is missing (i.e. participant did not
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start date
then

If stop date contains a full date and stop date is earlier
than study treatment start date then set start date =
January 1.

Else set start date = study treatment start date.

Else set start date = January 1.
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year)  
Missing end day and 
month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
 
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Element 
Reporting Detail 

The recorded partial date will be displayed in listings.
[Insert 
as 
required…] 
Concomitant medication details: 
Drug Name 
(Brand 
Name) 
Dosage 
form 
Strength 
Frequency 
Start date 
End date 
Recorded 
By 
 
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10.6. 
Appendix 6: Values of Potential Clinical Importance 
10.6.1. 
Laboratory Values 
All Individual laboratory measurements by subject will be provided with the CRFs of 
individual subject as clinical laboratory test report.   
10.6.2. 
ECG 
All Individual ECG measurement by subject will be provided with the CRFs. 
10.6.3. 
Vital Signs 
All Individual Vital Sign measurement by subject will be provided with the CRFs. 
 
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10.7. 
Appendix 7: Abbreviations & Trade Marks 
10.7.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R
Analysis and Reporting
CDISC 
Clinical Data Interchange Standards Consortium 
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling& Simulation 
CS
Clinical Statistics
CSR 
Clinical Study Report 
CTR
Clinical Trial Register
CVb/ CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF
Database Freeze
DBR
Database Release
DOB 
Date of Birth 
DP
Decimal Places
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IDSL 
Integrated Data Standards Library (GSK Standards Library) 
IMMS 
International Modules Management System 
IP
Investigational Product
ITT
Intent-To-Treat
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan 
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
 
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Abbreviation 
Description 
SDTM 
Study Data Tabulation Model 
SOP
Standard Operation Procedure 
TA
Therapeutic Area
TFL 
Tables, Figures & Listings 
10.7.2. 
Trademarks 
Trademarks 
of 
the 
GlaxoSmithKline 
Group of Companies 
Trademarks 
not 
ownedby 
the 
GlaxoSmithKline Group of Companies 
[SAS]
 
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10.8. 
Appendix8: List of Data Displays 
All data displays will use the term “subject” rather than “participant” in accordance with 
Accutest SOP and CDSIC Standards 
10.8.1. 
Study PopulationTables 
Subjects Enrolled and 
Randomized (N=) 
Total Subjects Dosed 
Test Product T (N=) 
Total Subjects Dosed 
Reference Product R (N=30) 
Total Subjects Completed 
the Study (N=) 
Total Subjects Analyzed 
 (N= ) 
 Period I 
 Period II 
Total Subjects Dosed 
Reference Product R (N=) 
Total Subject Considered for 
Efficacy Analysis (N=) 
Total Volunteers Screened 
(N=) 
Total Subjects Dosed 
Test Product T (N=) 
 
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10.8.2. 
Pharmacokinetic Tables 
The SAS System, Version: 9.4 
Accutest Research Laboratories (I) Pvt. Ltd. 
Study Code - 
Individual Pharmacokinetic Parameters of Griseofulvin for 'Test Products (T1 and T2)' 
Subject Sequence Period Treatment Cmax 
(ng/mL) 
Tmax
(hrs) 
AUC(0-t) 
(ng*hr/mL) 
AUC(0-inf) 
(ng*hr/mL) 
AUC
Ratio
(%) 
Residual
Area 
(%) 
Kel 
(hrs-1)
Kel_First
(hrs) 
Kel_Last
(hrs) 
Thalf
(hrs) 
The SAS System, Version: 9.4 
Accutest Research Laboratories (I) Pvt. Ltd. 
Study Code - 
Individual Pharmacokineric Parameters of Griseofulvin for 'Reference Product (R)' 
Subject Sequence Period Treatment Cmax 
(ng/mL)
Tmax
(hrs) 
AUC(0-t) 
(ng*hr/mL)
AUC(0-inf) 
(ng*hr/mL) 
AUC
Ratio
(%) 
Residual
Area 
(%) 
Kel 
(hrs-
1) 
Kel_First
(hrs) 
Kel_Last
(hrs) 
Thalf
(hrs) 
 
 
 
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10.8.3. 
Pharmacokinetic Figures 
The SAS System, Version: 9.4 
Accutest Research Laboratories (I) Pvt. Ltd. 
Study code - 
Mean Plasma Concentration of Griseofulvinfor 'Test Products (T1 and T2)' and Refernce Product (R) 
 
 
 
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10.8.4. 
ICH & Non- ICH Listings 

01
Protocol and protocol amendments 

02
Sample Case Report Form 

03
List of IECs or IRBs and Representative Written Information for Subject and Sample Consent Forms 

04
List and Description of Investigators and other Important Participants in the Study, Including their CVs or equivalent 
summaries of training and experience relevant to the performance of the study 

05
Signature of Principal or coordinating investigator or sponsor’s responsible personnel 

06
Listing of Subjects Receiving Test Drug(s)/Investigational Product(s) From Specific Batches, where more than One 
Batch was Used 

07
Randomization Scheme and Codes 

08
Audit Certificates 

09
Documentation of Statistical Methods 

9.1
Sample Size Calculation 
 
 
 
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
9.2
Actual Time Points Considered 

9.3
Mean Plasma Concentration 

9.4
Individual Subject’s Concentration Graph 

9.5
Individual Subject’s Kel Graph 

9.6
SAS Output 

10
Documentation of Inter-Laboratory Standardization Methods and Quality Assurance Procedures 

11
Publications Based on the Study 

12
Important Publications Referenced in the Report 
SUBJECT DATA LISTINGS 

13
Discontinued Subjects 

14
Protocol Deviations 

15
Subjects Excluded from the Efficacy Analysis 
 
 
 
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
16
Demographic Data 

17
Compliance and/or drug Concentration Data 

18
Individual Pharmacokinetic Data 

19
Adverse Event Listing 

20
Listing of Individual Laboratory Measurements by Subject 
CASE REPORT FORMS 

21
CRFs for Deaths, other Serious Adverse Events and Withdrawals for AE 

22
Other CRFs Submitted 

23
BIO-ANALYTICAL REPORT 
 
 
 
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