Clinical trial NCT04571515
Conditions: Pain Postoperative Pain Pain, Acute
Sponsor: Mylan Inc.
Start date: 2020-09-29; Completion date: 2020-12-22
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
MR-107A-01 is being studied to investigate its efficacy, safety, and dose-response after dental surgery.

Detailed description:

Arms: arm 1: Oral tablet one day of dosing arm 2: Oral tablet one day of dosing arm 3: Oral tablet one day of dosing arm 4: Oral tablet one day of dosing arm 5: Placebo tablet one day of dosing
Interventions: intervention 1: MR-107A-01 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol documents:
Prot_000.pdf: 
Study Title: A Randomized, Double Blind, Placebo-Controlled, Parallel Group, Dose-Response 
Study of Meloxicam Co-Crystal in The Treatment of Post-Surgical Dental Pain 
Protocol Number: MECC-TBZ-2001 
Document: Protocol Version 5.0 
Dated: September 15, 2020 
NCT04571515 


Protocol MECC-TBZ-2001
Page 1 of 102
Protocol Version 5.0 15 September 2020
Confidential
MECC-TBZ-2001 CLINICAL STUDY PROTOCOL
Protocol Title
A Randomized, Double Blind, Placebo-Controlled, Parallel Group, 
Dose-Response Study of Meloxicam Co-Crystal in The Treatment of 
Post-Surgical Dental Pain.
Protocol Number
MECC-TBZ-2001
Product
Meloxicam [Co-crystal of Meloxicam: Salicylic acid (1:1)]
Study Type
Phase 2b
Version
Version 5.0 15 September 2020
Protocol Date
Original Date
28 March 2020
Revision Dates
11 May 2020
25 June 2020
11 September 2020
15 September 2020
Registry Name
ClinicalTrials.gov
IND Number
Legal/Filing 
Sponsor
Mylan Inc.
1000 Mylan Blvd,
Canonsburg, Pennsylvania 15317,
United States 
Confidentiality: This protocol is the confidential, intellectual property of Mylan Inc. It should 
not be disclosed to a third party with the exception of regulatory agencies and study audit 
personnel that being Mylan employees, representatives, agents and/or contractors responsible 
for conducting the clinical study/trial, audits. Reproduction, modification, or adaption in part 
or in total is strictly forbidden without prior written approval by Mylan Inc.


Protocol MECC-TBZ-2001
Page 2 of 102
Protocol Version 5.0 15 September 2020
Confidential
DOCUMENT HISTORY
Document 
Version, Date
Summary of Changes with Rationale
Version 1.0 
28 Mar 2020
N/A
Version 2.0 
11 May 2020
Exclude subjects <18 years of age.
Addition of specific questioning of subjects regarding GI adverse events 
during the study and follow up period.
Clarification of double dummy design for drug blinding.
Version 3.0
25 June 2020
Exclude subjects taking strong inhibitors and inducers of CYP2C9.
Version 4.0
11 September 
2020
Including the measurement of salicylic acid in the PK samples.
Include text confirming that the dental surgery and related anesthesia, 
sedation, and prophylactic antibiotics are not investigational and will 
occur regardless of research.
Include a vital signs assessment prior to surgery.
Adapt the order of procedures that will not impact outcomes to fit with 
clinic preferred process.
Version 5.0 
15 September 
2020
Due to discontinuation of hydrocodone/acetaminophen 5/500 mg tablets, 
the rescue medication has been changed to 5/325 mg tablets.


Protocol MECC-TBZ-2001
Page 3 of 102
Protocol Version 5.0 15 September 2020
Confidential
PROTOCOL SYNOPSIS
Protocol Title
A Randomized, Double Blind, Placebo-Controlled, Parallel Group, 
Dose-Response Study of Meloxicam Co-Crystal in The Treatment of 
Post-Surgical Dental Pain.
Protocol 
Number
MECC-TBZ-2001
Study Sites
The study is planned to be conducted at 1 study site.
Study Period 
Planned
The study is planned to be conducted over a period of approximately 3 months.
Duration of 
Individual 
Treatment
The duration from screening to follow up is expected to be approximately 
1.5 months.
Subjects will be dosed with study drug on Day One.
End of Study
End of study is defined as last subject, last visit.
Background 
and Rationale
The effective treatment of pain is important to both patients and to wider society; 
inadequately controlled pain negatively affects quality of life and function, and 
in a post-surgical environment, it affects the functional recovery, the risk of 
post-surgical complications, and the risk of persistent postsurgical pain.
Finding alternatives to opioids, can expand safe and effective options in pain 
management to meet this important public health need and help to reduce the 
public health burden from adverse outcomes related to prescribed opioids.
Meloxicam is a member of the non-steroidal anti-inflammatory drugs (NSAIDs) 
group of medications that exhibit anti-inflammatory and analgesic activity in 
clinical studies. NSAIDs have demonstrated efficacy for the treatment of acute 
pain, however current oral formulations of meloxicam are not suitable for the 
treatment of acute pain due to a relatively slow absorption. In contrast, an IV 
formulation of meloxicam has recently demonstrated efficacy in models of acute 
pain.
Meloxicam [Co-crystal of Meloxicam: Salicylic acid (1:1)] (hereafter 
MECC-SA) is being developed to provide a rapid absorption of meloxicam from 
an oral dose. 
This is the first assessment of efficacy of MECC-SA in subjects with acute pain; 
however, it is anticipated to provide analgesia to these subjects due to the rapid 
absorption demonstrated in Study 
The efficacy dose-response 
profile of MECC-SA is currently unknown and the purpose of this study is to 
establish an understanding of the dose-response relationship for this formulation.
The dental pain model is considered an ideal model of post-surgical acute pain 
as it has high assay sensitivity and is highly predictive of efficacy in later stage 
models. It is also ideal as the surgery, the anesthetic regimen, and perioperative 


Protocol MECC-TBZ-2001
Page 4 of 102
Protocol Version 5.0 15 September 2020
Confidential
care protocols can be standardized across patients. The dental surgical model has 
demonstrated the efficacy of analgesic medications across a range of different 
pharmacology, including NSAIDs and opioids and, more specifically, has 
demonstrated efficacy for an IV formulation of meloxicam.
Primary 
Objectives
To evaluate the efficacy and safety of MECC-SA in subjects following dental 
surgery and to establish the dose-response relationship.
Primary 
endpoints
Overall (summed) pain intensity difference (SPID) over 0-24 hours.
Secondary 
Objectives
N/A
Secondary 
Endpoints
Efficacy

Overall (summed) pain intensity difference (SPID) over 0-2 hours, 
0-4 hours, 0-8 hours, 0-12 and 12-24 hours after initial dose of study 
drug.

Pain intensity difference (PID) over time.

Total pain relief (TOTPAR) over 0-2 hours, 0-4 hours, 0-8 hours, 
0-12 hours, 12-24 hours, and 0-24 hours.

Time to perceptible relief (as measured by double-stopwatch technique) 
after first dose.

Time to meaningful pain relief (as measured by double-stopwatch 
technique) after first dose.

Proportion of subjects with overall pain reductions from baseline of 
≥30% and ≥50% within 4 hours following the first dose.

Patient’s global assessment (PGA) of pain control from 0-24 hours.

Elapsed time from the start of study medication to first rescue 
medication administration.

Proportion of subjects using rescue medication from 0-24 hours.

Number of times rescue medication used from 0-24 hours. 
Safety

Adverse Events.

Laboratory safety tests.

ECGs.

Vital signs.
PK

Population PK parameters for meloxicam and salicylic acid (Cmax, 


Protocol MECC-TBZ-2001
Page 5 of 102
Protocol Version 5.0 15 September 2020
Confidential
pAUC0-4 and pAUC0-24).
Methodology 
This will be a randomized, double-blind, placebo-controlled, parallel group, 
dose-response study, randomizing approximately 110 male or female subjects 
who have had dental surgery (removal of ≥2 third molars) performed. Subjects 
will receive study drug on Day 1.
The study design is consistent with research design recommendations of the 
IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials) group for trials involving subjects with short-duration acute pain.
Subjects will attend screening at Visit 1, to occur within 30 days prior to the 
planned dental surgery.
The subjects will have the operation performed on Day 1 using appropriate local 
anesthesia and sedation (performed using nitrous oxide and a local injection of 
lidocaine with epinephrine). Subjects will also receive prophylactic antibiotics 
post-surgically.
Pain Intensity (PI) (using a 0-10-point numeric pain rating scale (NPRS) where 0 
is no pain and 10 is the worst pain imaginable) will be assessed during the 
5 hours following surgery. If the subject scores a NPRS ≥5 and a rating of 
moderate or severe pain on a 4-point categorical pain rating scale (i.e., none, 
mild, moderate, severe) during this time they will be eligible for randomization. 
A diary will be used to record the pain scores.
Subjects will be randomized to receive either MECC-SA (10 mg QD, 
15 mg QD, 10 mg BID or 15 mg BID) or placebo. 
Dosing of study medication must be within 15 minutes of the eligible pain score.
PI scores (NPRS) will be measured at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 12, 14, 16, 20 and 24 hours after the first dose of study medication, as 
well as immediately before any rescue medication and/or at the time of early 
termination.
Pain relief assessment (using a 5-point scale - none = 0, slight = 1, moderate = 2, 
good or a lot = 3, and complete = 4) will be measured at 15, 30, and 45 minutes 
and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 20 and 24 hours after the first dose of 
study medication, as well as immediately before any rescue medication and/or at 
the time of early termination.
A Patient Global Assessment (PGA) of pain control will be made at 24 hours 
post dose, rated on a 5-point scale, ranging from 0 to 4, where 0-poor, 1-fair, 
2 good, 3-very good, or 4-excellent and/or at the time of early termination. 
The times to first perceptible relief and meaningful pain relief will be determined 
using the double-stopwatch technique. The time to onset of first perceptible 
relief (time that the first watch is stopped) is defined as the post dose time at 
which the subject first begins to feel pain relief. The time to meaningful pain 
relief (time that the second watch is stopped) is defined as the post dose time at 
which the subject begins to feel meaningful pain relief. 
Rescue medication of immediate release hydrocodone/acetaminophen will be 
allowed at any time, but subjects will be encouraged to wait until at least 1 hour 
post-dose if possible. A PI score assessment will be made immediately prior to 


Protocol MECC-TBZ-2001
Page 6 of 102
Protocol Version 5.0 15 September 2020
Confidential
any rescue medication.
PK samples will be taken pre-dose and 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 
5, 6, 7, 8, 12, 14, 16, 20 and 24 hours after the first dose at Day 1.
Subjects will be discharged from the clinic following the 24-hour assessments; if 
the subject requires a longer duration of in-patient assessment due to reasons 
associated with the surgery this is acceptable.
A final follow up telephone call will occur approximately 5 days after the last 
dose of study drug administration.
Safety will be assessed via recording of AEs, safety laboratory testing and pre- 
and post-dose 12-lead ECGs and vital signs.
Adverse events of special interest will include those related to gastrointestinal 
(GI) AEs, particularly bleeds and those related to serious cardiovascular (CV) 
events.
Unless consent is withdrawn, subjects who prematurely terminate study drug 
will have discharge procedures performed at that time or at an early termination 
(ET) visit scheduled as soon as possible.
Study 
Treatment
Treatments to be received during the study will include one of the following 
treatment arms:
1.
MECC-SA 15 mg QD.
2.
MECC-SA 10 mg QD.
3.
MECC-SA 15 mg BID.
4.
MECC-SA 10 mg BID.
5.
Placebo BID.
To maintain the blind due to differences in appearance between the tablets, 
subjects will receive in a double dummy design, two tablets when dosed (one 
that is representative of a 10 mg tablet and one that is representative of a 15 mg 
tablet). Due to the double dummy design, neither the subject, nor the 
Investigator will know what treatment a subject receives. To maintain the blind 
between QD and BID arms, subjects assigned to QD arms will receive placebo at 
the second dose. Per the clinic procedures, subjects will also be blindfolded 
during dosing.
Inclusion/ 
exclusion 
criteria
Inclusion criteria
1.
Males and females ≥18 years of age. Females may be of either 
childbearing or non-childbearing potential. All females of childbearing 
potential must be using an acceptable, highly effective method of 
contraception and have a negative serum pregnancy test at screening.  
2.
Requirement for dental surgery for extraction of ≥2 x third molars, at 
least 1 of which involves partial or complete mandibular bony 
impaction.
3.
Pain Intensity (PI) using a Numeric Pain Rating Scale (NPRS) ≥5 during 


Protocol MECC-TBZ-2001
Page 7 of 102
Protocol Version 5.0 15 September 2020
Confidential
the 5 hours following the end of surgery. 
4.
Rating of moderate or severe pain on a 4-point categorical pain rating 
scale (i.e., none, mild, moderate, severe) during the 5 hours following 
the end of surgery.
5.
Able to understand and complete the study requirements (including 
literacy, to enable diary and questionnaire completion), provide written 
informed consent, and agree to abide by the study protocol and its 
restrictions.
Exclusion Criteria
1.
Previously dosed with MECC-SA.
2.
Subject with known hypersensitivity to aspirin, NSAIDs or other 
medication used in the study.
3.
Subjects with known hypersensitivity to items used in surgery.
4.
Known active GI bleeding or a history of peptic ulcer disease.
5.
Known active inflammatory bowel disease, e.g., Crohn’s Disease or 
ulcerative colitis.
6.
A history of bleeding disorders that may affect coagulation.
7.
A clinically significant history of respiratory insufficiency, hypotension, 
bradycardia, migraine, frequent headaches, seizures, renal, hepatic, 
cardiovascular metabolic, neurologic or psychiatric disease in the 
opinion of the Investigator.
8.
History of Hepatitis B or C or HIV infection.
9.
History of alcohol or drug abuse within the last 5 years prior to the 
study.
10. History of myocardial infarction or coronary artery bypass graft surgery 
within the 12 months prior to the study.
11. Clinically significant abnormality on the 12-lead ECG at screening 
which in the judgment of the investigator would put the subject at 
potential risk if enrolled into the study (these subjects should not be 
re-screened). Clinically significant abnormalities may include but are 
not limited to the following: left bundle branch block, Wolff-Parkinson-
White syndrome, clinically significant arrhythmias (e.g., ventricular 
tachycardia). 
12. History of long QT syndrome or screening ECG with QTcF >470 
milliseconds for female or >450 milliseconds for male subjects.
13. Current evidence of, or history within the 6 months prior to screening of 
unstable ischemic heart disease, NYHA Class II-IV right or left 
ventricular failure.
14. History of malignancy of any organ system treated or untreated, within 
the past 5 years whether or not there is evidence of local recurrence or 


Protocol MECC-TBZ-2001
Page 8 of 102
Protocol Version 5.0 15 September 2020
Confidential
metastases. The only exceptions are previous in situ carcinoma of the 
cervix, localized basal cell carcinoma of the skin or localized squamous 
carcinoma of the skin if the subject has been treated and is considered 
cured.
15. Use of any investigational drug within 28 days, or 5 half-lives, prior to 
screening whichever is longer.
16. Use of medications with the potential to interact with MECC-SA (as 
indicated in the current Investigator’s Brochure), or medications 
required during the study such as local anesthesia or sedatives, or 
medications with the potential to affect or confound pain status during 
the study. This includes (but not limited to) use of any of the following 
medications: 

Strong CYP2C9 inhibitors or inducers within 28 days or 5 half-lives 
(whichever is longer) prior to the study.

Long-term opioid use (>30 consecutive days in the past year) and/or 
use of extended release opioids within 30 days of the dental 
extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs 
within 28 days prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other 
than the nitrous oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to 
the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 
28 days prior to the study.

Pemetrexed within 28 days prior to the study.

Combination of diuretic with ACE inhibitor or angiotensin receptor 
blocker within 28 days prior to the study.

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.


Protocol MECC-TBZ-2001
Page 9 of 102
Protocol Version 5.0 15 September 2020
Confidential

Aspirin within 7 days prior to the surgery.

Analgesics (including opioids, acetaminophen and NSAIDs) within 
24 hours prior to the surgery.
17. Inability to refrain from any of the following medications pre-, intra-, or 
post-surgery:

Systemically administered corticosteroids.

Epidural or spinal anesthetics.

General anesthesia.

Analgesia other than those pre-specified for breakthrough pain 
relief.
18. BMI >35 kg/m2.
19. Pregnant or nursing females or females intending to become pregnant 
during the course of the study. 
20. Serum creatinine >1.5 x Upper Limit of Normal.
21. Serum ALT, AST, or bilirubin >2 x Upper Limit of Normal.
22. Clinically significant abnormal laboratory test(s) at screening deemed 
exclusionary by the Investigator.
23. Signs or symptoms of an infection or a fever that would increase the risk 
of surgery.
24. Other acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere 
with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this 
study.
Planned 
Number of 
Subjects
N=110 subjects (N=22/treatment arm) to give approximately N=100 evaluable 
subjects for the primary endpoint (N=20/treatment arm).
Statistical 
Methods
The primary efficacy endpoint is the overall (summed) pain intensity difference 
over 0-24 hours (SPID 0-24).
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 10 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
To analyze the primary endpoint, a 3-parameter Emax model will be fitted to the 
SPID 0-24 standardized means (observed mean for each dose and placebo 
divided by the pooled standard deviation) for placebo and 10 mg QD, 15 mg 
QD, 10 mg BID and 15 mg BID MECC-SA.  Standardized effect sizes will be 
estimated from the Emax model together with their 95% confidence intervals and 
p-values. Baseline pain intensity score (PI) will be used as a covariate in the Emax 
model. The numerical dose values will be 10, 15, 20, 30 and 0 for 10 mg QD, 
15 mg QD, 10 mg BID, 15 mg BID and placebo respectively.
Additional models may be explored utilizing a Multiple Comparison Procedure – 
Modeling (MCP-Mod) approach.
If the Emax model fails to converge, and no other suitable models are identified 
using MCP-Mod, an Analysis of covariance (ANCOVA) will be used to assess 
the difference between treatment groups for SPID 0-24. The ANCOVA model 
will include treatment and study site as fixed effects and baseline PI score as a 
covariate. The difference between MECC-SA and placebo will be estimated 
from the least squares means (LS means) along with the 95% confidence interval 
(CI) and associated 2-sided p-values. In addition, the standardized effect sizes 
for each dose will be calculated by dividing the differences in LS means for each 
dose and placebo by the pooled standard deviation.
PK parameters for meloxicam and salicylic acid (Cmax, pAUC0-4, pAUC0-24) will 
also be calculated.


Protocol MECC-TBZ-2001
Page 11 of 102
Protocol Version 5.0 15 September 2020
Confidential
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to the Study Conduct Section (6) for detailed 
information on each procedure and assessment required for compliance with the protocol.
Figure 1: 
Study Diagram
Screening
Day -30 to -2
MECC-SA 10 mg BID N=22
MECC-SA 15 mg BID N=22
Surgery, Randomization 
and Dose
Day 1
EoT and 
Discharge
Day 2
Telephone 
Follow Up
Day 5-7
MECC-SA 10 mg QD N=22
MECC-SA 15 mg QD N=22
Placebo N=22




Protocol MECC-TBZ-2001
Page 13 of 102
Protocol Version 5.0 15 September 2020
Confidential
Table 1: 
Study Schedule
VISIT
1
(Screen)
2
(In-
clinic)
2
(In-
clinic)
Follow up 
Telephone
Call
DAY
-30 to -2
1
2
5-7
Written informed consent
X
IVRS/IWRS registration
X
Demography and medical history
X
Review concomitant medications
X
X
X
X
General physical examination1
X
X15
Height 
X
Weight
X
Temperature
X2
Vital Signs (supine/semi-recumbent blood pressure, pulse 
rate)
X
X3
X15
12-lead ECG (supine/semi-recumbent)
X
X4
X15
Serum or urine pregnancy test5
X
X2
X15
Urinalysis6
X
X15
Urine drug screen
X
X2
Blood safety labs (hematology, chemistry) including 
FSH (V1)7
X
X15
PK Sample8
X
X
Diary training
X2
Review AEs9
X
X
X
X
Inclusion/exclusion criteria
X
X
Dispense diary for pain assessment recordings
X
Subject records AEs at home
X
X
Subject records AEs in the clinic
X
X
Perform dental surgery
X
Pain Assessments (Pain Intensity, Categorical Pain 
Rating) (prior to randomization)
X10
Randomize to study via IVRS/IWRS
X
Dispense study drug
X11
Administer study drug (within 15 minutes of eligible pain 
assessments)
X12
Administer study drug (12 hours after first dose)
X
Pain Intensity Assessments (post-randomization)
X13
X13
Pain Relief Assessments (post-randomization)
X13
X
Patient Global Assessment of Pain Control
X14
Record Rescue Medication Use
X
X
X


Protocol MECC-TBZ-2001
Page 14 of 102
Protocol Version 5.0 15 September 2020
Confidential
1
Including respiratory, cardiovascular, gastrointestinal, musculoskeletal, neurological systems, 
lymph nodes, skin, extremities, head, ears, eyes, nose, and thyroid gland.
2
Prior to surgery.
3
Vital signs (blood pressure and pulse rate) are taken prior to surgery, pre-dose and 24 hours 
post-dose performed after ECG measurements taken at the same nominal time.
4
12-lead ECG will be performed both pre-dose and 24 hours post-dose as single measures.
5
Serum pregnancy test at screening, urine at other visits.
6
Urinalysis for blood, protein, nitrites, leukocyte esterase, pH, glucose and ketones. If positive 
for blood, protein, nitrites or leukocytes esterase a sample for microscopy/culture should be 
analyzed by the central laboratory.
7
FSH to be measured in females who have been amenorrheic for at least 2 years, to confirm 
non-child bearing potential.
8
PK sample taken pre-dose and 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 
20 and 24 hours after the first dose of study medication.
9
All AEs will be recorded from time of consent until the telephone follow up/End of Study 
(EOS) Visit. The Investigator is also responsible for notifying the sponsor if they become 
aware of any AE after the study period has ended and it is considered related to the study 
medication. When assessing AEs, the subject will be specifically asked regarding the presence 
of any GI symptoms. 
10
Pain assessments (Pain Intensity and Categorical Pain Rating) performed for up to 5 hours post 
completion of surgery. Subjects with NPRS ≥5 and a rating of moderate or severe pain on a 
4-point categorical pain rating scale (i.e., none, mild, moderate, severe) during this time they 
will be eligible for randomization.
11
Drug is dispensed at ‘time zero’ and 12 hours later.
12
Dosing of study medication must be within 15 minutes of the eligible pain assessments.
13
Post-dose pain assessments made at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 
16, 20 and 24 hours after the first dose of study medication, and immediately before any dose 
of rescue medication. Assessments will also be made immediately following the time of first 
relief and time of meaningful relief.
14
Patient’s Global Assessment of Pain Control measured at 24 hours post-dose, or at time of 
early termination if applicable.
15
Procedures performed after the final pain assessment (24 hours post-dose).


Protocol MECC-TBZ-2001
Page 15 of 102
Protocol Version 5.0 15 September 2020
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY...........................................................................................................2
PROTOCOL SYNOPSIS...........................................................................................................3
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES .....................................11
1
INTRODUCTION............................................................................................................23
1.1
Indication..................................................................................................................23
1.2
Background and Rationale .......................................................................................23
1.3
Investigational Product.............................................................................................29
1.4
Ethics and Benefit-Risk Considerations...................................................................30
2
OBJECTIVES AND ENDPOINTS .................................................................................31
2.1
Objectives.................................................................................................................31
2.1.1
Primary Objectives...............................................................................................31
2.2
Endpoints..................................................................................................................31
2.2.1
Primary Endpoint .................................................................................................31
2.2.2
Secondary Endpoints............................................................................................31
3
Study Design ....................................................................................................................32
3.1
Overall Design .........................................................................................................32
3.2
Rationale for Study Design ......................................................................................32
3.3
End of Study Definition ...........................................................................................32
4
STUDY POPULATION ..................................................................................................32
4.1
Study Population ......................................................................................................32
4.2
Inclusion and Exclusion Criteria..............................................................................33
4.2.1
Inclusion Criteria..................................................................................................33
4.2.2
Exclusion Criteria.................................................................................................33
4.2.3
Criteria for Study Drug Termination, Withdrawal From the Study and Study 
Termination......................................................................................................................36
4.3
Replacement Policy..................................................................................................37


Protocol MECC-TBZ-2001
Page 16 of 102
Protocol Version 5.0 15 September 2020
Confidential
4.4
Lifestyle Guidelines .................................................................................................37
4.4.1
Meals and Dietary Restrictions ............................................................................37
4.4.2
Alcohol and Tobacco ...........................................................................................38
4.5
Contraception ...........................................................................................................38
4.5.1
Females - Non-Childbearing Potential.................................................................38
4.5.2
Females - Childbearing Potential.........................................................................38
4.6
Pregnancy Testing....................................................................................................39
5
STUDY DRUG ................................................................................................................39
5.1
Investigational Drug.................................................................................................39
5.1.1
Administration of Study Drugs ............................................................................39
5.2
Drug Inventory.........................................................................................................40
5.3
Study Medication Complaints..................................................................................40
5.4
Storage, Disposition of Unused Study Drug and Drug Accountability ...................40
5.5
Randomization .........................................................................................................41
5.6
Breaking the Blind ...................................................................................................41
5.7
Rescue Medication For Relief of Pain .....................................................................42
5.7.1
Pre-Dose...............................................................................................................42
5.7.2
Post-Dose .............................................................................................................42
5.8
Concomitant Medications ........................................................................................42
5.9
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug..............................................................42
5.10
Treatment Compliance.............................................................................................43
6
STUDY CONDUCT ........................................................................................................43
6.1
Screening Procedures...............................................................................................44
6.1.1
Screening (Visit 1) ...............................................................................................44
6.2
Treatment Phase.......................................................................................................45
6.2.1
Visit 2 (Day 1)......................................................................................................45


Protocol MECC-TBZ-2001
Page 17 of 102
Protocol Version 5.0 15 September 2020
Confidential
6.2.1.1
Pre-Dose Procedures .....................................................................................45
6.2.1.2
Dosing and Post-Dose Procedures.................................................................46
6.2.2
Visit 2 (Day 2)......................................................................................................47
6.2.2.1
Discharge Procedures ....................................................................................48
6.2.3
Early Termination (ET) visit................................................................................48
6.3
End of Study (EOS) Visit.........................................................................................49
7
Treatment Procedures and Assessment Criteria...............................................................50
7.1
Dental Surgery .........................................................................................................50
7.2
Efficacy Assessment ................................................................................................50
7.2.1
Pain Intensity (NPRS)..........................................................................................50
7.2.2
Categorical Pain Rating........................................................................................51
7.2.3
Pain Relief Assessment........................................................................................51
7.2.4
Patient Global Assessment (PGA) .......................................................................51
7.2.5
Time to First Perceptible Pain Relief...................................................................51
7.2.6
Time to Meaningful Pain Relief...........................................................................51
7.2.7
Rescue Medication Use........................................................................................52
7.3
Safety Assessment....................................................................................................52
7.3.1
Adverse Event Assessment ..................................................................................52
7.3.2
Laboratory Safety.................................................................................................52
7.3.3
Vital Signs - Blood Pressure and Pulse Rate .......................................................53
7.3.4
12-lead ECG.........................................................................................................54
7.3.5
General Physical Examination .............................................................................54
7.3.6
Blood Volume ......................................................................................................55
7.4
Pharmacokinetics .....................................................................................................55
7.4.1
Plasma for Analysis of Meloxicam......................................................................55
7.4.2
Shipment of Pharmacokinetic Samples................................................................56
7.5
Restrictions...............................................................................................................56


Protocol MECC-TBZ-2001
Page 18 of 102
Protocol Version 5.0 15 September 2020
Confidential
8
STATISTICAL CONSIDERATIONS.............................................................................56
8.1
Sample Size Determination......................................................................................56
8.2
Populations for Analyses..........................................................................................57
8.2.1
Safety Analysis Set ..............................................................................................57
8.2.2
Intent To Treat Analysis Set ................................................................................57
8.2.3
Per Protocol Analysis Set.....................................................................................57
8.2.4
Pharmacokinetic Analysis Set..............................................................................57
8.3
Statistical Analyses ..................................................................................................58
8.3.1
Definition of the Primary Efficacy Endpoint(s)...................................................58
8.3.2
Primary Analysis of Primary Endpoint................................................................58
8.3.3
Secondary/Sensitivity Analysis of Primary Endpoint..........................................58
8.3.4
Missing Data ........................................................................................................59
8.3.5
Sub-Group Analyses ............................................................................................59
8.3.6
Definition and Analysis of the Secondary Endpoints ..........................................59
8.3.6.1
Secondary SPID Endpoints and TOTPAR....................................................59
8.3.6.2
Pain Intensity Differences (PID) Over Time.................................................59
8.3.6.3
Time to Event Endpoints...............................................................................60
8.3.6.4
Responder Endpoints.....................................................................................60
8.3.6.5
Frequency of Rescue Medication Use...........................................................60
8.3.7
Pharmacokinetics .................................................................................................60
8.3.8
Safety Analyses....................................................................................................61
8.3.8.1
Adverse Events..............................................................................................61
8.3.8.2
Vital Signs .....................................................................................................61
8.3.8.3
ECG Analyses ...............................................................................................61
8.3.8.4
Laboratory Data.............................................................................................62
8.3.9
Planned Interim Analyses ....................................................................................62
9
ADMINISTRATIVE PROCEDURES.............................................................................62


Protocol MECC-TBZ-2001
Page 19 of 102
Protocol Version 5.0 15 September 2020
Confidential
9.1
Source Documentation Forms..................................................................................62
9.2
Access to Data/Source Documentation....................................................................63
9.3
Final Clinical Study Report and Case Report Forms (CRFs) ..................................63
9.4
Adherence to Protocol..............................................................................................63
9.5
Data Handling and Record Retention ......................................................................64
9.6
Confidentiality..........................................................................................................64
9.7
Ethics and Regulatory Authorities ...........................................................................65
9.7.1
Institutional Review Board/Ethics Committee.....................................................65
9.7.2
Regulatory Authority ...........................................................................................65
9.8
Informed Consent.....................................................................................................65
9.9
Disclosure and Publication of Clinical Study Data..................................................65
9.10
End of Trial ..............................................................................................................65
10
Adverse Events and Safety Reporting..............................................................................66
10.1
Definitions................................................................................................................66
10.2
Special Situations.....................................................................................................69
10.2.1
Adverse Events of Special Interest ..................................................................70
10.3
Collection and Recording of Adverse Events ..........................................................70
10.4
Classification of an Adverse Event..........................................................................71
10.4.1
Severity ............................................................................................................71
10.4.2
Causality...........................................................................................................71
10.4.3
Expectedness....................................................................................................72
10.4.4
Outcome ...........................................................................................................72
10.4.5
Action Taken With the Study Treatment .........................................................73
10.5
Reporting of Serious Adverse Events and Pregnancy Exposures............................73
10.5.1
Investigator Reporting: Notifying the Study Sponsor......................................73
10.5.2
Follow-up .........................................................................................................74
10.5.3
Investigator reporting: Notifying the Ethics Committee..................................74


Protocol MECC-TBZ-2001
Page 20 of 102
Protocol Version 5.0 15 September 2020
Confidential
10.5.4
Investigator Reporting of Pregnancy: Notifying the Study Sponsor ...............74
11
PROTOCOL AMENDMENT DETAILS........................................................................76
11.1
Global Amendment 1, 11 May 2020........................................................................76
11.1.1
Reason for Amendment....................................................................................76
11.1.2
Sections Changed.............................................................................................76
11.2
Global Amendment 2, 25 June 2020........................................................................86
11.2.1
Reason for Amendment....................................................................................86
11.2.2
Sections Changed.............................................................................................86
11.3
Global Amendment 3, 10 September 2020..............................................................90
11.3.1
Reason for Amendment....................................................................................90
11.3.2
Sections Changed.............................................................................................91
11.4
Global Amendment 4, 15 September 2020..............................................................99
11.4.1
Reason for Amendment....................................................................................99
11.4.2
Sections Changed.............................................................................................99
12
REFERENCE LIST .......................................................................................................101


Protocol MECC-TBZ-2001
Page 21 of 102
Protocol Version 5.0 15 September 2020
Confidential
LIST OF TABLES
Table 1: 
Study Schedule.....................................................................................................13
Table 2: 
List of Commonly Used Abbreviations ...............................................................22
Table 3: 
Adverse Events (%) Occurring in ≥2% of MOBIC Patients in 4 to 6 Weeks and 6 
Month Active-Controlled Osteoarthritis Trials........................................................................24
Table 4: 
MELO-1-19043 Pharmacokinetic Summary, Fasting Conditions.......................26
Table 5: 
MECC-1-19148 Pharmacokinetic Summary, Food Effect Study........................26
Table 6: 
MECC-SA Predicted Exposure After Single Doses, Once and Twice Daily 
Dosing vs., MOBIC and ANJESO...........................................................................................27
Table 7: 
Laboratory Safety Tests .......................................................................................52
Table 8: 
Blood Volume ......................................................................................................55
Table 9: 
Power Calculations For The Primary Endpoint ...................................................57
LIST OF FIGURES
Figure 1: 
Study Diagram .....................................................................................................11


Protocol MECC-TBZ-2001
Page 22 of 102
Protocol Version 5.0 15 September 2020
Confidential
Table 2: 
List of Commonly Used Abbreviations
AE
Adverse event
mg
Milligram
ACE
Angiotensin Converting 
Enzyme
NYHA
New York Heart Association
ALT
Alanine transaminase
INN
International Non-proprietary Name
ANOVA
Analysis of variance
ITT
Intent To Treat
AST
Aspartate transaminase
IVRS/IWRS
Interactive Voice Response System/ 
Interactive Web Response System
AUC
Area Under the Curve
MECC-SA
Meloxicam [Co-crystal of Meloxicam: 
Salicylic acid (1:1)] 
BID
Twice Daily
mL
Milliliter
BMI
Body Mass Index
mmHg
Millimeter of mercury
BP
Blood Pressure
MMRM
Mixed Model Repeated Measures
bpm
Beats per minute
MNAR
Missing Not At Random
cm
Centimeter
ms
Millisecond
Cmax
Maximum plasma concentration
NSAID
Non-Steroidal Anti-Inflammatory 
Drug
CRF
Case Report Form
NPRS
Numeric Pain Rating Scale
COX
Cyclooxygenase
pAUC
Partial Area Under the Curve
CRO
Contract Research Organization
PGA
Patient Global Assessment
CV
Cardiovascular
PI
Pain Intensity
CV
Coefficient of Variation
PK
Pharmacokinetic
ECG
Electrocardiogram
PPAS
Per Protocol Analysis Set
EU
European Union
PR
Pulse Rate
FAS
Full Analysis Set
prn
pro re nata
FDA
Food and Drug Administration
QC
Quality Control
FSH
Follicle stimulating hormone
QD
Once Daily
GCP
Good Clinical Practice
QTc
QT corrected
GI
Gastrointestinal
QTcF
QT corrected (Fredericia’s correction)
GM
Geometric Mean
RoW
Rest of World
HIV
Human Immunodeficiency 
Virus
SAE
Serious Adverse Event
HR
Heart Rate
SAP
Statistical Analysis Plan
ICF
Informed Consent Form
SD
Standard Deviation
ICH
International Conference on 
Harmonization
SID
Subject Identification
IRB
Institutional Review Board
SOP
Standard Operating Procedure
kg
Kilogram
SPID
Summed Pain Intensity Difference
LOCF
Last Observation Carried 
Forward
T½
Half life
LS mean
Least Squares mean
Tmax
Time of maximum concentration
MAR
Missing At Random
TOTPAR
Total pain relief
mFAS
Modified Full Analysis Set
US
United States
MI
Missing imputation
WoCBP
Women of Childbearing Potential


Protocol MECC-TBZ-2001
Page 23 of 102
Protocol Version 5.0 15 September 2020
Confidential
1
INTRODUCTION
1.1
Indication
Acute, post-operative pain.
1.2
Background and Rationale
The effective treatment of pain is important to both patients and to wider society; 
inadequately controlled pain negatively affects quality of life and function, and in a 
post-surgical environment, it affects the functional recovery, the risk of post-surgical 
complications, and the risk of persistent post-surgical pain [1].
Opioids have been used to treat many forms of pain in the USA, sometimes unnecessarily or 
inappropriately, leading to extensive misuse of these powerful medications and culminating 
in the current health crisis. It is estimated that 115 Americans die every day from opioid 
induced overdoses and that in 2015 alone, the cost to the US economy of the opioid epidemic 
was $504 billion [2], with a drug overdose rate in 2015 of 16.3 per 100,000 [3], increasing to 
21.7 per 100,000 in 2017 [4]. Clearly the misuse of opioids has a huge impact both on 
individual patients and their families but also on the wider society. The Centers for Disease 
Control have also determined through a meta-analysis that opioid therapy prescribed to treat 
acute pain is associated with a greater likelihood of long-term opioid use [5]. Therefore, 
reducing opioid use or replacing opioids with alternative drugs would be advisable. Advice 
from groups such as Washington State Agency Medical Directors’ Group is that post-surgical 
use of opioids should be avoided where possible with alternative drugs offered as analgesia or 
minimized [6].
Alternatives to opioids can expand safe and effective options in pain management to meet 
this important public health need and help to reduce the public health burden from adverse 
outcomes related to prescribed opioids. 
Meloxicam is a member of the non-steroidal anti-inflammatory drugs (NSAIDs) group of 
medications that exhibit anti-inflammatory, anti-pyretic and analgesic activity in clinical 
studies. Non-steroidal anti-inflammatory drugs have demonstrated efficacy for the treatment 
of chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis [7] and acute 
pain [8]; [9]. NSAIDs are currently recommended by the American College of Rheumatology 
for the treatment of osteoarthritis [10] and have indications for the treatment of rheumatoid 
arthritis (RA); however, most recent treatment guidelines for RA have focused on disease 
modification rather than analgesia [11]; [12]. NSAIDs are considered generally safe for 
short-term use with the following exceptions: patients with NSAID-exacerbated respiratory 
disease, patients with prior myocardial infarction who are receiving antithrombotic therapy, 
patients with asthma, and patients with a history of renal disease [13].
The apparent primary mechanism of action of meloxicam, and of other NSAIDs, is the 
reduction of prostaglandin (PG) production through its inhibitory activity against 


Protocol MECC-TBZ-2001
Page 24 of 102
Protocol Version 5.0 15 September 2020
Confidential
cyclo-oxygenase (COX-1 and COX-2) [14]. Meloxicam is currently approved in oral 
formulations in USA as a treatment for chronic diseases: osteoarthritis, rheumatoid arthritis, 
and juvenile rheumatoid arthritis pauciarticular and polyarticular course (at the 7.5 mg dose 
only in children that weigh ≥60 kg). An IV formulation of meloxicam is currently approved 
in USA for the management of moderate-severe pain. 
Meloxicam is available in tablet form; (MOBIC® [Boehringer Ingelheim] and various generic 
forms and QMIIZ® orally disintegrating tablets [Tersera Therapeutics]) and in capsule form 
(VIVLODEX® [Iroko Pharmaceuticals]). MOBIC is approved at doses of 7.5 and 15 mg once 
per day and VIVLODEX is approved at doses of 5 and 10 mg once per day. Meloxicam has 
been extensively studied in humans as MOBIC and VIVLODEX in chronic pain indications, 
including osteoarthritis and rheumatoid arthritis. Meloxicam has also recently been approved 
by US FDA in an intravenous formulation as ANJESO® (Baudax Bio, Inc) at a dose of 30 mg 
for the management of moderate-severe pain.
Based on the demonstration that meloxicam is effective for the treatment of chronic pain such 
as osteoarthritis at doses of ≥7.5 mg/day and that this effect is mediated by inhibition of 
cyclooxygenase, a concentration of approximately 1090 ng/mL, which is similar to the steady 
state concentration of 7.5 mg meloxicam, would be considered sufficient for mediating an 
analgesic response [15]. Ex vivo assays performed on samples taken from subjects receiving 
7.5 mg meloxicam have demonstrated an 83% inhibition of COX-2 [15].
Gastrointestinal (GI) AEs were the most frequently reported AEs in all treatment groups 
across MOBIC trials, reflective of the safety profile of meloxicam. The most commonly 
reported AEs in both short-term and long-term studies of MOBIC in osteoarthritis are 
summarized in Table 3.
Table 3: 
Adverse Events (%) Occurring in ≥2% of MOBIC Patients in 4 to 6 
Weeks and 6 Month Active-Controlled Osteoarthritis Trials
4 to 6 Weeks Controlled Trials
6 Month Controlled Trials
MOBIC 7.5 mg 
Daily
MOBIC 15 mg 
Daily
MOBIC 7.5 mg 
Daily
MOBIC 15 mg 
Daily
No. of Patients
8955
256
169
306
Gastrointestinal
11.8
18.0
26.6
24.2
Abdominal pain
2.7
2.3
4.7
2.9
Constipation
0.8
1.2
1.8
2.6
Diarrhea
1.9
2.7
5.9
2.6
Dyspepsia
3.8
7.4
8.9
9.5
Flatulence
0.5
0.4
3.0
2.6
Nausea
2.4
4.7
4.7
7.2
Vomiting
0.6
0.8
1.8
2.6
Body as a Whole
Accident 
household
0.0
0.0
0.6
2.9
Edema (a)
0.6
2.0
2.4
1.6
Pain
0.9
2.0
3.6
5.2
Central and Peripheral 
Nervous System


Protocol MECC-TBZ-2001
Page 25 of 102
Protocol Version 5.0 15 September 2020
Confidential
4 to 6 Weeks Controlled Trials
6 Month Controlled Trials
MOBIC 7.5 mg 
Daily
MOBIC 15 mg 
Daily
MOBIC 7.5 mg 
Daily
MOBIC 15 mg 
Daily
Dizziness
1.1
1.6
2.4
2.6
Headache
2.4
2.7
3.6
2.6
Hematologic
Anemia
0.1
0.0
4.1
2.9
Musculoskeletal
Arthralgia
0.5
0.0
5.3
1.3
Back pain
0.5
0.4
3.0
0.7
Psychiatric
Insomnia
0.4
0.0
3.6
1.6
Respiratory
Coughing
0.2
0.8
2.4
1.0
Upper respiratory 
tract infection
0.2
0.0
8.3
7.5
Skin
Pruritus
0.4
1.2
2.4
0.0
Rash (b)
0.3
1.2
3.0
1.3
Urinary
Micturition 
frequency
0.1
0.4
2.4
1.3
Urinary tract 
infection
0.3
0.4
4.7
6.9
a.
WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined
b.
WHO preferred terms rash, rash erythematous, and rash maculo-papular combined
Higher doses of MOBIC (22.5 mg and greater) have been associated with an increased risk of 
serious GI events, 
 
 
MECC-SA contains salicylic acid as a co-former, this is at a low dose (up to 11.6 mg for BID 
dosing of MECC-SA 15 mg) which is anticipated to have negligible physiological effects. 
However, it is acknowledged that salicylic acid (and acetylsalicylic acid) at higher doses can 
cause adverse effects, such as local gastrointestinal effects such as ulceration of the GI tract, 
particularly when administered with other NSAIDs. As the potential for local GI toxicity for 
salicylic acid is not known all GI symptoms should be assessed and documented.
As discussed in the most recent specific Cochrane Review of meloxicam [16] and the general 
review of NSAIDs for the treatment of acute pain [8], current oral formulations of meloxicam 
(e.g., MOBIC and VIVLODEX) are not indicated for, nor are they suitable for, the treatment 
of acute pain due to the delayed absorption of the product. 
Meloxicam however, has demonstrated efficacy in a number of clinical studies using 
intramuscular (IM) and intravenous (IV) formulations, including short-term studies in dental 
extraction [17]; [18] and post-bunionectomy surgery [19]; [20]. Furthermore, some data are 
suggestive that IM meloxicam has a more rapid onset than oral meloxicam in rheumatoid 
arthritis pain [21] and sciatica [22]. 


Protocol MECC-TBZ-2001
Page 26 of 102
Protocol Version 5.0 15 September 2020
Confidential
MECC-SA is being developed to provide a rapid absorption of meloxicam from an oral dose. 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 27 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
 
 
 
 
 
 
 
 
 especially as ANJESO 
(IV meloxicam) 30 mg has a reported Cmax of 7972.5 ng/mL and an AUCinf of 
121437.6 ng.hr/mL.
Acknowledging that a BID dosing regime is planned in this study, and based on the fasted 
data from Study 
, predicted exposure for BID dosing of MECC-SA are 
summarized in Table 6.
 


Protocol MECC-TBZ-2001
Page 28 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 29 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
 
 
1.3
Investigational Product
MECC-SA is being developed to provide a rapid absorption of meloxicam from an oral dose. 
The meloxicam component of the co-crystal formulation is considered to be the primary 
active component of the product.
Salicylic acid is used as the co-former in the MECC-SA tablets. Considering that meloxicam 
is a BCS Class II compound, the rate-limiting step for meloxicam absorption is solubility. 
The intended use of salicylic acid in MECC-SA is to increase the rate of absorption of 
meloxicam by increasing its solubility and dissolution. The dose of salicylic acid (5.8 mg and 
11.6 mg considering QD and BID dosing of MECC-SA 15 mg, respectively) used in 
MECC-SA formulation is considered as a subtherapeutic dose (approved oral clinical doses 
of acetylsalicylic acid are in the range of 50- 325 mg/day) with negligible physiological 
effects. Whilst the side effect profile of acetylsalicylic acid is well known, including local 
effects on the GI tract, it is acknowledged that the local side effects of its metabolite (via 
hydrolysis in the GI tract, liver and plasma) salicylic acid when given orally are unknown, 
although a fraction of acetylsalicylic acid is metabolized to salicylic acid in the GI tract prior 
to absorption. Considering the low dose of salicylic acid in the formulation, MECC-SA is not 
considered a new fixed combination drug.
Based upon the available data, it can be considered that salicylic acid that is incorporated into 
MECC-SA is (1) at sub-therapeutic levels with negligible physiological effects and (2) 
enhances the effectiveness of meloxicam by increasing its solubility and dissolution thereby 
increasing its rate of absorption. Therefore, the product would not be considered a new 
fixed-combination drug.
The efficacy dose response profile of MECC-SA is currently unknown, and the purpose of 
this study is to establish an understanding of the dose response relationship for this 
formulation.


Protocol MECC-TBZ-2001
Page 30 of 102
Protocol Version 5.0 15 September 2020
Confidential
1.4
Ethics and Benefit-Risk Considerations
As discussed in Section 1.2, meloxicam has been extensively studied and subsequently 
prescribed for the treatment of chronic pain associated with osteoarthritis and rheumatoid 
arthritis but oral forms of meloxicam have not been used to treat acute pain due to slow 
absorption of the drug. A rapidly absorbing form of meloxicam should demonstrate efficacy 
in the treatment of acute pain and if the drug has a similar overall exposure (and lower than 
that of IV meloxicam) to that of other oral meloxicam products the safety profile should be 
similar. 
This is the first assessment of efficacy of MECC-SA in subjects with acute pain, however it is 
anticipated to provide analgesia to these subjects due to the rapid absorption demonstrated in 
study 
 It is estimated that a 15 mg dose of MECC-SA would exceed 
1090 ng/mL within 30-45 minutes of dosing, therefore acute analgesia could be anticipated at 
or around this time. Assuming linearity of exposure for meloxicam, a 10 mg dose of 
MECC-SA would exceed 1090 ng/mL at around 1.25 hours. It can therefore be anticipated 
that a 10 mg dose would achieve acute analgesia, however it may not be as efficacious as 
15 mg. 
As some studies of ANJESO [19]; [20] might indicate some loss of efficacy prior to 24 hours 
whereby the confidence intervals for the IV meloxicam and placebo overlap at later 
timepoints, the inclusion of BID doses of MECC-SA will assess whether BID dosing 
provides a better duration of action than QD dosing. 
 
 
 
 
The administration of MECC-SA 15 mg BID should therefore be 
well tolerated.
As MECC-SA will be administered under controlled conditions in a clinic-based study, the 
risks and benefits to individual subjects can be carefully assessed; rescue medication will be 
available to subjects (whether taking active or placebo) if the pain associated with the 
surgical procedure is too great post-dose.
The use of placebo in the study is appropriate to ensure that any change from baseline in pain 
assessments related to the study drug can be adjusted for the ‘placebo-response’ that is 
common in pain studies. All subjects will be allowed to use rescue medication if the pain 
associated with the surgical procedure is too great post-dose.
Complete information for MECC-SA may be found in the Single Reference Safety 
Document, which for this study is the MECC-SA Investigator’s Brochure.


Protocol MECC-TBZ-2001
Page 31 of 102
Protocol Version 5.0 15 September 2020
Confidential
2
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objectives
To evaluate the efficacy and safety of MECC-SA in subjects following dental surgery and to 
establish the dose response relationship.
2.2
Endpoints
2.2.1
Primary Endpoint

Overall (summed) pain intensity difference (SPID) over 0-24 hours.
2.2.2
Secondary Endpoints
Efficacy

Overall (summed) pain intensity difference (SPID) over 0-2 hours, 0-4 hours, 
0-8 hours, 0-12 hours and 12-24 hours after initial dose of study drug.

Pain intensity difference (PID) over time.

Total pain relief (TOTPAR) over 0-2 hours, 0-4 hours, 0-8 hours, 0-12 hours, 
12-24 hours, and 0-24 hours.

Time to perceptible relief (as measured by double-stopwatch technique) after first 
dose.

Time to meaningful pain relief (as measured by double-stopwatch technique) after 
first dose.

Proportion of subjects with overall pain reductions from baseline of ≥30% and ≥50% 
within 4 hours following the first dose.

Patient’s global assessment (PGA) of pain control from 0-24 hours.

Elapsed time from the start of study medication to first rescue medication 
administration.

Proportion of subjects using rescue medication from 0-24 hours.

Number of times rescue medication used from 0-24 hours.
Safety 

Adverse Events.

Laboratory safety tests.

ECGs.


Protocol MECC-TBZ-2001
Page 32 of 102
Protocol Version 5.0 15 September 2020
Confidential

Vital signs.
PK

Population PK parameters for meloxicam and salicylic acid (Cmax, pAUC0-4 and 
pAUC0-24).
3
STUDY DESIGN
3.1
Overall Design
This will be a randomized, double-blind, placebo-controlled, parallel group, dose-ranging 
study, randomizing approximately 110 male or female subjects that have had third molar 
dental surgery. Subjects will receive a dose of study drug on Day 1 after surgery and a further 
dose approximately 12 hours later.
3.2
Rationale for Study Design
The study design is consistent with research design recommendations of the IMMPACT 
(Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) group for trials 
involving subjects with short-duration acute pain [23].
The dental surgical pain model has been in widespread use for over 50 years, is well 
characterized, and is frequently used to investigate the pharmacodynamic properties of 
analgesic molecules (onset/offset, dose response, and potency). Efficacy in the dental model 
is highly predictive of efficacy in later stage models and has a high assay sensitivity [24]. The 
model is also ideal as the surgery, the anesthetic regimen, and perioperative care protocols 
can be standardized across patients. 
The dental surgical pain model has demonstrated the efficacy of analgesic medications across 
a range of different pharmacology, including NSAIDs and opioids [24] and specifically has 
demonstrated efficacy for an IV formulation of meloxicam [18] recently approved as 
ANJESO.
This study will specifically identify if MECC-SA has efficacy in a model of acute 
post-operative pain and will enable the identification of the most appropriate dose and regime 
of MECC-SA to continue in development.
3.3
End of Study Definition
End of study is defined as last subject, last visit.
4
STUDY POPULATION
4.1
Study Population
Approximately 110 subjects will be randomized to give approximately N=100 evaluable 
subjects for the primary endpoint (N=20/treatment arm).


Protocol MECC-TBZ-2001
Page 33 of 102
Protocol Version 5.0 15 September 2020
Confidential
Screening to end of study for each subject will be approximately 1.5 months in duration.
4.2
Inclusion and Exclusion Criteria
4.2.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate medically qualified 
member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Males and females ≥18 years of age. Females may be of either childbearing or 
non-childbearing potential. All females of childbearing potential must be using an 
acceptable, highly effective method of contraception and have a negative serum 
pregnancy test at screening.  
2. Requirement for dental surgery for extraction of ≥2 x third molars, at least 1 of which 
involves partial or complete mandibular bony impaction. 
3. Pain Intensity (PI) using a Numeric Pain Rating Scale (NPRS) ≥5 during the 5 hours 
following the end of surgery. 
4. Rating of moderate or severe pain on a 4-point categorical pain rating scale (i.e., none, 
mild, moderate, severe) during the 5 hours following the end of surgery.
5. Able to understand and complete the study requirements (including literacy, to enable 
diary and questionnaire completion), provide written informed consent, and agree to 
abide by the study protocol and its restrictions.
4.2.2
Exclusion Criteria
Subject candidates must not be enrolled in the study if they meet any of the following criteria:
1. Previously dosed with MECC-SA.
2. Subject with known hypersensitivity to aspirin, NSAIDs or other medication used in the 
study.
3. Subjects with known hypersensitivity to items used in surgery.
4. Active GI bleeding or a history of peptic ulcer disease.
5. Active inflammatory bowel disease, e.g., Crohn’s Disease or ulcerative colitis.
6. A history of bleeding disorders that may affect coagulation.
7. Significant history of respiratory insufficiency, hypotension, bradycardia, migraine, 
frequent headaches, seizures, renal, hepatic, cardiovascular metabolic, neurologic or 
psychiatric disease, in the opinion of the Investigator.
8. History of Hepatitis B or C or HIV infection.
9. History of alcohol or drug abuse within the last 5 years prior to the study.


Protocol MECC-TBZ-2001
Page 34 of 102
Protocol Version 5.0 15 September 2020
Confidential
10. History of myocardial infarction or coronary artery bypass graft surgery within the 
12 months prior to the study.
11. Clinically significant abnormality on the 12-lead ECG at screening which in the judgment 
of the investigator would put the subject at potential risk if enrolled into the study (these 
subjects should not be re-screened). Clinically significant abnormalities may include but 
are not limited to the following: left bundle branch block, Wolff-Parkinson-White 
syndrome, clinically significant arrhythmias (e.g., ventricular tachycardia). 
12. History of long QT syndrome or screening ECG with QTcF >470 milliseconds for female 
or >450 milliseconds for male subjects.
13. Current evidence of, or history within the 6 months prior to screening of unstable 
ischemic heart disease, NYHA Class II-IV right or left ventricular failure.
14. History of malignancy of any organ system treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases. The only exceptions 
are previous in situ carcinoma of the cervix, localized basal cell carcinoma of the skin or 
localized squamous carcinoma of the skin if the subject has been treated and is considered 
cured.
15. Use of any investigational drug within 28 days, or 5 half-lives, prior to screening 
whichever is longer.
16. Use of medications with the potential to interact with MECC-SA (as indicated in the 
current Investigator’s Brochure), or medications required during the study such as local 
anesthesia or sedatives, or medications with the potential to affect or confound pain status 
during the study. This includes (but not limited to) use of any of the following 
medications: 

Strong CYP2C9 inhibitors or inducers within 28 days or 5 half-lives (whichever is 
longer) prior to the study.

Long term opioid use (>30 consecutive days in the past year) and/or use of extended 
release opioids within 30 days of the dental extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs within 28 days 
prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other than the nitrous 
oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.


Protocol MECC-TBZ-2001
Page 35 of 102
Protocol Version 5.0 15 September 2020
Confidential

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 28 days prior to the 
study.

Pemetrexed within 28 days prior to the study.

Combination of diuretic with ACE inhibitor or angiotensin receptor blocker within 
28 days prior to the study.

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.

Aspirin within 7 days prior to the surgery.

Analgesics (including opioids, acetaminophen and NSAIDs) within 24 hours prior to 
the surgery.
17. Inability to refrain from any of the following medications pre-, intra-, or post-surgery:

Systemically administered corticosteroids.

Epidural or spinal anesthetics.

General anesthesia.

Analgesia other than those pre-specified for breakthrough pain relief.
18. BMI >35 kg/m2.
19. Pregnant or nursing females or females intending to become pregnant during the course 
of the study. 
20. Serum creatinine >1.5 x Upper Limit of Normal.
21. Serum ALT, AST, or bilirubin >2 x Upper Limit of Normal.
22. Clinically significant abnormal laboratory test(s) at screening deemed exclusionary by the 
Investigator.
23. Signs or symptoms of an infection or a fever that would increase the risk of surgery.
24. Other acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.


Protocol MECC-TBZ-2001
Page 36 of 102
Protocol Version 5.0 15 September 2020
Confidential
4.2.3
Criteria for Study Drug Termination, Withdrawal From the Study and Study 
Termination
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center.
Every effort should be made to retain subjects in the study. When available, a reason for not 
completing the study will be recorded in the case report form (CRF).
If, a subject discontinues from the study prematurely, due to any reason as provided in the 
below withdrawal criteria, the site should request the subjects’ consent for being followed-up 
during further study visits to perform safety and efficacy assessments as per Table 1. 
Subjects must be withdrawn from the study prior to randomization under the following 
circumstances:

The subject withdraws consent.

The subject has a positive pregnancy test at Visit 2 (Day 1) or at any preceding point 
prior to this following Screening (Visit 1).

Despite education/reinforcement, the subject shows persistent inadequate compliance 
with required study visits/procedures, potentially compromising safety monitoring 
while on study drug based on investigator’s discretion.

The subject takes prohibited treatment presenting a safety concern to dosing with 
study drug.

If it is in the subject’s best interest based on decision of the Principal Investigator or 
Sub-Investigator e.g., due to occurrence of an AE and/or other findings considered to 
present a safety concern prior to dosing with study drug. Specifically, the following 
would mandate withdrawal:
o
The subject experiences a GI bleed or significant CV event prior to Visit 2 
(Day 1). 
o
The subject has significant abnormalities observed (after appropriate repeat 
assessments to confirm the findings) on 12 lead ECGs such as left bundle 
branch block, Wolff-Parkinson-White syndrome, clinically significant 
arrhythmias (e.g., ventricular tachycardia) or QTcF >500 msec.
A subject may be required to terminate study drug for reasons including the following:

The subject withdraws consent.

For female subjects, diagnosis of pregnancy or stated intention to become pregnant. 
All efforts should be made by the site to obtain consent from the pregnant women, so 
that they are followed until delivery or termination.


Protocol MECC-TBZ-2001
Page 37 of 102
Protocol Version 5.0 15 September 2020
Confidential

Despite education/reinforcement, the subject shows persistent inadequate compliance 
with required study visits/procedures, potentially compromising safety monitoring 
while on study drug based on investigator’s discretion.

The subject takes prohibited treatment presenting a safety concern to continued 
dosing with study drug.

The subject requires more than 6 tablets/day (equivalent to 30 mg hydrocodone and 
1950 mg acetaminophen) rescue medication.

At the investigator’s discretion (it is recommended that the investigator discusses with 
medical monitor prior to decision), if it is in the subject’s best interest due to 
occurrence of an AE and/or other findings considered to present a safety concern to 
continued dosing with study drug and warrants treatment withdrawal. Specifically, the 
following would mandate withdrawal:
o
The subject experiences a GI bleed or significant CV event.
o
The subject has significant abnormalities observed (after appropriate repeat 
assessments to confirm the findings) on 12-lead ECGs such as left bundle 
branch block, Wolff-Parkinson-White syndrome, clinically significant 
arrhythmias (e.g., ventricular tachycardia) or QTcF >500 msec.

If the blind is broken for a subject by the Investigator.
The Principal Investigator and/or Mylan reserves the right to terminate the study for any 
reason.
The study will be terminated early if there are significant subject safety concerns that are 
indicative of a change to the risk: benefit profile for the overall study population. In this case 
the IRB will be informed accordingly.
Subjects who prematurely terminate the study will have discharge procedures performed 
prior to leaving the clinic or an Early Termination (ET) visit scheduled as soon as possible. 
4.3
Replacement Policy
Subjects who are withdrawn from the study will not be replaced.
4.4
Lifestyle Guidelines
Subjects are to observe the following restrictions during the study.
4.4.1
Meals and Dietary Restrictions
In order to avoid interference with sedation and operative procedures subjects should fast 
from midnight prior to the surgery.
Subjects will be allowed to eat food after 2 hours post-first dose.
Subjects should not consume any water or other drinks for 2 hours prior to the surgery.


Protocol MECC-TBZ-2001
Page 38 of 102
Protocol Version 5.0 15 September 2020
Confidential
Subjects may consume water and other drinks ad libitum following completion of the 
surgery.
Subjects will be given snacks and meals at appropriate times (after the fasting period) during 
confinement in the clinic.
4.4.2
Alcohol and Tobacco
At all study visits, subjects will be required to: 

Abstain from alcohol for at least 24 hours prior to admission for the surgery at Visit 2 
(Day 1) and continue abstaining from alcohol until after discharge on Visit 2 (Day 2). 

Abstain from smoking or vaping (or other tobacco based products) following 
admission for the surgery at Visit 2 (Day 1) and continue abstaining from smoking or 
vaping until after discharge on Visit 2 (Day 2).
4.5
Contraception
4.5.1
Females - Non-Childbearing Potential
Female subjects of non-childbearing potential must meet at least one of the following criteria:
1. Postmenopausal females, defined as females, who have been amenorrheic for at least 
2 years and confirmed via serum FSH.
2. Females who have a documented hysterectomy and/or bilateral oophorectomy.
All other females will be considered to be of childbearing potential.
4.5.2
Females - Childbearing Potential
Female subjects of childbearing potential must use an acceptable, highly effective method of 
contraception starting 28 days prior to dosing and continuing at least 28 days following the 
last treatment, such methods include at least one of the following:

Abstinence (periodic abstinence is not acceptable)

Tubal ligation

Intrauterine device or intrauterine system

Barrier method, like condom, with spermicide

Male partner who has had a vasectomy for at least 6 months. Male partners with 
vasectomies of <6 months are NOT considered protected

Hormonal contraceptives (oral, injected, transdermal, or implanted) with the 
exception of low dose gestagens, i.e., only containing lynestrenol or norethisterone, 
since they do not inhibit ovulation and are therefore not considered as highly 
effective. The subject must remain on the hormonal contraceptive throughout the 


Protocol MECC-TBZ-2001
Page 39 of 102
Protocol Version 5.0 15 September 2020
Confidential
study and must have been on a stable regimen of hormonal contraceptives for an 
adequate period prior to the study to ensure effectiveness (e.g., 3 months)
4.6
Pregnancy Testing
A serum pregnancy test will be performed on all female subjects at Screening. Urine 
pregnancy testing will be performed on all females of childbearing potential at subsequent 
visits as described in the schedule of activities (results will be reviewed and must be negative 
prior to dosing). In the event of a positive test, the subject will be withdrawn from the study 
(or will not enter the study if during screening).
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the sponsor as per Section 10.5.
5
STUDY DRUG
5.1
Investigational Drug
MECC-SA will be provided as 10 and 15 mg tablets.

15 mg tablets (and matching placebo) 
 

10 mg tablets (and matching placebo) 
 
Placebo is a tablet identical to the corresponding dose of active study drug.
To maintain the blind, subjects will take in a double dummy design, two tablets (one that is 
representative of a 10 mg tablet and one that is representative of a 15 mg tablet) of study drug 
or placebo will be administered on one day, Visit 2 (Day 1). Due to the double dummy 
design, neither the subject, nor the Investigator will know what treatment a subject receives. 
To maintain the blind, regarding QD and BID dosing, subjects assigned to QD treatment arms 
will receive placebo at the second dose. Additionally, per the clinic procedures, subjects will 
be blindfolded during dosing.
Study drugs will be administered following randomization and approximately 12 hours 
following the first dose.
5.1.1
Administration of Study Drugs
Study drug (two tablets containing MECC-SA or matching placebo) will be administered in a 
double dummy design at the clinic at each dosing time.
Subjects should take the study drugs with about 240 mL of water at ambient temperature in 
each period under the supervision of trained study personnel. 
This activity will be followed by mouth and hand check of the subjects to assess compliance 
to dosing.


Protocol MECC-TBZ-2001
Page 40 of 102
Protocol Version 5.0 15 September 2020
Confidential
Study drugs must be swallowed whole and must not be chewed, crushed or divided.
In the event of any significant dosing errors, the Medical Monitor, or Mylan study contact 
should be contacted immediately.
5.2
Drug Inventory
Mylan will supply: 

MECC-SA and matching placebo.
The Investigator site will supply:

Medication required for sedation and anesthesia during the surgery.

Rescue medication for pain relief following randomization, 
hydrocodone/acetaminophen (5/325 mg).

All materials associated with the surgical procedure.
5.3
Study Medication Complaints
In the event the subject has a complaint/concern during study participation regarding the 
study supplied study medication, they should contact the site.
In the event of a complaint/concern regarding any study medication provided by Mylan for 
this study, as a minimum the following information should be sent by the site via e-mail to 

Study number

Principal Investigator name

Subject ID

Date of occurrence of incident/complaint

Description of incident/complaint (facts)

Confirmation if the complaint caused or resulted in a SAE? If “Yes”, confirmation 
that the SAE has been reported
Additional information and potentially the return of study medication may be requested by 
Mylan in order to investigate the complaint.
5.4
Storage, Disposition of Unused Study Drug and Drug Accountability
The Investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the investigator site.
Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator’s Brochure may be superseded by the label storage.


Protocol MECC-TBZ-2001
Page 41 of 102
Protocol Version 5.0 15 September 2020
Confidential
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Mylan or designee. At sites where daily monitoring and 
recording is not possible at weekends, then on the next working day after the weekend the 
temperature record (e.g., max/min thermometers) should be checked immediately for any 
temperature excursions. Devices used for temperature monitoring should be regularly 
calibrated. Affected material must be placed into quarantine until the impact of the excursion 
has been assessed and confirmed by Mylan. 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. If Mylan supply drug accountability forms these must be used. 
Alternatively, Mylan may approve use of standard institution forms. In either case, the forms 
must identify the study drug, including batch or code numbers, and account for its disposition 
on a subject-by-subject basis, including specific dates and quantities. The forms must be 
signed by the individual who dispensed the drug, and copies must be provided to Mylan or 
designee.
At the end of the study, Mylan will provide instructions as to disposition of any unused 
investigational product. If Mylan authorizes destruction at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Mylan. Destruction 
must be adequately documented.
5.5
Randomization 
Assignment of Subject Identification (SID) number, randomization number and study 
medication, as well as site drug inventory control will be managed by an automated 
Interactive Voice/Web Response system (IVRS/IWRS). A manual containing complete 
instructions for internet or telephone access and use will be provided to each site prior to 
study start. At their first clinic visit, the IVRS/IWRS will assign a SID. Each SID will be 
unique and serve as the primary subject identifier throughout all phases of the study. The SID 
must appear on all CRF pages, source documents, laboratory data, ECG and diary data. 
Subjects qualifying to enter the study drug treatment phase, will be assigned an additional 
“randomization number” by the IVRS/IWRS at randomization. Subjects will be allocated to 
treatment within blocks for the given allocation ratio.
At Visit 2 (Day 1) eligible subjects will be randomized to receive MECC-SA (10 mg QD, 
15 mg QD, 10 mg BID or 15 mg BID) or matching placebo in a 1:1:1:1:1 ratio through the 
IVRS/IWRS.
5.6
Breaking the Blind
Emergency subject unblinding will be managed by an automated IVRS/IWRS. 


Protocol MECC-TBZ-2001
Page 42 of 102
Protocol Version 5.0 15 September 2020
Confidential
A manual containing complete instructions for internet or telephone access and use will be 
provided to each site prior to study start.
Subject unblinding should be discouraged unless knowing the treatment received by the 
subject would change the way an AE is treated.
5.7
Rescue Medication For Relief of Pain
Any use of rescue medication while the subject is in the clinic will be recorded, including the 
dose and time of administration.
5.7.1
Pre-Dose
If a subject requires the use of rescue medication prior to administration of study drug, the 
subject will not be eligible for randomization.
5.7.2
Post-Dose
Rescue medication of immediate release hydrocodone/acetaminophen (5/325 mg) will be 
allowed to treat breakthrough pain, subjects will be encouraged to refrain from rescue 
medication until at least 1-hour post-dose. A dose of rescue medication will be allowed as 
needed up to once every two hours. A maximum of 6 tablets (equivalent to 30 mg 
hydrocodone and 1950 mg acetaminophen) will be allowed; if a subject requires greater than 
this the subject should be withdrawn from the study.
Pain Intensity will be measured immediately before any rescue medication is administered.
5.8
Concomitant Medications
All concomitant medications taken during the study (from signing informed consent to 
post-study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the CRF. All subjects will be questioned about concomitant medication at 
each clinic visit and at follow up.
Medications taken prior to dosing with study medication will be documented as a prior 
medication. Medications taken after dosing with study medication will be documented as 
concomitant medications.
Subjects will abstain from all prohibited medications as described in the exclusion criteria 
section of this protocol (Section 4.2.2). Use of prohibited medication during the study will be 
deemed a protocol deviation and such subjects will be assessed by Mylan or designee 
regarding potential need to early terminate study drug (e.g., for safety reasons – see 
Section 4.2.3).
5.9
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug
Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, 
nausea, vomiting and epigastric pain, which are generally reversible with supportive care. 


Protocol MECC-TBZ-2001
Page 43 of 102
Protocol Version 5.0 15 September 2020
Confidential
Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal 
failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular 
collapse and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic 
ingestion of NSAID and may occur following an overdose.
Subjects should be managed with symptomatic and supportive care following an NSAID 
overdose or symptoms suggestive of excessive pharmacological effect. Accelerated removal 
of meloxicam by 4 g oral doses of cholestyramine given three times a day has been 
demonstrated in a clinical trial [25].
5.10 Treatment Compliance
Subjects will be dosed in the clinic on Visit 2 (Day 1) of the study, a visual check of the 
subject’s mouth and hands will be made to ensure compliance of dosing.
6
STUDY CONDUCT
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the investigator. They will be provided with a written copy of the 
informed consent form (ICF) for the study and given sufficient time to consider the study’s 
implications before deciding to participate. Subjects agreeing to participate in the study will 
sign the ICF and be given a duplicate copy before undergoing any screening or pre-screening 
(if required) procedures. A unique SID will be issued at the time of consent by IVRS/IWRS 
system. 
Once a subject enrolls in this trial the site will make every effort to retain the subject for the 
planned duration of the trial. Clinical trial site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following.

Thorough explanation of the complete clinical trial visit schedule and procedural 
requirements during the informed consent process and re-emphasis at each clinic visit.

A simple explanation of the key data and key time points that are critical for the trial's 
successful analysis, and the importance of all the treatment groups to the overall 
success of the trial.

Discussion at screening, and subsequent regular review of possible barriers to clinic 
visit attendance and full study participation and compliance.

Collection of contact information at screening (address, phone numbers, email), 
which is regularly reviewed at subsequent clinic visits.

Use of appropriate and timely study visit reminders.

Immediate and multifaceted follow-up on missed clinic visits.
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 


Protocol MECC-TBZ-2001
Page 44 of 102
Protocol Version 5.0 15 September 2020
Confidential
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the CRF. Regardless of 
site plans to support and retain subjects within the trial, subjects may voluntarily withdraw 
from the trial for any reason and at any time.
For a subject that completes the study and all procedures it is anticipated that the duration of 
study would be approximately 1.5 months. 
For details and timings of assessments, refer to Section 7.
6.1
Screening Procedures
Each prospective subject must agree to participate in screening procedures by signing the 
most recent ICF before any screening procedure is initiated. The Principal Investigator or 
Medical Sub-Investigator will review the inclusion and exclusion criteria to confirm 
eligibility of each subject prior to enrollment.
6.1.1
Screening (Visit 1)
Subjects will commence screening procedures within 30 days prior to the planned surgical 
procedure and subsequent randomization, to confirm that they meet the selection criteria for 
the study. If the time between screening procedures and potential randomization exceeds 
30 days as a result of unexpected delays, then the subject will need to be discussed with 
Mylan or designee to consider potential for re-screening (if re-screening is agreed, the subject 
will need to be re consented and assigned a new SID via IVRS/IWRS). Re-screening for 
other reasons may be possible following discussion with the Mylan or designee. If 
re-screening occurs this will be clearly documented within the site file.
At Screening (Visit 1), the following will be completed; procedures can be performed in a 
different order, but informed consent must be obtained prior to any procedures and the 
12-lead ECG must be performed prior to vital signs or obtaining blood samples.

Written informed consent. 

IVRS/IWRS registration. 

Complete medical history, demographics. 

Complete history of all prescription or non-prescription drugs, dietary supplements 
taken within 28 days prior to consent. History of alcohol or illicit drug use.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent blood pressure (BP) and pulse rate 
(PR). 


Protocol MECC-TBZ-2001
Page 45 of 102
Protocol Version 5.0 15 September 2020
Confidential

Measure height and weight.

Serum pregnancy test for all female subjects. 

Blood will be collected for safety laboratory tests. Laboratory tests at screening 
include confirmation of non-childbearing potential in any female who has been 
amenorrheic for at least 2 years, via serum FSH. 

Urinalysis (for blood, protein etc.). Sample to be tested for microscopy/culture if 
positive for blood, protein, nitrites or leukocyte esterase.

Urine drug screen.

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Check study inclusion/exclusion criteria.

Review AEs (AEs are to be recorded starting from signature of consent).

Schedule Visit 2 (Day 1) and remind the subject of lifestyle and study drug and 
concomitant medication requirements for visits.
o
Subjects should be reminded to fast from midnight prior to the surgery.
Subjects may be discharged from the clinic following completion of all assessments.
6.2
Treatment Phase
6.2.1
Visit 2 (Day 1)
The following procedures will be completed; procedures can be performed in a different 
order as long as they are performed at the correct nominal time and would not impact on 
other tests, e.g., 12-lead ECGs that are taken at the same nominal time as vital signs or blood 
samples are taken prior to those other procedures:
6.2.1.1 Pre-Dose Procedures

Check the subject has fasted from midnight.

Review AEs.

Review concomitant medications.

Record vital signs – supine or semi-recumbent blood pressure (BP) and pulse rate 
(PR).

Perform urine drug screen.

Urine pregnancy test (if female of childbearing potential).

Check study inclusion/exclusion criteria.


Protocol MECC-TBZ-2001
Page 46 of 102
Protocol Version 5.0 15 September 2020
Confidential

Record body temperature.

Diary training.

Perform dental surgery, using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will 
also receive prophylactic antibiotics post-surgery.

Pain assessments (Pain Intensity (0-10-point numeric pain rating scale – NPRS) and 
Categorical Pain Rating (4-point scale – none, mild, moderate, severe)) will be made 
during the 5 hours post-surgery until a baseline pain assessment is achieved.
o
Subjects with NPRS ≥5 and a rating of moderate or severe pain on a 4-point 
categorical pain rating scale (i.e., none, mild, moderate, severe) during this 
time they will be eligible for randomization.

Randomization using IVRS/IWRS.
o
To occur such that dosing occurs within 15 minutes of the eligible pain scores.

12-lead ECG – supine or semi-recumbent taken prior to dosing.

Vital signs (BP and PR) – supine or semi-recumbent taken prior to dosing.

Blood for a PK sample taken prior to dosing.
6.2.1.2 Dosing and Post-Dose Procedures

Administer first dose of study drug (two tablets to maintain the blind).
o
Within 15 minutes of the baseline pain scores.

Administer second dose of study drug (two tablets to maintain the blind).
o
Approximately 12 hours after the first dose.

Pain Intensity (0-10-point NPRS) measured at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 
4, 5, 6, 7, 8, 12, 14, and 16 hours after the first dose of study medication and 
immediately before any rescue medication and/or at the time of early termination. 
Assessments will also be made immediately following the time of first relief and time 
of meaningful relief.
o
Pain scores should be made at the nominal time in the event of more than one 
procedure taking place at the same nominal time.

Pain Relief Assessments (5-point scale - none = 0, slight = 1, moderate = 2, good or a 
lot = 3, and complete = 4) measured at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 
7, 8, 12, 14, and 16 hours after the first dose of study medication and immediately 
before any rescue medication and/or at the time of early termination. Assessments 
will also be made immediately following the time of first relief and time of 
meaningful relief.


Protocol MECC-TBZ-2001
Page 47 of 102
Protocol Version 5.0 15 September 2020
Confidential
o
Pain scores should be made at the nominal time in the event of more than one 
procedure taking place at the same nominal time.

Time of first perceptible relief is recorded (double-stopwatch method) – time the first 
stopwatch is stopped.
o
Defined as post-dose time at which the subject first begins to feel pain relief.

Time of meaningful relief is recorded (double-stopwatch method) – time the second 
stopwatch is stopped.
o
Defined as the post-dose time at which the subject begins to feel meaningful 
pain relief.

PK sample taken at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, and 
16 hours after the first dose of study medication. 
o
Where PK samples and pain assessments occur at the same time, the pain 
assessment should be made prior to the PK sample.

Adverse events should be assessed throughout the day.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Any use of rescue medication should be recorded throughout the day.
o
Rescue medication will be allowed at any time, but subjects will be 
encouraged to wait until at least 1-hour post-dose if possible.
6.2.2
Visit 2 (Day 2)

Adverse events should be assessed throughout the day.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Any use of rescue medication should be recorded throughout the day.

Pain Intensity (0-10-point NPRS) measured at 20 and 24 hours after the first dose 
(Day 1) of study medication and immediately before any rescue medication.
o
Pain scores should be made at the nominal time in the event of more than one 
procedure taking place at the same nominal time.

Pain Relief Assessments (5-point scale - none = 0, slight = 1, moderate = 2, good or a 
lot = 3, and complete = 4) measured at 20 and 24 hours after the first dose of study 
medication and immediately before any rescue medication and/or at the time of early 
termination.


Protocol MECC-TBZ-2001
Page 48 of 102
Protocol Version 5.0 15 September 2020
Confidential

Patient Global Assessment (PGA) of pain control will be made at 24 hours after the 
first dose. 

PK sample taken at 20 and 24 hours after the first dose of study medication.
6.2.2.1 Discharge Procedures

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent BP and PR. 

Urine pregnancy test (if female of childbearing potential). 

Urinalysis (dipstick for blood, protein etc.). Sample to be sent for microscopy/culture 
if positive for blood, protein, nitrites or leukocyte esterase.

Blood will be collected for safety laboratory tests. 

Review concomitant medications.

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Discharge subject from the clinic.
o
Provide appropriate post-discharge pain medications, per standard of care.
o
If a subject requires a longer duration of in-patient assessment due to reasons 
associated with the operation this is acceptable.
6.2.3
Early Termination (ET) visit
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the investigator or sponsor for reasons as 
per Section 4.2.3. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The investigator will contact Mylan or designee in the event that a 
subject fails to complete the study or violates the protocol.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 


Protocol MECC-TBZ-2001
Page 49 of 102
Protocol Version 5.0 15 September 2020
Confidential
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
conduct the procedures detailed below prior to leaving the clinic or return to the clinic for an 
ET visit and will have this scheduled as soon as possible after their last dose of study drug.
At the Early Termination (ET) visit (or discharge from the clinic) the following procedures 
will be completed:

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent BP and PR. 

Urine pregnancy test (if female of childbearing potential). 

Urinalysis (dipstick for blood, protein etc.). Sample to be sent for microscopy/culture 
if positive for blood, protein, nitrites or leukocyte esterase.

Blood will be collected for safety laboratory tests.

Review concomitant medications.

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
Subjects may be discharged from the clinic at the discretion of the investigator following 
completion of all ET assessments.
Subjects who decide to discontinue from treatment and agree to remain in the study, are 
required to adhere to the study protocol, thus perform all activities and as per the scheduled 
study visits for completion of all assessments and procedures as outlined in Table 1.
6.3
End of Study (EOS) Visit
The End of Study (EOS) Visit will be performed by telephone on Day 5-7 of the study. 
Procedures will be completed in the following order:

Review concomitant medications.

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Review rescue medication used.


Protocol MECC-TBZ-2001
Page 50 of 102
Protocol Version 5.0 15 September 2020
Confidential
Subjects will be reminded that AEs should be reported to the study staff up to 30 days after 
the last dose of study medication.
7
TREATMENT PROCEDURES AND ASSESSMENT CRITERIA
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The Mylan study team will be 
informed of these incidents in a timely fashion.
Activities specific to this protocol are summarized in Table 1 and expanded upon further 
below.
7.1
Dental Surgery
The dental surgery and related anesthesia, sedation, and prophylactic antibiotics are not 
investigational and will occur regardless of research.
The dental surgery (extraction of ≥2 x third molars, at least 1 of which involves partial or 
complete mandibular bony impaction) will be performed on Visit 2 (Day 1).
The procedure will be performed using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will also 
receive prophylactic antibiotics post surgically.
7.2
Efficacy Assessment
7.2.1
Pain Intensity (NPRS)
Pain Intensity (PI) (using a 0-10 point numeric pain rating scale (NPRS) where 0 is no pain 
and 10 is the worst pain imaginable) [26] will be assessed during the 5 hours following 
surgery. If the subject scores a NPRS ≥5 (and moderate or severe pain on the categorical 
scale) within 5 hours following surgery, they will be eligible for randomization.
Assessments will be made following surgery until a baseline pain is achieved.
Assessments will be made at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 
20, and 24 hours after the first dose of study medication, and immediately before any rescue 
medication and/or at the time of early termination.
Assessments will also be made immediately following the time of first relief and time of first 
meaningful relief.
The PI will be recorded in a diary.


Protocol MECC-TBZ-2001
Page 51 of 102
Protocol Version 5.0 15 September 2020
Confidential
7.2.2
Categorical Pain Rating
A pain rating using a 4-point categorical rating scale (none, mild, moderate, severe) will be 
used to assess eligibility for randomization. If the subject records moderate or severe (and a 
NPRS ≥5) within 5 hours following surgery, they will be eligible for randomization.
Assessments will be made following surgery until a baseline pain is achieved.
The categorical pain rating will be recorded in a diary.
7.2.3
Pain Relief Assessment
A pain relief assessment will be made using a using a 5-point scale - none = 0, slight = 1, 
moderate = 2, good or a lot = 3, and complete = 4.
Assessments will be made at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 
20, and 24 hours after the first dose of study medication, and immediately before any rescue 
medication and/or at the time of early termination.
Assessments will also be made immediately following the time of first relief and time of first 
meaningful relief.
The pain relief assessment will be recorded in a diary.
7.2.4
Patient Global Assessment (PGA)
A Patient Global Assessment (PGA) of pain control will be rated on a 5-point scale, ranging 
from 0 to 4, where 0-poor, 1-fair, 2 good, 3-very good, or 4-excellent. 
Assessments will be made at 24 hours after the first dose of study medication or at time of 
early termination if applicable.
The PGA will be recorded in a diary.
7.2.5
Time to First Perceptible Pain Relief
Time to first perceptible pain relief will be assessed using a double stopwatch approach. 
The time to onset of first perceptible pain relief (time that the first watch stopped) is defined 
as the post-dose time at which the subject first begins to feel pain relief. 
7.2.6
Time to Meaningful Pain Relief
Time to meaningful pain relief will be assessed using a double stopwatch approach. 
The time to onset of meaningful pain relief (time that the second watch stopped) is defined as 
the post-dose time at which the subject first begins to feel meaningful pain relief.


Protocol MECC-TBZ-2001
Page 52 of 102
Protocol Version 5.0 15 September 2020
Confidential
7.2.7
Rescue Medication Use
Rescue medication of immediate release hydrocodone/acetaminophen will be allowed at any 
time, but subjects will be encouraged to wait until at least 1-hour post-dose if possible. A PI 
score assessment will be made immediately prior to any rescue medication.
The time and dose of any rescue medication taken by a subject will be recorded in the CRF.
7.3
Safety Assessment
7.3.1
Adverse Event Assessment
If a subject reports any symptoms before drug administration, they will be evaluated by 
medical staff and necessary measurements will be performed. The Principal Investigator or 
Medical Sub-Investigator will be notified before dosing to determine the course of action.
Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant worsening from the screening procedures 
will be recorded as adverse events.
Subjects will be routinely queried in regard to the presence or absence of AEs using open 
ended questions. When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms. The clinic will provide documentation of any adverse events 
in the subject’s CRF. The AE source documentation will minimally include the following 
information: date and time of assessment, the outcome of the response, and identification of 
the clinic staff member collecting the information.
7.3.2
Laboratory Safety
The following safety laboratory tests (Table 7) will be performed at Screening (Visit 1) and 
Visit 2 (Day 2).
Table 7: 
Laboratory Safety Tests


Protocol MECC-TBZ-2001
Page 53 of 102
Protocol Version 5.0 15 September 2020
Confidential
Hematology
Chemistry
Urinalysis
Other 
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea and Creatinine
Glucose (non-fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
AST, ALT
Total Bilirubin
Direct/Indirect bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
CRP
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Microscopy/culturea
Serum FSHb
Serum/urine hCGc
Breath/blood alcohol 
testd
Urine drug screene
a. Only if urinalysis is positive for blood, protein, nitrites or leukocyte esterase.
b.Females who are amenorrheic for at least 2 years at Screening.
c. Serum hCG for all female subjects at Screening and urine hCG for females of childbearing potential at 
other visits.
d.At the Investigator’s discretion an alcohol test may be performed. Where necessary blood or breath alcohol 
tests can be performed.
e. Urine drug screen to include the following as a minimum cocaine, cannabinoids, opiates, buprenorphine, 
benzodiazepines and amphetamines. 
Hematology and chemistry will be analyzed by a local laboratory. Urinalysis will be 
conducted at the laboratory and if urine is positive for blood, protein, nitrites, or leukocyte 
esterase, will be analyzed via microscopy/culture by a laboratory. 
Additionally a urine drug test will be performed at Screening (Visit 1) and on admission at 
Visit 2 (Day 1). If a subject has a positive test for amphetamines but is prescribed medication 
such as to treat ADHD, they would still be acceptable at the Investigator’s discretion.
Blood volumes to be collected and blood and urine sample handling instructions will be per 
the local laboratory’s standard procedures. The Investigator will provide collection materials 
for packaging and shipment of samples to the laboratory.
Any clinically significant findings in laboratory safety data should be recorded as an AE. 
Determination of clinical significance and seriousness will be based on the Investigator's 
medical judgment.
7.3.3
Vital Signs - Blood Pressure and Pulse Rate
Blood pressure (BP) and pulse rate (PR) will be measured at Screening (Visit 1), Visit 2 (Day 
1), and Visit 2 (Day 2) at times specified in Table 1 and Section 6. Additional collection 
times, or changes to collection times of blood pressure and pulse rate will be permitted, as 
necessary, to ensure appropriate collection of safety data.


Protocol MECC-TBZ-2001
Page 54 of 102
Protocol Version 5.0 15 September 2020
Confidential
Supine or semi-recumbent BP will be measured with the subject’s arm supported at the level 
of the heart and recorded to the nearest mmHg after 5 minutes of rest. Where possible, the 
same arm (preferably the dominant arm) will be used throughout the study.
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time. The use of automated devices for measuring BP and PR 
are acceptable, although, when done manually, PR will be measured in the brachial/radial 
artery for at least 30 seconds. Any clinically significant changes in BP and PR should be 
recorded as an AE. Determination of clinical significance and seriousness will be based on 
the Investigator's medical judgment.
7.3.4
12-lead ECG
In this study, 12-lead ECGs will be recorded using clinic ECG devices. ECGs should be 
collected at measured at Screening (Visit 1), Visit 2 (Day 1), and Visit 2 (Day 2) at times 
specified in Table 1 and Section 6. All 12-lead ECGs will be single recordings.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
5 minutes in a supine or semi-recumbent position. Pre-dose ECGs should be performed prior 
to commencing blood sampling or vital signs assessments. 
To ensure safety of the subjects, a medically qualified individual at the site will assess ECG 
recordings and make any comparisons to baseline measurements.
At screening, the QTcF must be ≤470 msec for female or ≤450 msec for male subjects, and 
the ECG must show no clinically significant rate or rhythm abnormalities for the subject to be 
eligible (See Section 4.2.2). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. Any clinically 
significant ECG abnormalities measured at screening should be assessed for their effects on 
subject eligibility of the study and recorded in medical history. ECG parameters will not be 
recorded in the CRFs, but any clinically significant changes between the screening and 
subsequent ECGs should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the Investigator's medical judgment.
7.3.5
General Physical Examination
A full general physical examination will consist of an examination of the abdomen, 
cardiovascular system, lungs, lymph nodes, musculoskeletal and neurological systems, skin, 
extremities, head, ears, eyes, nose, and thyroid gland by trained medical personnel at the site. 
A full physical examination will be performed at Screening (Visit 1) and Visit 2 (Day 2).
Height and weight will be assessed at Screening (Visit 1). 


Protocol MECC-TBZ-2001
Page 55 of 102
Protocol Version 5.0 15 September 2020
Confidential
Physical examination results will not be recorded in the CRFs, but any clinical significant 
finding at Screening (Visit 1) should be recorded under medical history and changes between 
Screening (Visit 1) and subsequent examinations should be recorded as an AE. Determination 
of clinical significance and seriousness will be based on the investigator's medical judgment.
7.3.6
Blood Volume
Total blood sampling volume for an individual subject is approximately 103.5 mL. 
Additional blood samples may be taken for safety assessments, provided the total volume 
taken during the study does not exceed 500 mL during any period of 30 consecutive days, 
and the ethics committee/IRB is notified of the blood collection.
Table 8: 
Blood Volume
Number of Sampling Times
Sample Type
Sample 
Volume (mL)
Screening
Study Period
Total Volume (mL)
Safety Labs
21 (Screen)
10.5 (Discharge)
1
1
31.5
PK
4
0
18
72
TOTAL
103.5
7.4
Pharmacokinetics
7.4.1
Plasma for Analysis of Meloxicam
Blood samples will be collected at the following times, with the date and time of each sample 
being recorded in the CRF:

Pre-dose and 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 20, and 
24 hours after the first dose of study medication.
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time 
relative to dosing. However, samples obtained within 10% of the nominal time (e.g., within 
6 minutes of a 60-minute sample) for samples prior to ≤8 hours from dosing and ±1 hour for 
samples ≥12 hours from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and CRF.
PK sample handling instructions will be provided to the Investigator prior to initiation of the 
study.
Samples will be analyzed using validated analytical methods in compliance with Mylan 
standard operating procedures.
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method. These data will be 
used for internal exploratory purposes and will not be included in the clinical report. 


Protocol MECC-TBZ-2001
Page 56 of 102
Protocol Version 5.0 15 September 2020
Confidential
7.4.2
Shipment of Pharmacokinetic Samples
The shipment details and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.5
Restrictions
Study restrictions include all items listed in the Lifestyle Guidelines (Section 4.4) and the 
concomitant medications as described in the exclusion criteria section of this protocol 
(Section 4.2.2) and will be prohibited throughout the duration of the study. If concomitant 
medications change during the study, a discussion between the Principal Investigator or a 
Medical Sub-Investigator along with Mylan should occur, and a decision to continue or 
discontinue the subject will be made based on the medication’s pharmacology and 
pharmacokinetics.
8
STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.
8.1
Sample Size Determination
N=110 subjects (N=22/treatment arm) to give approximately N=100 evaluable subjects for 
the primary endpoint (N=20/treatment arm). This is on the basis of an approximately 10% 
dropout rate.
In order to derive the required sample size for the primary endpoint, simulations were 
performed according to the method described below:
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 57 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
The numerical dose values were 10, 15, 20, 30 and 0 for 10 mg QD, 15 mg QD, 10 mg BID, 
15 mg BID and placebo respectively.
 
 
 
 
 
 
8.2
Populations for Analyses
8.2.1
Safety Analysis Set
The safety analysis set (SS) will include all subjects who received at least one dose of study 
drug. Data will be summarized according to the treatment a subject actually received.
8.2.2
Intent To Treat Analysis Set
The ITT analysis set includes all randomized subjects who received study drug, including 
subjects who discontinued study treatment or received protocol allowed rescue medication.
8.2.3
Per Protocol Analysis Set
The per protocol analysis set (PP) will include all subjects in the ITT who had no major 
protocol violation that would impact on the primary efficacy endpoint. Significant protocol 
deviations are defined in Section 9.4 and will be further defined in the SAP. The list of major 
protocol deviations will be finalized prior to database lock and unblinding as part of the final 
blinded data review (BDR). Data will be summarized and analyzed according to the treatment 
a subject actually received at randomization.
8.2.4
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PK) will include all subjects who receive a dose of study 
medication and who provide at least one post dose concentration sample for the Population 
PK analysis.


Protocol MECC-TBZ-2001
Page 58 of 102
Protocol Version 5.0 15 September 2020
Confidential
8.3
Statistical Analyses
8.3.1
Definition of the Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the overall (summed) pain intensity difference (SPID) over 
0-24 hours.
8.3.2
Primary Analysis of Primary Endpoint
The primary analysis of the primary efficacy endpoint will be based on the intention-to-treat 
(ITT) population. 
The primary efficacy endpoint is the overall (summed) pain intensity difference over 
0-24 hours (SPID 0-24).
A 3-parameter Emax model will be fitted to the SPID 0-24 standardized means (observed 
mean for each dose and placebo divided by the pooled standard deviation) for placebo and 
5 mg, 10 mg and 15 mg MECC-SA. Standardized effect sizes will be estimated from the Emax 
model together with their 95% confidence intervals and p-values. Baseline pain intensity 
score (PI) will be used as a covariate in the Emax model.
The numerical dose values will be 10, 15, 20, 30 and 0 for 10 mg QD, 15 mg QD, 10 mg 
BID, 15 mg BID and placebo respectively.
Additional models may be explored utilizing a Multiple Comparison Procedure – Modeling 
(MCP-Mod) approach [27].
If the Emax model fails to converge, and no other suitable models are identified using 
MCP-Mod, an Analysis of covariance (ANCOVA) will be used to assess the difference 
between treatment groups for SPID 0-24. The ANCOVA model will include treatment and 
study site as fixed effects and baseline PI score as a covariate. The difference between 
MECC-SA and placebo will be estimated from the least squares means (LS means) along 
with the 95% confidence interval (CI) and associated 2-sided p-values. In addition, the 
standardized effect sizes for each dose will be calculated by dividing the differences in LS 
means for each dose and placebo by the pooled standard deviation.
Impact of Protocol Allowed Rescue Medication Use
For the primary analysis of the primary efficacy endpoint a 2-hour windowed last observation 
carried forward (W2LOCF) approach will be used whereby the PI score obtained before a 
given rescue medication will be carried forward to replace the PI scores collected at each 
observation timepoint within 2 hours following the rescue dose.
8.3.3
Secondary/Sensitivity Analysis of Primary Endpoint
Analyses for the primary endpoint will be repeated for the PP (8.2.3).
As a sensitivity analysis of the W2LOCF approach, a W4LOCF will also be used whereby 
the PI score obtained before a given rescue medication will be carried forward to replace the 


Protocol MECC-TBZ-2001
Page 59 of 102
Protocol Version 5.0 15 September 2020
Confidential
PI scores collected at each observation within 4 hours following the rescue dose. The analysis 
will be conducted in both the ITT and the PP analysis sets.
8.3.4
Missing Data
The amount of missing data is expected to be minimal given the short duration of the study.

Missing pain assessments for subjects who discontinued early due to lack of efficacy, 
an AE, or intolerance to study drug will be imputed using a baseline observation 
carried forward (BOCF) approach.

Missing pain assessments due to other reasons for discontinuing will be imputed using 
a last observation carried forward (LOCF) approach.

In addition to the BOCF/LOCF approaches outlined above, missing data may be 
imputed using appropriate multiple imputation (MI) methods. Further information 
will be provided in the SAP.

Intermittent missing pain assessments between two non-missing scores will be 
imputed using linear interpolation. 
The impact on the computation of the primary efficacy endpoint and the methods for 
handling missing data may be assessed in secondary/sensitivity analyses and any pre-planned 
analyses will be fully described in the SAP. As this is a Phase 2 study, additional post-hoc 
analyses may be carried out in order to more fully understand the data.
8.3.5
Sub-Group Analyses
Subgroup analyses may be specified in the SAP. As this is a Phase 2 study, additional 
post-hoc analyses may be carried out in order to more fully understand the data.
8.3.6
Definition and Analysis of the Secondary Endpoints
All hypotheses will be tested at a two-sided significance level of 0.05. Nominal p-values will 
be presented for all secondary endpoints without adjustment for multiple comparisons (since 
this is a Phase 2 study).
8.3.6.1 Secondary SPID Endpoints and TOTPAR
The SPID endpoints for the time intervals 0-2, 0-4, 0-8, 0-12 and 12-24 hours will be 
analyzed using the Emax/ANCOVA model used for the analysis of the primary endpoint.
The TOTPAR endpoints for the time intervals 0-2, 0-4, 0-8, 0-12, 12-24 and 0-24 hours will 
be analyzed using the Emax/ANCOVA model used for the analysis of the primary endpoint.
8.3.6.2 Pain Intensity Differences (PID) Over Time
PID scores over time will be analyzed using a longitudinal mixed model for repeated 
measures (MMRM) with fixed effects for treatment, study site, time, treatment by time 
interaction and baseline PI score. Subject will be fitted as a random effect. Variance 


Protocol MECC-TBZ-2001
Page 60 of 102
Protocol Version 5.0 15 September 2020
Confidential
estimation will be based on an unstructured covariance matrix. Missing data will be assumed 
to be Missing At Random (MAR). Least squares means (LS means) will be plotted by time to 
show the pain-relieving efficacy of both MECC-SA and placebo over 24 hours.
8.3.6.3 Time to Event Endpoints
The following analysis methods apply to the time-to-event endpoints listed:

Time to perceptible pain relief (PPR).

Time to meaningful pain relief (MPR).

Elapsed time from the start of study medication to first rescue medication 
administration.
Time to event endpoints will be analyzed and plotted using Kaplan-Meier methodology and 
differences between MECC-SA and placebo evaluated using the log-rank test. The median 
time to event will be calculated and presented.
8.3.6.4 Responder Endpoints
The following analysis methods apply to the responder endpoints listed:

Proportion of subjects with overall pain reductions from baseline of ≥30% and ≥50% 
within 4 hours following the first dose based on the PI scores. Both these analyses 
will be presented for both methods of handling rescue medication use (W2LOCF and 
W4LOCF approaches).

Proportion of subjects using rescue medication during 0-24 hours.

Patient’s Global Assessment (PGA) of pain control for 0-24 hours after the initial 
dose scored on the 5-point scale will be dichotomized and the percentage of subjects 
reporting a PGA score of 2 (good) or better defined as a responder.
The number and percentage of responders in each treatment group will be summarized. A 
comparison between MECC-SA and placebo will be evaluated with the odds ratio (OR) and 
corresponding 95% confidence interval from a logistic regression model with treatment group 
and baseline PI as a covariate.
8.3.6.5 Frequency of Rescue Medication Use 
The frequency of rescue medication use will be summarized and graphically presented for the 
0-24 hours period after the first dose of study treatment.
8.3.7
Pharmacokinetics
For all pharmacokinetic data analyses, the PK population will be used.
Samples for PK determination of drug concentrations of meloxicam and salicylic acid, in 
plasma will be determined by a bioanalytical laboratory using validated bioanalytical 


Protocol MECC-TBZ-2001
Page 61 of 102
Protocol Version 5.0 15 September 2020
Confidential
methods. Details of the validated bioanalytical method used will be provided in a separate 
bioanalytical report.
The plasma concentration data for meloxicam and salicylic acid will be listed, summarized on 
the basis of time intervals, and plotted using a scatter plot with time relative to the preceding 
meloxicam dosing time. Summary statistics (mean, standard deviation, minimum, maximum, 
number of subjects, and coefficient of variation) will be calculated for plasma concentrations 
for each time interval and by treatment group.
Population PK (PPK) analysis of meloxicam and salicylic acid concentrations will be 
performed using modeling. The PPK analysis will be conducted and reported separately. 
Details of the PPK model building will be described in a separate PPK analysis plan.
If the dose-response relationship cannot be established in this study (for example, no doses 
are effective, or all doses are equally effective) then exploratory exposure-response analysis 
may be conducted using individual predictions of exposure from the PPK analysis in this 
study. Outcomes from this analysis will be reported separately, if conducted.
8.3.8
Safety Analyses
Analysis of all safety data will be performed on the Safety Population and will be presented 
by the treatment received. 
8.3.8.1 Adverse Events
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Authorities (MedDRA). The occurrence of AEs and SAEs will be summarized in terms of 
incidence, as well as in terms of total number of AEs. Analysis of AEs in terms of incidence 
by severity and by relatedness will also be provided. 
Prior and concomitant medications will be coded using the latest version of WHO Drug 
Dictionary and will be summarized. Medical history will be listed by subject and coded using 
the latest version of MedDRA and will be summarized. 
8.3.8.2 Vital Signs
Blood Pressure and pulse rate will be listed and descriptively summarized (N, mean, standard 
deviation, minimum and maximum) by treatment group and visit. Baseline (defined as the 
pre-dose value collected on Visit 2 (Day 1) and changes from baseline will be similarly 
summarized. 
8.3.8.3 ECG Analyses
ECG data; QT, QTc (Fridericia’s), heart rate (HR), QRS duration, PR and RR interval will be 
listed.


Protocol MECC-TBZ-2001
Page 62 of 102
Protocol Version 5.0 15 September 2020
Confidential
Baseline (defined as the pre-dose value collected on Visit 2 (Day 1) and change from baseline 
for QT, QTcF, HR, QRS, RR and PR will be summarized using descriptive statistics (N, 
mean, standard deviation, minimum and maximum) by treatment and study week.
For QTcF a classification of absolute values and increases from baseline will be performed. 
The number of subjects with maximum absolute QTcF <450 msec, 450 msec ≤QTcF 
<480 msec, 480 msec ≤QTcF <500 msec and QTcF values ≥500 msec will be tabulated by 
treatment and visit. The number of subjects with maximum increase from baseline QTcF 
<30 msec, 30 msec ≤QTcF <60 msec and QTcF ≥60 msec will be tabulated by treatment and 
visit.
8.3.8.4 Laboratory Data
Descriptive summaries of observed values and change from baseline (defined as the samples 
collected on Screening (Visit 1)) will be presented for clinical laboratory evaluations (Serum 
chemistry and hematology) by treatment group. Assessments of laboratory variables 
according to clinical relevance will be tabulated by visit and treatment group for each clinical 
laboratory parameter in frequency tables. Additionally, for each laboratory parameter, shifts 
in value from baseline to all post-baseline visits will be presented by treatment group in shift 
tables.
The assessment of categorical urinalysis variables will be tabulated by visit for each urine 
parameter by treatment group in frequency tables. Additionally, for each of the urine 
parameters, shifts in assessments from baseline to all post-baseline visits will be presented for 
each treatment group in shift tables.
8.3.9
Planned Interim Analyses
Not Applicable.
9
ADMINISTRATIVE PROCEDURES
9.1
Source Documentation Forms
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance.
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g., laboratory data) or 
entered manually into CRF/database.


Protocol MECC-TBZ-2001
Page 63 of 102
Protocol Version 5.0 15 September 2020
Confidential
9.2
Access to Data/Source Documentation
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections.
9.3
Final Clinical Study Report and Case Report Forms (CRFs)
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of any 
protocol deviations. The final report will also include reasons for withdrawals and any 
necessary treatment(s). The report will also include tables presenting demographics (separate 
summary tables for enrolled and completed subjects), and AEs recorded during the study. In 
addition, the clinical study report will include a Quality Assurance statement, documenting 
that the report has been reviewed for completeness, accuracy, and compliance with the 
protocol and applicable local and federal regulations. For final clinical reporting purposes 
only, AEs deemed “definite”, “probable” or “possible” will be included in the 
treatment-related summaries/listings.
Case Report Forms (CRFs) containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
Principal Investigator must sign each subject’s CRF after completion of data entry, signifying 
that the data entered in the CRF is complete and accurate. Electronic CRFs may be provided.
9.4
Adherence to Protocol
Except for an emergency situation in which proper care for the protection, safety and 
well-being of the study subjects requires medical treatment, the study will be conducted as 
described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report.
For the purposes of assessing protocol deviations, procedures conducted ±10% of the 
nominal timepoint will not be considered a protocol deviation.
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data:

Subject did not meet efficacy-defined inclusion criteria (e.g., inclusion criteria 3 and 
4)

Subject did not meet exclusion criteria which may potentially impact the primary 
efficacy endpoint (to be reviewed and assessed on a case-by-case basis)


Protocol MECC-TBZ-2001
Page 64 of 102
Protocol Version 5.0 15 September 2020
Confidential

Subject who is not 100% compliant with study medication

Subject received an excluded concomitant treatment or medication that may impact 
the primary efficacy endpoint (e.g., a concomitant NSAID or other analgesic that is 
not pre-specified for rescue medication)
Additional criteria may be specified in the SAP.
9.5
Data Handling and Record Retention
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the trial 
subjects remains protected.
A CRF is required to be completed for each subject receiving study medication. The CRF is 
property of the sponsor and the Investigator must review all CRFs prior to submission to the 
sponsor.
The CRF may be considered as the source document. The investigator must seek prospective 
agreement to the sponsor in writing to use the CRF as source document prior the start of the 
study. In addition, items directly recorded in the CRF must be documented that they will be 
considered as source.
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted.
The investigator must obtain in writing the sponsor’s agreement to dispose of any records, 
even if the retention period has been reached.
9.6
Confidentiality
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee.
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data.


Protocol MECC-TBZ-2001
Page 65 of 102
Protocol Version 5.0 15 September 2020
Confidential
9.7
Ethics and Regulatory Authorities
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH-E6) in addition to the regulatory requirements of the country where the study is 
being conducted as well as the country where the study will be submitted.
9.7.1
Institutional Review Board/Ethics Committee
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
consent to the investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the sponsor prior to enrolling any subjects into the study.
9.7.2
Regulatory Authority
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted to the local Regulatory Authorities 
for review and approval prior to trial start. Upon completion, the Regulatory Authorities will 
be notified the study has ended. The study will only be undertaken in compliance with the 
local regulatory requirements.
9.8
Informed Consent
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document(s) to be used will be submitted by the Investigator to an 
independent institutional review board (e.g., IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The Investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record.
9.9
Disclosure and Publication of Clinical Study Data
The disclosure and publication of clinical study data will be detailed in the clinical trial 
agreement with the Investigators.
9.10 End of Trial
The end of trial is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later.


Protocol MECC-TBZ-2001
Page 66 of 102
Protocol Version 5.0 15 September 2020
Confidential
10 ADVERSE EVENTS AND SAFETY REPORTING
The adverse event collection period begins at signing of informed consent and continues until 
the telephone End of Study (EOS) Visit. Adverse events occurring during this period need to 
be reported to the sponsor according to Section 10.3. The Investigator is also responsible for 
notifying the sponsor if he/she becomes aware of any adverse event after the study period has 
ended and it is considered related to the study medication (i.e., an adverse drug reaction). 
Once an AE is detected, it should be followed until its resolution or until it is judged by the 
principal investigator to be stable or permanent.
10.1 Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory or physical findings, symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product whether or not considered related to the 
medicinal product.
Clinically significant changes from baseline in laboratory assessments, vital signs, and 
physical examination are to be recorded as adverse events. Clinically significant 
abnormalities include:

a result associated with accompanying signs/symptoms 

a result that requires additional diagnostic testing or medical/surgical intervention 

a result that leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy 

a result considered to be an adverse event by the investigator or sponsor
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 

An abnormal safety assessment (e.g., laboratory, vital signs, ECG) associated with a 
clinical diagnosis that has been recorded as an AE does not require a separate AE 
entry

Events meeting the definition of an AE also include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.


Protocol MECC-TBZ-2001
Page 67 of 102
Protocol Version 5.0 15 September 2020
Confidential

Signs, symptoms, or the clinical sequelae of a suspected drug-drug or drug-food 
interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. (Please refer to the Section 10.2 for further 
details) 

A symptom or medical complication related to a protocol-mandated intervention, 
including screening procedures
Serious Adverse Event
Adverse events are classified as serious or non-serious. A serious adverse event is any AE 
that is: 

fatal

life-threatening
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 

requires inpatient hospitalization or prolongation of existing hospitalization
Note: In patient hospitalization is defined as 24 hours in a hospital or an overnight stay. An 
elective hospital admission to treat a condition present before exposure to the study drug or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization or accommodation problems and without medical background does not need to 
be considered an SAE.
o
Events NOT to be reported as SAEs are hospitalizations for the following: 

Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition 

Treatment, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not 
worsen 

Admission to a hospital or other institution for general care due to 
social or economic reasons (e.g., no access to local ambulatory medical 
care) 

Treatment on an emergency, outpatient basis for an event not fulfilling 
any of the definitions of serious given above and not resulting in 
hospital admission 


Protocol MECC-TBZ-2001
Page 68 of 102
Protocol Version 5.0 15 September 2020
Confidential

Hospitalization also does not include the following: Rehabilitation 
facilities, Hospice facilities, Respite care (e.g., caregiver relief), Skilled 
nursing facilities, Nursing homes 

results in persistent or significant disability or incapacity

a congenital anomaly or birth defect

an important medical event (medically significant)
o
Note: medical and scientific judgment should be exercised in deciding whether 
it is appropriate to consider other situations serious, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject and / or may require 
intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events are 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.
o
The seriousness criterion of “medically significant” should only be selected 
when none of the other seriousness criteria apply to the event but the 
investigator still considers the event as serious.
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. 
Adverse Drug Reaction
All noxious and unintended responses to an investigational product related to any dose of the 
investigational product should be considered adverse drug reactions (ADRs). The phrase 
“responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility. All AEs judged by 
either the reporting Investigator or the Sponsor as having a reasonable causal relationship to 
an investigational product will be designated as ADRs.
All AEs, with the causal relationship to the study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.”
Expected/Unexpected Adverse Event
An expected AE is defined as one whose nature, severity or outcome is consistent with the 
applicable reference safety information described of the study drugs. 
An AE is to be considered unexpected if the nature, severity or outcome is not consistent with 
the applicable product reference safety information.


Protocol MECC-TBZ-2001
Page 69 of 102
Protocol Version 5.0 15 September 2020
Confidential
Preexisting Condition
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline medical history and not reported as an AE. A baseline or preexisting 
condition should be recorded as an adverse event only if the frequency, intensity, or the 
character of the condition worsens during the study period.
General Physical Examination Findings
Any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event. 
Post-study Adverse Event/Serious Adverse Event
At the last scheduled contact with the subject the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study. 
The sponsor should also be notified if the investigator becomes aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
10.2 Special Situations
The following situations may by associated with a serious outcome and should be evaluated 
for expedited reporting to the sponsor.

Any diagnosis of Cancer or Neoplasm is to be reported as a serious adverse event.

Emergency Room Visits:  Events that result in emergency room visits that do not 
result in admission to the hospital are not routinely considered to be serious events; 
however, these events should be evaluated for one of the other serious outcomes (e.g., 
life-threatening, other serious [medically significant] events).

Overdose: Overdose per se will not be reported as an AE/SAE unless this is an 
intentional overdose taken with possible suicidal/self-harming intent; this should be 
reported regardless of sequelae. Signs and symptoms associated with accidental 
overdose are to be recorded as adverse events or as serious AEs. If adverse events 
associated with overdose fulfil any of the serious criteria (as defined in section 
‘Serious Adverse Event’), a completed SAE report form is required to be submitted.

Reports of Drug-drug interaction and Drug Abuse and Medication Errors: drug 
interactions or abuse of the study medication must be recorded as AEs. Medication 
errors will be captured as protocol deviations while any associated signs or symptoms 
must be recorded as AEs on the CRF. In addition, any serious consequence of drug 


Protocol MECC-TBZ-2001
Page 70 of 102
Protocol Version 5.0 15 September 2020
Confidential
interactions, drug abuse, or medication error must be reported immediately if these 
fulfil any of the SAE criteria.
10.2.1 Adverse Events of Special Interest
Adverse events of special interest given that MECC-SA is an NSAID will include the 
following:

Myocardial Infarction/Unstable Angina

Stroke/transient ischemic attack (TIA)

Heart Failure

Cardiac Arrhythmia (Atrial & Ventricular)

Gastrointestinal haemorrhages NEC

Gastrointestinal ulceration and perforation
Any AESI should be reported per the SAE reporting process per Section 10.5.
10.3 Collection and Recording of Adverse Events
During the Adverse Event Reporting Period, the PI will record all adverse events. At each 
contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events should be 
recorded immediately in the source document, and in the appropriate adverse event module of 
the case report form (CRF). Information to be collected includes AE name or term (in 
standard medical terminology) and final diagnosis, event description, time and date of onset, 
clinician’s assessment of severity, seriousness, relationship to study product (assessed only 
by those with the training and authority to make a diagnosis), action taken with the study 
drug, treatment for the event and time (if available) and date of resolution/stabilization of the 
event.
Any findings from protocol specified safety assessments that are associated with the 
indication being studied are not to be reported as AEs or SAEs, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
All clearly related signs, symptoms, and abnormal results of diagnostic procedures should be 
grouped under one diagnosis on the CRF where possible and appropriate.
The clinical course of each event should be followed until resolution or stabilization.  
Adverse events that are still ongoing at the end of the study period must be followed up to 
determine the outcome. Any adverse event that occurs after the study period and is related to 
the study treatment or study participation should be recorded; and if serious, the investigator 
should also immediately report it to the Sponsor.


Protocol MECC-TBZ-2001
Page 71 of 102
Protocol Version 5.0 15 September 2020
Confidential
10.4 Classification of an Adverse Event
10.4.1 Severity
The Investigator will assign a severity rating to each AE. For purposes of consistency, the 
following scale is to be used:
Grade 1 - MILD
Does not interfere with subject's usual function.
Grade 2 - MODERATE
Interferes to some extent with subject's usual function.
Grade 3 - SEVERE
Interferes significantly with subject's usual function.
It is important to distinguish between severe AEs and Serious AEs. Severity is a classification 
of intensity, whereas an SAE is an AE that meets any of the regulatory specified criteria (see 
definitions, Serious Adverse Event).
10.4.2 Causality
For all adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event. The investigator is required to assess causality 
of each AE.
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. The 
Investigator must make an assessment of the relationship of each AE (serious and 
non-serious) to the study treatment(s) and record this relationship in the CRF.
Factors that need to be considered when making a causality assessment include: Temporal 
relationship, Clinical and pathological characteristics of the event(s), Pharmacological 
plausibility, Exclusion of confounding factors (medical and medication history), Drug 
interactions, De-challenge/re-challenge, Dose relationship.
A suspected relationship (definite, probable, possible) between the events and the study 
medication means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. The Investigator is responsible for assessing relationship of AEs to study treatment 
in accordance with the following definitions:
Category
Causality
Description
DEFINITE
Causal relationship is certain
For example: the temporal relationship between 
drug exposure and the adverse event (AE) 
onset/course is reasonable, there is a clinically 
compatible response to de-challenge, other causes 
have been eliminated; the event must be definitive 
pharmacologically or phenomenologically, using a 
satisfactory re-challenge procedure if necessary.
PROBABLE
High degree of certainty for 
For example: the temporal relationship between 
drug exposure and AE onset/course is reasonable, 


Protocol MECC-TBZ-2001
Page 72 of 102
Protocol Version 5.0 15 September 2020
Confidential
Category
Causality
Description
causal relationship
there is a clinically compatible response to 
de-challenge (re-challenge is not required), and 
other causes have been eliminated or are unlikely.
POSSIBLE
Causal relationship is 
uncertain
For example: the temporal relationship between 
study treatment exposure and the AE onset/course 
is reasonable or unknown, de-challenge 
information is either unknown or equivocal; could 
also be explained by disease or other drugs.
UNLIKELY
Causal relationship is
improbable
Another explanation is more likely such as disease, 
environment, or other medication.
Does not represent a known reaction to study drug.
UNRELATED/NOT 
RELATED
No possible relationship
The temporal relationship between drug exposure 
and the AE onset/course is unreasonable or 
incompatible, or a causal relationship to study drug 
is impossible
For SAEs, if the relationship to the study treatment(s) is considered to be unlikely or not 
related, an alternative suspected etiology should be provided when possible (e.g., 
concomitant medications, intercurrent illness/events, study-related procedure).
10.4.3 Expectedness
The Sponsor or its designated representative will be responsible for determining whether an 
AE is expected or unexpected based on the reference safety information. The reference safety 
information mentioned in the IB will be used in this study for the expectedness assessment of 
SAEs.
10.4.4 Outcome
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Sponsor or its 
designated representative.
The outcome at the time of last observation will be classified as:
RECOVERED/RESOLVED where the subject recuperated and is free of any 
pathological conditions resulting from the prior disease or injury.
RECOVERED WITH SEQUELAE where the subject recuperated but retained pathological 
conditions resulting from the prior disease or injury. 
NOT RECOVERED/NOT RESOLVED (i.e. ongoing) where the subject has not recuperated 
from the condition or injury and the event is still considered ongoing.


Protocol MECC-TBZ-2001
Page 73 of 102
Protocol Version 5.0 15 September 2020
Confidential
RECOVERING where the subject has begun to recuperate from the condition or injury, but 
the event is considered ongoing at a reduced intensity.
FATAL the condition or injury results in the subject’s death. The investigator should identify 
the principal cause of death and assign Fatal outcome to that event. Other concurrent ongoing 
AE/SAEs present at the time of death would remain Not recovered/Not resolved.
UNKNOWN can be selected if none of the other situations apply or are known. Follow-up 
should be conducted to obtain one of the preceding outcomes.
10.4.5 Action Taken With the Study Treatment
Action
Description
Treatment interrupted
The treatment was temporarily discontinued
Treatment withdrawn
The treatment was permanently discontinued
Unknown
Not known, not observed, not recorded, or refused
No action taken
The AE did not result in any modification of dose or frequency of dosing
Not applicable
The AE occurred prior to first dose or following last scheduled dose
10.5 Reporting of Serious Adverse Events and Pregnancy Exposures
Investigators and the Sponsor or its designated representative must conform to the serious 
adverse event reporting timelines, formats and requirements of the various entities to which 
they are responsible. 
10.5.1 Investigator Reporting: Notifying the Study Sponsor
Immediate notification of SAEs by the investigator to Mylan PSRM is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Mylan will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Serious adverse events must be reported to the study sponsor within 24 hours of awareness. 
To report such events, a Serious Adverse Event (SAE) Report form must be completed and 
signed by the investigator or designee and forwarded to:
 


Protocol MECC-TBZ-2001
Page 74 of 102
Protocol Version 5.0 15 September 2020
Confidential
If the initial notification using the completed ‘SAE report form’ is not possible, the 
notification may be made via email/fax or over telephone with the following minimum 
necessary information

Study identifier

Study Center

Subject number

A description of the event

Current status (outcome of event-if known 
and whether study medication is continuing)

The reason why the event is classified as 
serious

Investigator assessment of the causality 
between the event and study treatment
The investigator should provide further information on the as soon as possible, preferably 
within 48 hours of awareness. This should include a copy of the completed SAE Report form, 
and any other diagnostic information and medical records that will assist in the understanding 
of the event.  
Subject identifying information must not be visible on SAE forms or any supporting 
documentation provided by the Investigator. Any information that could be used to identify 
the subject (e.g., name, address, medical record number) must be de-identified before 
submission to Mylan or its designee. The subject’s study specific ID number should be 
recorded on every page of documentation forwarded to the sponsor.
The PI should provide the final diagnosis as the SAE term whenever possible in the SAE 
report form and CRF. The signs and symptoms should be provided in the narrative only, not 
as SAE terms. The PI should only list all signs and symptoms as SAE terms if no diagnosis is 
available at the time of report.
10.5.2 Follow-up
New information and any important missing information from prior reports on a serious 
adverse event must be provided promptly to the study sponsor. In addition, the Investigator 
may be requested by Mylan/designee to obtain specific additional follow-up information in 
an expedited fashion. The investigator should respond to targeted follow-up requests as soon 
as possible and preferably within 48 hours from receipt of the request. 
10.5.3 Investigator reporting: Notifying the Ethics Committee
Investigators are responsible for safety reporting to their local Ethics Committee (LEC) and 
complying with their local EC’s reporting requirements. Copies of each report and 
documentation of LEC notification and receipt will be kept in the investigator’s study file.
10.5.4 Investigator Reporting of Pregnancy: Notifying the Study Sponsor 
All subjects who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation as 


Protocol MECC-TBZ-2001
Page 75 of 102
Protocol Version 5.0 15 September 2020
Confidential
detailed in the inclusion and exclusion criteria. Pregnancy testing will be conducted 
throughout the study, as detailed in the schedule of assessments.
A subject who is found to be pregnant at the screening visit will be excluded from the study 
and will be a screening failure. 
Subjects who have been enrolled in the study should be instructed to contact the Investigator 
or study staff immediately if pregnancy occurs or is suspected. Early termination visit 
assessments are required as soon as possible after learning of the pregnancy. Pregnant 
females will be discontinued from study treatment by the Investigator. A male that has a 
partner that becomes pregnant during the study will not be discontinued from study treatment. 
Details of the pregnancy should be recorded on the Pregnancy Report form and reported to 
 within 24 hours of awareness by email 
 or 
 from the time of initial awareness, even if beyond the closure of 
the clinical database. 
The Investigator is also responsible for following the pregnancy every 3 months or until 
delivery or termination and informing the Sponsor about its outcome. Reports where the 
embryo or fetus may have been exposed to the study drug(s), should be followed-up in order 
to collect information on the:

outcome of the pregnancy,

outcome for both mother and fetus (malformation/anomalies diagnosed since initial 
report)

development of the child after birth (developmental assessment, infant illnesses, 
hospitalizations, drug therapies, breastfeeding)
Healthy newborns should be followed-up at 1 month after birth to confirm no congenital 
anomalies were subsequently detected (if possible).
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
termination of a pregnancy for medical reasons will be recorded as an AE or an SAE. A 
spontaneous abortion is always considered to be a SAE and will be reported to the Sponsor.
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered an elective procedure and not an AE; nevertheless, Mylan requests the outcome 
(e.g., elective termination) be reported within 24 hours of awareness and sent as a follow-up 
on the Delivery and Infant Follow-up Form). 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as at least 
possibly related to the study treatment, must be promptly reported to Mylan PSRM.
If the study center becomes aware of a pregnancy in a female partner of a male subject, study 
personnel should contact their clinical research associate to obtain a partner pregnancy ICF. 


Protocol MECC-TBZ-2001
Page 76 of 102
Protocol Version 5.0 15 September 2020
Confidential
Consent of the pregnant partner must be obtained before any details of the pregnancy can be 
shared with Mylan or its designated representative. If the pregnant partner provides consent 
to have the pregnancy followed, the study center should collect the information specified on 
the Pregnancy Report form and forward the completed form to Mylan PSRM every 3 months 
until the pregnancy outcome has been obtained. 
11 PROTOCOL AMENDMENT DETAILS
11.1 Global Amendment 1, 11 May 2020
11.1.1 Reason for Amendment
 exclude subjects <18 years of age was 
made along with a request to ensure proactive monitoring for GI adverse events.
In addition, clarifications and correction of typographical errors/inconsistencies have been 
made. The corrections include minor changes to the sample size justification sections to 
reflect the BID dosing regimens; this does not change the number of subjects required for the 
study.
11.1.2 Sections Changed
Synopsis – Study Treatment
Changed From
To maintain the blind due to differences in appearance between the tablets, subjects will be 
blindfolded and receive two tablets when dosed; to maintain the blind between QD and BID 
arms, subjects assigned to QD arms will receive placebo at the second dose.
Changed To
To maintain the blind due to differences in appearance between the tablets, subjects will 
receive in a double dummy design, two tablets when dosed (one that is representative of a 
10 mg tablet and one that is representative of a 15 mg tablet). Due to the double dummy 
design, neither the subject, nor the Investigator will know what treatment a subject receives. 
To maintain the blind between QD and BID arms, subjects assigned to QD arms will receive 
placebo at the second dose. Per the clinic procedures, subjects will also be blindfolded during 
dosing.
Synopsis Inclusion Criteria
Changed From
1.
Males and females ≥16 years of age. Females may be of either childbearing or 
non-childbearing potential. All females of childbearing potential must be using an acceptable, 
highly effective method of contraception and have a negative serum pregnancy test at 
screening.


Protocol MECC-TBZ-2001
Page 77 of 102
Protocol Version 5.0 15 September 2020
Confidential
Changed To
1.
Males and females ≥18 years of age. Females may be of either childbearing or 
non-childbearing potential. All females of childbearing potential must be using an acceptable, 
highly effective method of contraception and have a negative serum pregnancy test at 
screening.
Synopsis – Statistical Methods
Changed From
In order to derive the required sample size for the primary endpoint, a
 
 
 
 
 
 
 
 
 
 
 
 
 
Changed To
In order to derive the required sample size for the primary endpoint, a 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 78 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
Table 1: Study Schedule
Changed From
9
All AEs will be recorded from time of consent until the telephone follow up/End of 
Study (EOS) Visit. The Investigator is also responsible for notifying the sponsor if they 
become aware of any AE after the study period has ended and it is considered related to the 
study medication.
Changed To
9
All AEs will be recorded from time of consent until the telephone follow up/End of 
Study (EOS) Visit. The Investigator is also responsible for notifying the sponsor if they 
become aware of any AE after the study period has ended and it is considered related to the 
study medication. When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
1.2
Background and Rationale
Changed From
Higher doses of MOBIC (22.5 mg and greater) have been associated with an increased risk of 
serious GI events, 
 
 
Changed To
Higher doses of MOBIC (22.5 mg and greater) have been associated with an increased risk of 
serious GI events, 
 
 
MECC-SA contains salicylic acid as a co-former, this is at a low dose (up to 11.6 mg for BID 
dosing of MECC-SA 15 mg) which is anticipated to have negligible physiological effects. 
However, it is acknowledged that salicylic acid (and acetylsalicylic acid) at higher doses can 
cause adverse effects, such as local gastrointestinal effects such as ulceration of the GI tract, 
particularly when administered with other NSAIDs. As the potential for local GI toxicity for 
salicylic acid is not known all GI symptoms should be assessed and documented.


Protocol MECC-TBZ-2001
Page 79 of 102
Protocol Version 5.0 15 September 2020
Confidential
1.3
Investigational Product
Changed From
Salicylic acid is used as the co-former in the MECC-SA tablets. Considering that meloxicam 
is a BCS Class II compound, the rate-limiting step for meloxicam absorption is solubility. 
The intended use of salicylic acid in MECC-SA is to increase the rate of absorption of 
meloxicam by increasing its solubility and dissolution.
Changed To
Salicylic acid is used as the co-former in the MECC-SA tablets. Considering that meloxicam 
is a BCS Class II compound, the rate-limiting step for meloxicam absorption is solubility. 
The intended use of salicylic acid in MECC-SA is to increase the rate of absorption of 
meloxicam by increasing its solubility and dissolution. The dose of salicylic acid (5.8 mg and 
11.6 mg considering QD and BID dosing of MECC-SA 15 mg, respectively) used in 
MECC-SA formulation is considered as a subtherapeutic dose (approved oral clinical doses 
of acetylsalicylic acid are in the range of 50- 325 mg/day) with negligible physiological 
effects. Whilst the side effect profile of acetylsalicylic acid is well known, including local 
effects on the GI tract, it is acknowledged that the local side effects of its metabolite (via 
hydrolysis in the GI tract, liver and plasma) salicylic acid when given orally are unknown, 
although a fraction of acetylsalicylic acid is metabolized to salicylic acid in the GI tract prior 
to absorption. Considering the low dose of salicylic acid in the formulation, MECC-SA is not 
considered a new fixed combination drug.
1.4
Ethics and Benefit-Risk Considerations
Changed From
The age of subjects (including those aged 16-18 years) is reflective of the population of 
subjects needing the removal of third molars. The use of NSAIDs in adolescent subjects is 
common, with side effects similar to those of adult subjects [28]; [29]. Further, the systemic 
exposure of meloxicam in adolescent subjects is similar to that of adult subjects [30].
Changed To
The age of subjects (including those aged 16-18 years) is reflective of the population of 
subjects needing the removal of third molars. The use of NSAIDs in adolescent subjects is 
common, with side effects similar to those of adult subjects [28]; [29]. Further, the systemic 
exposure of meloxicam in adolescent subjects is similar to that of adult subjects [30].
4.2.1
Inclusion Criteria
Changed From
1.
Males and females ≥16 years of age. Females may be of either childbearing or 
non-childbearing potential. All females of childbearing potential must be using an acceptable, 


Protocol MECC-TBZ-2001
Page 80 of 102
Protocol Version 5.0 15 September 2020
Confidential
highly effective method of contraception and have a negative serum pregnancy test at 
screening.
Changed To
1.
Males and females ≥18 years of age. Females may be of either childbearing or 
non-childbearing potential. All females of childbearing potential must be using an acceptable, 
highly effective method of contraception and have a negative serum pregnancy test at 
screening.
5.1
Investigational Drug
Changed From
MECC-SA will be provided as 10 and 15 mg tablets.

15 mg tablets (and matching placebo) 
 

10 mg tablets (and matching placebo) 
 
Placebo is a tablet identical to the corresponding dose of active study drug.
To maintain the blind, subjects will be blindfolded and take two tablets of study drug or 
placebo will be administered on one day, Visit 2 (Day 1). To maintain the blind, regarding 
QD and BID dosing, subjects assigned to QD treatment arms will receive placebo at the 
second dose.
Study drugs will be administered following randomization and approximately 12 hours 
following the first dose.
Changed To
MECC-SA will be provided as 10 and 15 mg tablets.

15 mg tablets (and matching placebo) 
 

10 mg tablets (and matching placebo) 
 
Placebo is a tablet identical to the corresponding dose of active study drug.
To maintain the blind, subjects will take in a double dummy design, two tablets (one that is 
representative of a 10 mg tablet and one that is representative of a 15 mg tablet) of study drug 
or placebo will be administered on one day, Visit 2 (Day 1). Due to the double dummy 
design, neither the subject, nor the Investigator will know what treatment a subject receives. 
To maintain the blind, regarding QD and BID dosing, subjects assigned to QD treatment arms 


Protocol MECC-TBZ-2001
Page 81 of 102
Protocol Version 5.0 15 September 2020
Confidential
will receive placebo at the second dose. Additionally, per the clinic procedures, subjects will 
be blindfolded during dosing. 
Study drugs will be administered following randomization and approximately 12 hours 
following the first dose.
5.1.1
Administration of Study Drugs
Changed From
Study drug (two tablets containing MECC-SA or matching placebo) will be administered in 
the clinic at each dosing time.
Changed To
Study drug (two tablets containing MECC-SA or matching placebo) will be administered in a 
double dummy design at the clinic at each dosing time.
6.2.1.2 Dosing and Post Dose Procedures
Changed From

Adverse events should be assessed throughout the day.
Changed To

Adverse events should be assessed throughout the day.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
6.2.2
Visit 2 (Day 2)
Changed From

Adverse events should be assessed throughout the day.
Changed To

Adverse events should be assessed throughout the day.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
6.2.2.1 Discharge Procedures
Changed From

Adverse events should be assessed throughout the day.
Changed To

Adverse events should be assessed throughout the day.


Protocol MECC-TBZ-2001
Page 82 of 102
Protocol Version 5.0 15 September 2020
Confidential
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
6.2.3
Early Termination (ET) visit
Changed From

Adverse Event assessment.
Changed To

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
6.3
End of Study (EOS) Visit
Changed From

Adverse Event assessment.
Changed To

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.
7.3.1
Adverse Event Assessment
Changed From
Subjects will be routinely queried in regard to the presence or absence of AEs using open 
ended questions. 
Changed To
Subjects will be routinely queried in regard to the presence or absence of AEs using open 
ended questions. When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms. 
7.3.6
Blood Volume
Changed From
Total blood sampling volume for an individual subject is approximately 201.5 mL. 
Additional blood samples may be taken for safety assessments, provided the total volume 
taken during the study does not exceed 500 mL during any period of 30 consecutive days, 
and the ethics committee/IRB is notified of the blood collection.


Protocol MECC-TBZ-2001
Page 83 of 102
Protocol Version 5.0 15 September 2020
Confidential
Number of Sampling Times
Sample Type
Sample 
Volume (mL)
Screening
Study Period
Total Volume (mL)
Safety Labs
21 (Screen)
10.5 (Discharge)
1
1
21.5
PK
10
0
18
180
TOTAL
201.5
Changed To
Total blood sampling volume for an individual subject is approximately 103.5 mL. 
Additional blood samples may be taken for safety assessments, provided the total volume 
taken during the study does not exceed 500 mL during any period of 30 consecutive days, 
and the ethics committee/IRB is notified of the blood collection.
Number of Sampling Times
Sample Type
Sample 
Volume (mL)
Screening
Study Period
Total Volume (mL)
Safety Labs
21 (Screen)
10.5 (Discharge)
1
1
31.5
PK
4
0
18
72
TOTAL
103.5
8.1
Sample Size Determination
Changed From
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 84 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
 
 
 
 
 
Changed To
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol MECC-TBZ-2001
Page 85 of 102
Protocol Version 5.0 15 September 2020
Confidential
 
The same power calculation method was applied to the secondary endpoints SPID 0-8 and 
TOTPAR24. 
 
9.8
Informed Consent
Changed From
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. For 
subjects <18 years of age, where necessary, according to local regulations, parental consent 
and subject assent will be obtained. 
Changed To
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study.


Protocol MECC-TBZ-2001
Page 86 of 102
Protocol Version 5.0 15 September 2020
Confidential
11.2 Global Amendment 2, 25 June 2020
11.2.1 Reason for Amendment
 the role of 
CYP2C9 in the metabolism of meloxicam, Mylan has amended the Protocol to exclude 
subjects taking strong inhibitors and inducers of CYP2C9.
11.2.2 Sections Changed
Synopsis – Exclusion Criteria
Changed From
16.
Use of medications with the potential to interact with MECC-SA (as indicated in the 
current Investigator’s Brochure), or medications required during the study such as local 
anesthesia or sedatives, or medications with the potential to affect or confound pain status 
during the study. This includes (but not limited to) use of any of the following medications: 

Long term opioid use (>30 consecutive days in the past year) and/or use of extended 
release opioids within 30 days of the dental extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs within 28 days 
prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other than the nitrous 
oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 28 days prior to the 
study.

Pemetrexed within 28 days prior to the study.

Combination of diuretic with ACE inhibitor or angiotensin receptor blocker within 
28 days prior to the study.

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.


Protocol MECC-TBZ-2001
Page 87 of 102
Protocol Version 5.0 15 September 2020
Confidential

Aspirin within 7 days prior to the surgery.

Analgesics (including opioids, acetaminophen and NSAIDs) within 24 hours prior to 
the surgery.
Changed To
16.
Use of medications with the potential to interact with MECC-SA (as indicated in the 
current Investigator’s Brochure), or medications required during the study such as local 
anesthesia or sedatives, or medications with the potential to affect or confound pain status 
during the study. This includes (but not limited to) use of any of the following medications: 

Strong CYP2C9 inhibitors or inducers within 28 days or 5 half-lives (whichever is 
longer) prior to the study.

Long term opioid use (>30 consecutive days in the past year) and/or use of extended 
release opioids within 30 days of the dental extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs within 28 days 
prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other than the nitrous 
oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 28 days prior to the 
study.

Pemetrexed within 28 days prior to the study.

Combination of diuretic with ACE inhibitor or angiotensin receptor blocker within 
28 days prior to the study.

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.

Aspirin within 7 days prior to the surgery.


Protocol MECC-TBZ-2001
Page 88 of 102
Protocol Version 5.0 15 September 2020
Confidential

Analgesics (including opioids, acetaminophen and NSAIDs) within 24 hours prior to 
the surgery.
3.1
Overall Design
Changed From
This will be a randomized, double-blind, placebo-controlled, parallel group, dose-ranging 
study, randomizing approximately 110 male or female subjects that have had third molar 
dental surgery. Subjects will receive a single dose of study drug on Day 1.
Changed To
This will be a randomized, double-blind, placebo-controlled, parallel group, dose-ranging 
study, randomizing approximately 110 male or female subjects that have had third molar 
dental surgery. Subjects will receive a dose of study drug on Day 1 after surgery and a further 
dose approximately 12 hours later.
4.2.2
Exclusion Criteria
Changed From
16.
Use of medications with the potential to interact with MECC-SA (as indicated in the 
current Investigator’s Brochure), or medications required during the study such as local 
anesthesia or sedatives, or medications with the potential to affect or confound pain status 
during the study. This includes (but not limited to) use of any of the following medications: 

Long term opioid use (>30 consecutive days in the past year) and/or use of extended 
release opioids within 30 days of the dental extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs within 28 days 
prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other than the nitrous 
oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 28 days prior to the 
study.

Pemetrexed within 28 days prior to the study.


Protocol MECC-TBZ-2001
Page 89 of 102
Protocol Version 5.0 15 September 2020
Confidential

Combination of diuretic with ACE inhibitor or angiotensin receptor blocker within 
28 days prior to the study.

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.

Aspirin within 7 days prior to the surgery.

Analgesics (including opioids, acetaminophen and NSAIDs) within 24 hours prior to 
the surgery.
Changed To
16.
Use of medications with the potential to interact with MECC-SA (as indicated in the 
current Investigator’s Brochure), or medications required during the study such as local 
anesthesia or sedatives, or medications with the potential to affect or confound pain status 
during the study. This includes (but not limited to) use of any of the following medications: 

Strong CYP2C9 inhibitors or inducers within 28 days or 5 half-lives (whichever is 
longer) prior to the study.

Long term opioid use (>30 consecutive days in the past year) and/or use of extended 
release opioids within 30 days of the dental extraction.

Antiepileptic drugs within 28 days prior to the study.

Tricyclic anti-depressants, monoamine oxidase inhibitors, or SNRIs within 28 days 
prior to the study.

Sedative or hypnotic drugs within 28 days prior to the study (other than the nitrous 
oxide used during the operation).

Use of “medical” or recreational marijuana within 28 days prior to the study.

Warfarin within 28 days prior to the study.

Apixaban within 28 days prior to the study.

Lithium within 28 days prior to the study.

Methotrexate within 28 days prior to the study.

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) within 28 days prior to the 
study.

Pemetrexed within 28 days prior to the study.

Combination of diuretic with ACE inhibitor or angiotensin receptor blocker within 
28 days prior to the study.


Protocol MECC-TBZ-2001
Page 90 of 102
Protocol Version 5.0 15 September 2020
Confidential

Gabapentin or pregabalin within 28 days prior to the study.

Cholestyramine within 7 days prior to the study.

Meloxicam within 7 days prior to the surgery.

Aspirin within 7 days prior to the surgery.

Analgesics (including opioids, acetaminophen and NSAIDs) within 24 hours prior to 
the surgery.
8.1
Sample Size Determination
Changed From
Table 9:
Power Calculations For The Primary Endpoint
 
 
Changed To
Table 9:
Power Calculations For The Primary Endpoint
 
 
11.3 Global Amendment 3, 10 September 2020
11.3.1 Reason for Amendment
, the protocol has been amended to include a statement that dental 
surgery and related anesthesia, sedation, and prophylactic antibiotics are not investigational 
and will occur regardless of research.
In addition, 
 a vital signs assessment has been added prior to 
surgery and the order of some procedures has been amended to better fit with clinic preferred 
processes.
Measuring salicylic acid concentrations have also been added to the PK samples.


Protocol MECC-TBZ-2001
Page 91 of 102
Protocol Version 5.0 15 September 2020
Confidential
11.3.2 Sections Changed
Synopsis
Changed From
PK parameters for meloxicam (Cmax, pAUC0-4, pAUC0-24) will also be calculated.
Changed To
PK parameters for meloxicam and salicylic acid (Cmax, pAUC0-4, pAUC0-24) will also be 
calculated.
Table 1: Study Schedule
Changed From
3
Vital signs (blood pressure and pulse rate) are taken pre-dose and 24 hours post dose 
performed after ECG measurements taken at the same nominal time.
Changed To
3
Vital signs (blood pressure and pulse rate) are taken prior to surgery, pre-dose and 
24 hours post dose performed after ECG measurements taken at the same nominal time.
Section 2.2.2
Changed From
PK

Population PK parameters for meloxicam (Cmax, pAUC0-4 and pAUC0-24).
Changed To
PK
Population PK parameters for meloxicam and salicylic acid (Cmax, pAUC0-4 and pAUC0-24).
Section 6.1.1 Screening (Visit 1)
Changed From
At Screening (Visit 1), the following will be completed in the specified order:

Written informed consent. 

IVRS/IWRS registration. 

Complete medical history, demographics. 

Complete history of all prescription or non-prescription drugs, dietary supplements 
taken within 28 days prior to consent. History of alcohol or illicit drug use.


Protocol MECC-TBZ-2001
Page 92 of 102
Protocol Version 5.0 15 September 2020
Confidential

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Measure height and weight.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent blood pressure (BP) and pulse rate 
(PR). 

Serum pregnancy test for all female subjects. 

Urinalysis (for blood, protein etc.). Sample to be tested for microscopy/culture if 
positive for blood, protein, nitrites or leukocyte esterase.

Urine drug screen.

Blood will be collected for safety laboratory tests. Laboratory tests at screening 
include confirmation of non-childbearing potential in any female who has been 
amenorrheic for at least 2 years, via serum FSH. 

Review AEs (AEs are to be recorded starting from signature of consent).

Check study inclusion/exclusion criteria.

Schedule Visit 2 (Day 1) and remind the subject of lifestyle and study drug and 
concomitant medication requirements for visits.
Changed To
At Screening (Visit 1), the following will be completed; procedures can be performed in a 
different order, but informed consent must be obtained prior to any procedures and the 
12-lead ECG must be performed prior to vital signs or obtaining blood samples.

Written informed consent. 

IVRS/IWRS registration. 

Complete medical history, demographics. 

Complete history of all prescription or non-prescription drugs, dietary supplements 
taken within 28 days prior to consent. History of alcohol or illicit drug use.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent blood pressure (BP) and pulse rate 
(PR). 

Measure height and weight.

Serum pregnancy test for all female subjects. 


Protocol MECC-TBZ-2001
Page 93 of 102
Protocol Version 5.0 15 September 2020
Confidential

Blood will be collected for safety laboratory tests. Laboratory tests at screening 
include confirmation of non-childbearing potential in any female who has been 
amenorrheic for at least 2 years, via serum FSH. 

Urinalysis (for blood, protein etc.). Sample to be tested for microscopy/culture if 
positive for blood, protein, nitrites or leukocyte esterase.

Urine drug screen.

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Check study inclusion/exclusion criteria.

Review AEs (AEs are to be recorded starting from signature of consent).

Schedule Visit 2 (Day 1) and remind the subject of lifestyle and study drug and 
concomitant medication requirements for visits.
Section 6.2.1 Visit 2 (Day 1)
Changed From
6.2.1
Visit 2 (Day 1)
Procedures will be completed in the following order:
6.2.1.1 Pre-Dose Procedures

Review AEs.

Check the subject has fasted from midnight.

Review concomitant medications.

Perform urine drug screen.

Urine pregnancy test (if female of childbearing potential).

Check study inclusion/exclusion criteria.

Record body temperature.

Diary training.

Perform dental surgery, using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will 
also receive prophylactic antibiotics post-surgery.

Pain assessments (Pain Intensity (0-10-point numeric pain rating scale – NPRS) and 
Categorical Pain Rating (4-point scale – none, mild, moderate, severe)) will be made 
during the 5 hours post-surgery until a baseline pain assessment is achieved.


Protocol MECC-TBZ-2001
Page 94 of 102
Protocol Version 5.0 15 September 2020
Confidential
o
Subjects with NPRS ≥5 and a rating of moderate or severe pain on a 4-point 
categorical pain rating scale (i.e., none, mild, moderate, severe) during this 
time they will be eligible for randomization.

Randomization using IVRS/IWRS.
o
To occur such that dosing occurs within 15 minutes of the eligible pain scores.

12-lead ECG – supine or semi-recumbent taken prior to dosing.

Vital signs (BP and PR) – supine or semi-recumbent taken prior to dosing.

Blood for a PK sample taken prior to dosing.
Changed To
6.2.1
Visit 2 (Day 1)
The following procedures will be completed; procedures can be performed in a different 
order as long as they are performed at the correct nominal time and would not impact on 
other tests, e.g., 12-lead ECGs that are taken at the same nominal time as vital signs or blood 
samples are taken prior to those other procedures:
6.2.1.1 Pre-Dose Procedures

Check the subject has fasted from midnight.

Review AEs.

Review concomitant medications.

Record vital signs – supine or semi-recumbent blood pressure (BP) and pulse rate 
(PR).

Perform urine drug screen.

Urine pregnancy test (if female of childbearing potential).

Check study inclusion/exclusion criteria.

Record body temperature.

Diary training.

Perform dental surgery, using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will 
also receive prophylactic antibiotics post-surgery.

Pain assessments (Pain Intensity (0-10-point numeric pain rating scale – NPRS) and 
Categorical Pain Rating (4-point scale – none, mild, moderate, severe)) will be made 
during the 5 hours post-surgery until a baseline pain assessment is achieved.


Protocol MECC-TBZ-2001
Page 95 of 102
Protocol Version 5.0 15 September 2020
Confidential
o
Subjects with NPRS ≥5 and a rating of moderate or severe pain on a 4-point 
categorical pain rating scale (i.e., none, mild, moderate, severe) during this 
time they will be eligible for randomization.

Randomization using IVRS/IWRS.
o
To occur such that dosing occurs within 15 minutes of the eligible pain scores.

12-lead ECG – supine or semi-recumbent taken prior to dosing.

Vital signs (BP and PR) – supine or semi-recumbent taken prior to dosing.

Blood for a PK sample taken prior to dosing.
Section 6.2.2.1 Discharge Procedures
Changed From

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent BP and PR. 

Urine pregnancy test (if female of childbearing potential). 

Urinalysis (dipstick for blood, protein etc.). Sample to be sent for microscopy/culture 
if positive for blood, protein, nitrites or leukocyte esterase.

Blood will be collected for safety laboratory tests. 

Review concomitant medications.

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Discharge subject from the clinic.
o
Provide appropriate post-discharge pain medications, per standard of care.
o
If a subject requires a longer duration of in-patient assessment due to reasons 
associated with the operation this is acceptable.
Changed To

Record 12-lead ECG – supine or semi-recumbent.

Record vital signs – supine or semi-recumbent BP and PR. 

Urine pregnancy test (if female of childbearing potential). 


Protocol MECC-TBZ-2001
Page 96 of 102
Protocol Version 5.0 15 September 2020
Confidential

Urinalysis (dipstick for blood, protein etc.). Sample to be sent for microscopy/culture 
if positive for blood, protein, nitrites or leukocyte esterase.

Blood will be collected for safety laboratory tests. 

General physical examination, including respiratory, cardiovascular, gastrointestinal, 
musculoskeletal, neurological systems, lymph nodes, skin, extremities, head, ears, 
eyes, nose, and thyroid gland.

Review concomitant medications.

Adverse Event assessment.
o
When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms.

Discharge subject from the clinic.
o
Provide appropriate post-discharge pain medications, per standard of care.
o
If a subject requires a longer duration of in-patient assessment due to reasons 
associated with the operation this is acceptable.
Section 7.1 Dental Surgery
Changed From
The dental surgery (extraction of ≥2 x third molars, at least 1 of which involves partial or 
complete mandibular bony impaction) will be performed on Visit 2 (Day 1).
The procedure will be performed using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will also 
receive prophylactic antibiotics post surgically.
Changed To
The dental surgery and related anesthesia, sedation, and prophylactic antibiotics are not 
investigational and will occur regardless of research.
The dental surgery (extraction of ≥2 x third molars, at least 1 of which involves partial or 
complete mandibular bony impaction) will be performed on Visit 2 (Day 1).
The procedure will be performed using appropriate local anesthesia and sedation (performed 
using nitrous oxide and a local injection of lidocaine with epinephrine). Subjects will also 
receive prophylactic antibiotics post surgically.
Section 7.4
Changed From
7.4
Pharmacokinetics
7.4.1
Plasma for Analysis of Meloxicam


Protocol MECC-TBZ-2001
Page 97 of 102
Protocol Version 5.0 15 September 2020
Confidential
Changed To
7.4
Pharmacokinetics
7.4.1
Plasma for Analysis of Meloxicam and Salicylic Acid
Section 8.3.7 Pharmacokinetics
Changed From
For all pharmacokinetic data analyses, the PK population will be used.
Samples for PK determination of drug concentrations of meloxicam, in plasma will be 
determined by a bioanalytical laboratory using validated bioanalytical methods. Details of the 
validated bioanalytical method used will be provided in a separate bioanalytical report.
The plasma concentration data for meloxicam will be listed, summarized on the basis of time 
intervals, and plotted using a scatter plot with time relative to the preceding meloxicam 
dosing time. Summary statistics (mean, standard deviation, minimum, maximum, number of 
subjects, and coefficient of variation) will be calculated for plasma concentrations for each 
time interval and by treatment group.
Population PK (PPK) analysis of meloxicam concentrations will be performed using 
modeling. The PPK analysis will be conducted and reported separately. Details of the PPK 
model building will be described in a separate PPK analysis plan.
If the dose-response relationship cannot be established in this study (for example, no doses 
are effective, or all doses are equally effective) then exploratory exposure-response analysis 
may be conducted using individual predictions of exposure from the PPK analysis in this 
study. Outcomes from this analysis will be reported separately, if conducted.
Changed To
For all pharmacokinetic data analyses, the PK population will be used.
Samples for PK determination of drug concentrations of meloxicam and salicylic acid, in 
plasma will be determined by a bioanalytical laboratory using validated bioanalytical 
methods. Details of the validated bioanalytical method used will be provided in a separate 
bioanalytical report.
The plasma concentration data for meloxicam and salicylic acid will be listed, summarized on 
the basis of time intervals, and plotted using a scatter plot with time relative to the preceding 
meloxicam dosing time. Summary statistics (mean, standard deviation, minimum, maximum, 
number of subjects, and coefficient of variation) will be calculated for plasma concentrations 
for each time interval and by treatment group.
Population PK (PPK) analysis of meloxicam and salicylic acid concentrations will be 
performed using modeling. The PPK analysis will be conducted and reported separately. 
Details of the PPK model building will be described in a separate PPK analysis plan.


Protocol MECC-TBZ-2001
Page 98 of 102
Protocol Version 5.0 15 September 2020
Confidential
If the dose-response relationship cannot be established in this study (for example, no doses 
are effective, or all doses are equally effective) then exploratory exposure-response analysis 
may be conducted using individual predictions of exposure from the PPK analysis in this 
study. Outcomes from this analysis will be reported separately, if conducted.
Section 10.1 Definitions
Changed From
Events NOT to be reported as SAEs are hospitalizations for the following: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Treatment, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen 

Admission to a hospital or other institution for general care due to social or economic 
reasons (e.g., no access to local ambulatory medical care) 

Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission 

Hospitalization also does not include the following: Rehabilitation facilities, Hospice 
facilities, Respite care (e.g., caregiver relief), Skilled nursing facilities, Nursing 
homes
Changed To
o
Events NOT to be reported as SAEs are hospitalizations for the following: 

Routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition 

Treatment, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not 
worsen 

Admission to a hospital or other institution for general care due to 
social or economic reasons (e.g., no access to local ambulatory medical 
care) 

Treatment on an emergency, outpatient basis for an event not fulfilling 
any of the definitions of serious given above and not resulting in 
hospital admission 

Hospitalization also does not include the following: Rehabilitation 
facilities, Hospice facilities, Respite care (e.g., caregiver relief), Skilled 
nursing facilities, Nursing homes 


Protocol MECC-TBZ-2001
Page 99 of 102
Protocol Version 5.0 15 September 2020
Confidential
11.4 Global Amendment 4, 15 September 2020
11.4.1 Reason for Amendment
Due to the discontinuation of hydrocodone/acetaminophen 5/500 mg tablets, the rescue 
medication for the study has been changed to 5/325 mg tablets.
11.4.2 Sections Changed
4.2.3 Criteria for Study Drug Termination, Withdrawal From the Study and Study 
Termination
Changed From

The subject requires more than 6 tablets/day (equivalent to 3000 mg acetaminophen) 
rescue medication.
Changed To

The subject requires more than 6 tablets/day (equivalent to 30 mg hydrocodone and 
1950 mg acetaminophen) rescue medication.
5.2 Drug Inventory
Changed From
The Investigator site will supply:

Medication required for sedation and anesthesia during the surgery.

Rescue medication for pain relief following randomization, 
hydrocodone/acetaminophen (5/500 mg).

All materials associated with the surgical procedure.
Changed To
The Investigator site will supply:

Medication required for sedation and anesthesia during the surgery.

Rescue medication for pain relief following randomization, 
hydrocodone/acetaminophen (5/325 mg).

All materials associated with the surgical procedure.
5.7.2 Post-Dose
Changed From
Rescue medication of immediate release hydrocodone/acetaminophen (5/500 mg) will be 
allowed to treat breakthrough pain, subjects will be encouraged to refrain from rescue 
medication until at least 1-hour post-dose. A dose of rescue medication will be allowed as 
needed up to once every two hours. A maximum of 6 tablets (equivalent to 3000 mg 


Protocol MECC-TBZ-2001
Page 100 of 102
Protocol Version 5.0 15 September 2020
Confidential
acetaminophen) will be allowed; if a subject requires greater than this the subject should be 
withdrawn from the study.
Pain Intensity will be measured immediately before any rescue medication is administered.
Changed To
Rescue medication of immediate release hydrocodone/acetaminophen (5/325 mg) will be 
allowed to treat breakthrough pain, subjects will be encouraged to refrain from rescue 
medication until at least 1-hour post-dose. A dose of rescue medication will be allowed as 
needed up to once every two hours. A maximum of 6 tablets (equivalent to 30 mg 
hydrocodone and 1950 mg acetaminophen) will be allowed; if a subject requires greater than 
this the subject should be withdrawn from the study.
Pain Intensity will be measured immediately before any rescue medication is administered.


Protocol MECC-TBZ-2001
Page 101 of 102
Protocol Version 5.0 15 September 2020
Confidential
12 REFERENCE LIST
1.
Kehlet, H., T.S. Jensen, and C.J. Woolf, Persistent postsurgical pain: risk factors and 
prevention. Lancet, 2006. 367(9522): p. 1618-25.
2.
Jones, G.H., et al., The opioid epidemic in the United States-Overview, origins, and 
potential solutions. Cancer, 2018. 124(22): p. 4279-4286.
3.
Rudd, R.A., et al., Increases in Drug and Opioid-Involved Overdose Deaths - United 
States, 2010-2015. MMWR Morb Mortal Wkly Rep, 2016. 65(50-51): p. 1445-1452.
4.
Hedegaard H, M.A., Warner M., Drug overdose deaths in the United States, 1999–
2017. NCHS Data Brief, 2018. 329.
5.
Dowell, D., T.M. Haegerich, and R. Chou, CDC Guideline for Prescribing Opioids 
for Chronic Pain--United States, 2016. JAMA, 2016. 315(15): p. 1624-45.
6.
AMDG, Prescribing Opioids for Postoperative Pain - Supplemental Guidance. 
Washington State Agency Medical Directors' Group, 2018.
7.
da Costa, B.R., et al., Effectiveness of non-steroidal anti-inflammatory drugs for the 
treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet, 
2017. 390(10090): p. e21-e33.
8.
Moore, R.A., et al., Single dose oral analgesics for acute postoperative pain in adults 
- an overview of Cochrane reviews. Cochrane Database Syst Rev, 2015(9): p. 
CD008659.
9.
Moore, R.A. and S. Derry, Diclofenac Potassium in Acute Postoperative Pain and 
Dysmenorrhoea: Results from Comprehensive Clinical Trial Reports. Pain Res 
Manag, 2018. 2018: p. 9493413.
10.
Hochberg, M.C., et al., American College of Rheumatology 2012 recommendations 
for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the 
hand, hip, and knee. Arthritis Care Res (Hoboken), 2012. 64(4): p. 465-74.
11.
Singh, J.A., et al., 2015 American College of Rheumatology Guideline for the 
Treatment of Rheumatoid Arthritis. Arthritis Rheumatol, 2016. 68(1): p. 1-26.
12.
Smolen, J.S., et al., EULAR recommendations for the management of rheumatoid 
arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 
update. Ann Rheum Dis, 2017. 76(6): p. 960-977.
13.
Aminoshariae, A., J.C. Kulild, and M. Donaldson, Short-term use of nonsteroidal 
anti-inflammatory drugs and adverse effects: An updated systematic review. J Am 
Dent Assoc, 2016. 147(2): p. 98-110.
14.
Gates, B.J., et al., Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety. 
Expert Opin Pharmacother, 2005. 6(12): p. 2117-40.
15.
Blain, H., et al., Limitation of the in vitro whole blood assay for predicting the COX 
selectivity of NSAIDs in clinical use. Br J Clin Pharmacol, 2002. 53(3): p. 255-65.


Protocol MECC-TBZ-2001
Page 102 of 102
Protocol Version 5.0 15 September 2020
Confidential
16.
Moore, R.A., S. Derry, and H.J. McQuay, Single dose oral meloxicam for acute 
postoperative pain in adults. Cochrane Database Syst Rev, 2009(4): p. CD007552.
17.
Isiordia-Espinoza, M.A., et al., Pre-emptive analgesic effectiveness of meloxicam 
versus tramadol after mandibular third molar surgery: a pilot study. J Oral 
Maxillofac Surg, 2012. 70(1): p. 31-6.
18.
Christensen, S.E., et al., A Randomized Double-Blind Controlled Trial of Intravenous 
Meloxicam in the Treatment of Pain Following Dental Impaction Surgery. J Clin 
Pharmacol, 2018. 58(5): p. 593-605.
19.
Gottlieb, I.J., et al., Evaluation of the safety and efficacy of an intravenous 
nanocrystal formulation of meloxicam in the management of moderate-to-severe pain 
after bunionectomy. J Pain Res, 2018. 11: p. 383-393.
20.
Pollak, R.A., et al., Efficacy and Safety of Intravenous Meloxicam in Patients With 
Moderate-to-Severe Pain Following Bunionectomy: A Randomized, Double-Blind, 
Placebo-controlled Trial. Clin J Pain, 2018. 34(10): p. 918-926.
21.
Combe, B., et al., Comparison of intramuscular and oral meloxicam in rheumatoid 
arthritis patients. Inflamm Res, 2001. 50 Suppl 1: p. S10-6.
22.
Auvinet, B., et al., Comparison of the onset and intensity of action of intramuscular 
meloxicam and oral meloxicam in patients with acute sciatica. Clin Ther, 1995. 17(6): 
p. 1078-98.
23.
Cooper, S.A., et al., Research design considerations for single-dose analgesic clinical 
trials in acute pain: IMMPACT recommendations. Pain, 2016. 157(2): p. 288-301.
24.
Singla, N.K., P.J. Desjardins, and P.D. Chang, A comparison of the clinical and 
experimental characteristics of four acute surgical pain models: dental extraction, 
bunionectomy, joint replacement, and soft tissue surgery. Pain, 2014. 155(3): p. 441-
56.
25.
Busch, U., G. Heinzel, and H. Narjes, The effect of cholestyramine on the 
pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug 
(NSAID), in man. Eur J Clin Pharmacol, 1995. 48(3-4): p. 269-72.
26.
Breivik, H., et al., Assessment of pain. Br J Anaesth, 2008. 101(1): p. 17-24.
27.
Branson, M., J. Pinheiro, and F. Bretz, Searching for an adequate dose: Combining 
Multiple Comparisons and Modeling Techniques in Dose-Response Studies. Novartis 
Biometrics Technical Report, 2003. Number 2003-08-20.
28.
Eccleston, C., et al., Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic 
non-cancer pain in children and adolescents. Cochrane Database Syst Rev, 2017. 8: 
p. CD012537.
29.
MOBIC, MOBIC USPI. 2020.
30.
Burgos-Vargas, R., et al., Pharmacokinetics of meloxicam in patients with juvenile 
rheumatoid arthritis. J Clin Pharmacol, 2004. 44(8): p. 866-72.

SAP_001.pdf: 
Study Title: A Randomized, Double Blind, Placebo-Controlled, Parallel Group, Dose-Response 
Study of Meloxicam Co-Crystal in The Treatment of Post-Surgical Dental Pain 
Protocol Number: MECC-TBZ-2001 
Document: Statistical Analysis Plan Version 1.0 
Dated: February 5, 2021 
NCT04571515 


 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE:  
A RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP, DOSE-RESPONSE STUDY OF MELOXICAM 
CO-CRYSTAL IN THE TREATMENT OF POST-SURGICAL DENTAL 
PAIN 
PROTOCOL NUMBER:  
MECC-TBZ-2001 
SPONSOR: 
Mylan Inc 
IND NUMBER: 
 
PREPARED BY: 
 
 
 
 
 
 
 
This document is confidential and proprietary to Mylan. This study is being conducted in compliance with 
good clinical practice, including the archiving of essential documents. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Mylan, except that this document may 
be disclosed to appropriate Institutional Review Boards under the condition that they keep the information 
confidential. 
 
 
 
 


ACKNOWLEDGEMENT AND SIGNATURE SHEET 
 
Approved: 
_ 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
Approved: 
__
__
__ 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
0.0 
2020-10-05 
Initial draft 
 
1.0 
2021-02-05 
Various updates and clarifications 
See section 11.2 
 
 
 
 
 
 


TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ............................................................... 7 
2. 
PURPOSE OF THE ANALYSES ......................................................... 9 
3. 
PROTOCOL SUMMARY .................................................................. 10 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS........... 12 
4.1. 
Assessment Time Windows ................................................................ 13 
5. 
ANALYSIS SETS .............................................................................. 14 
6. 
STUDY SUBJECTS ........................................................................... 15 
6.1. 
Disposition of Subjects ....................................................................... 15 
6.2. 
Demographic and Other Baseline Characteristics ................................. 15 
6.3. 
Prior and Concomitant Medications .................................................... 16 
6.3.1. 
Prior Medications ............................................................................... 16 
6.3.2. 
Concomitant Medications ................................................................... 16 
6.4. 
Medical History.................................................................................. 16 
7. 
STUDY OPERATIONS ..................................................................... 17 
7.1. 
Protocol Deviations ............................................................................ 17 
7.2. 
Randomization ................................................................................... 17 
7.3. 
Measures of Treatment Compliance .................................................... 17 
8. 
ENDPOINT EVALUATION .............................................................. 19 
8.1. 
Overview of Efficacy Analysis Methods.............................................. 19 
8.1.1. 
Multicenter Studies............................................................................. 19 
8.1.2. 
Timing of Analyses ............................................................................ 19 
8.1.3. 
Multiple Comparisons/Multiplicity...................................................... 19 
8.2. 
Primary Efficacy Endpoint.................................................................. 19 
8.2.1. 
Computation of the Primary Endpoint ................................................. 19 
8.2.2. 
Primary Analysis of the Primary Endpoint........................................... 20 
8.2.3. 
Sensitivity Analyses of the Primary Analysis....................................... 21 
8.3. 
Secondary Endpoints .......................................................................... 21 
8.3.1. 
Secondary SPID Endpoints ................................................................. 21 
8.3.2. 
Total Pain Relief (TOTPAR) .............................................................. 21 
8.3.3. 
Pain Intensity Differences over Time................................................... 22 
8.3.4. 
Time to Event outcomes ..................................................................... 22 
8.3.5. 
Responder endpoints........................................................................... 22 
8.3.6. 
Frequency of Rescue Medication Use.................................................. 23 
8.3.7. 
Pharmacokinetics ............................................................................... 23 


8.4. 
Examination of Subgroups .................................................................. 24 
9. 
SAFETY EVALUATION................................................................... 25 
9.1. 
Overview of Safety Analysis Methods................................................. 25 
9.2. 
Adverse Events .................................................................................. 25 
9.3. 
Deaths, Serious Adverse Events (SAE), and Other Significant Adverse 
Events ................................................................................................ 26 
9.4. 
Clinical Laboratory Evaluation ........................................................... 26 
9.5. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety................................................................................................. 26 
9.5.1. 
Vital Signs ......................................................................................... 26 
9.5.2. 
ECGs ................................................................................................. 27 
9.5.3. 
Physical Exams .................................................................................. 27 
10. 
INTERIM ANALYSES AND DATA MONITORING ........................ 28 
11. 
CHANGES TO THE ANALYSES...................................................... 29 
11.1. 
Changes to the Analyses Planned in the protocol ................................. 29 
11.2. 
Analyses Changed or Added from the Initial Draft............................... 29 
12. 
REFERENCES................................................................................... 31 
13. 
APPENDIX........................................................................................ 32 
13.1. 
Schedule of Events ............................................................................. 32 
13.2. 
Random Seeds.................................................................................... 34 
14. 
ATTACHMENTS .............................................................................. 35 
 
 


LIST OF TABLES 
Table 1: 
List of Abbreviations ............................................................................ 7 
 


1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BDR 
Blinded Data Review 
BID 
Twice daily 
BMI 
Body Mass Index 
BOCF 
Baseline observation carried forward 
CI 
Confidence interval 
CRF 
Case Report Form 
CSR 
Clinical study report 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
ET 
Early termination 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HR 
Heart rate 
ICH 
International Council for Harmonization 
IMMPACT 
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 
IP 
Investigational product  
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response system 
LOCF 
Last observation carried forward 
LS 
Least squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MCP-Mod 
Multiple Comparison Procedure – Modeling 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
mITT 
Modified Intent-to-treat 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 


NPRS 
Numeric Pain Rating Scale 
PD 
Pharmacodynamic 
PGA 
Patient Global Assessment 
PI 
Pain intensity 
PID 
Pain intensity difference 
PK 
Pharmacokinetic 
PP 
Per Protocol  
PPK 
Population Pharmacokinetic 
QD 
Once daily 
RM 
Rescue medication 
SAE 
 Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SE 
Standard error 
SID 
Subject Identification 
SOC 
System organ class 
SPID 
Summed Pain Intensity Difference 
SS 
Safety Analysis Set 
TEAE 
Treatment Emergent Adverse Events 
TIA 
Transient ischemic attack 
TOTPAR 
Total pain relief 
W2LOCF 
2-hour windowed last observation carried forward 
W4LOCF 
4-hour windowed last observation carried forward 
WHO-DD 
World Health Organization Drug Dictionary 


2. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) provides a detailed description of the strategy and 
statistical methodology to be used for analysis of data from the MECC-TBZ-2001 protocol, 
version 5.0 (amendment 4), dated 15SEP2020. 
The purpose of the SAP is to describe the pre-specified statistical approaches to the analysis 
of study data prior to database lock. This analysis plan is meant to supplement the study 
protocol. If differences occur between analyses described in the SAP and the current 
protocol, those found in this SAP will assume primacy. Any deviations from this plan will be 
described in the Clinical Study Report. 


3. 
PROTOCOL SUMMARY 
This will be a randomized, double-blind, placebo-controlled, parallel group, dose-response 
study, randomizing approximately 110 male or female subjects who have had dental surgery 
(removal of ≥2 third molars) performed. Subjects will receive study drug on Day 1. 
The study design is consistent with research design recommendations of the IMMPACT 
(Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) group for trials 
involving subjects with short-duration acute pain. 
Subjects will attend screening at Visit 1, to occur within 30 days prior to the planned dental 
surgery. 
The subjects will have the operation performed on Day 1 using appropriate local anesthesia 
and sedation (performed using nitrous oxide and a local injection of lidocaine with 
epinephrine). Subjects will also receive prophylactic antibiotics post-surgically. 
Pain Intensity (PI) (using a 0-10-point numeric pain rating scale (NPRS) where 0 is no pain 
and 10 is the worst pain imaginable) will be assessed during the 5 hours following surgery. If 
the subject scores a NPRS ≥5 and a rating of moderate or severe pain on a 4-point categorical 
pain rating scale (i.e., none, mild, moderate, severe) during this time they will be eligible for 
randomization. 
A diary will be used to record the pain scores. 
Subjects will be randomized to receive either MECC-SA (10 mg QD, 15 mg QD, 10 mg BID 
or 15 mg BID) or placebo. 
Dosing of study medication must be within 15 minutes of the eligible pain score. PI scores 
(NPRS) will be measured at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 
20 and 24 hours after the first dose of study medication, as well as immediately before any 
rescue medication and/or at the time of early termination. 
Pain relief assessment (using a 5-point scale - none = 0, slight = 1, moderate = 2, good or a 
lot = 3, and complete = 4) will be measured at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 
7, 8, 12, 14, 16, 20 and 24 hours after the first dose of study medication, as well as 
immediately before any rescue medication and/or at the time of early termination. 
A Patient Global Assessment (PGA) of pain control will be made at 24 hours post dose, rated 
on a 5-point scale, ranging from 0 to 4, where 0-poor, 1-fair, 2 good, 3-very good, or 4-
excellent and/or at the time of early termination. 
The times to first perceptible relief and meaningful pain relief will be determined using the 
double-stopwatch technique. The time to onset of first perceptible relief (time that the first 
watch is stopped) is defined as the post dose time at which the subject first begins to feel pain 
relief. The time to meaningful pain relief (time that the second watch is stopped) is defined as 
the post dose time at which the subject begins to feel meaningful pain relief. 
Rescue medication of immediate release hydrocodone/acetaminophen will be allowed at any 
time, but subjects will be encouraged to wait until at least 1 hour post-dose if possible. A PI 
score assessment will be made immediately prior to any rescue medication. 
Pharmacokinetic (PK) samples will be taken pre-dose and 15, 30, and 45 minutes and 1, 1.5, 
2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 20 and 24 hours after the first dose at Day 1. 


Subjects will be discharged from the clinic following the 24-hour assessments; if the subject 
requires a longer duration of in-patient assessment due to reasons associated with the surgery 
this is acceptable. 
A final follow-up telephone call will occur approximately 5 days after the last dose of study 
drug administration. 
Safety will be assessed via recording of adverse events (AEs), safety laboratory testing and 
pre and post-dose 12-lead electrocardiogram (ECGs) and vital signs. 
Adverse events of special interest will include those related to gastrointestinal (GI) AEs, 
particularly bleeds and those related to serious cardiovascular (CV) events. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will have 
discharge procedures performed at that time or at an early termination (ET) visit scheduled as 
soon as possible. 


4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the 
data from the study. Departures from these general policies will be described, if applicable, in 
the appropriate sections of this SAP. When this situation occurs, the rules set forth in the 
specific section take precedence over the general policies. 
 
For categorical variables, summary statistics will consist of the number and percentage of 
subjects in each category; percentages will be out of the number of subjects in the population 
being reported, unless otherwise noted. All percentages will be rounded to one decimal point. 
The number and percentage of subjects will always be presented in the form XX (XX.X%) 
where the percentage is in parentheses. To ensure completeness, all summaries for categorical 
and discrete variables will include all categories, even if none of the subjects had a response 
in a particular category. Denominators for each analysis will be based on the population of 
interest (e.g., safety population; subjects with non-missing data). 
 
For continuous variables, summary statistics will consist of the number of subjects with data, 
mean, median, standard deviation (SD), minimum, and maximum values. The summary 
statistic n will be the number of subjects with non-missing values. All means and medians 
will be reported to one more significant digit than the values being analyzed. Standard errors 
(SE) and SDs will be reported to two more significant digits than the values being analyzed. 
The minimum and maximum will be reported to the same number of significant digits as the 
values being analyzed. 
 
For tests of hypothesis of treatment group differences, the associated p-value will be reported. 
All p-values will be rounded to three decimal places; p-values that round to 0.000 will be 
presented as “<0.001”. P-values are descriptive for outcomes and analyses other than the 
primary endpoint.  
 
In general, the baseline value will be considered the last non-missing measurement observed 
prior to the first dose of study treatment. 
 
For efficacy, subjects will be analyzed according to randomized treatment. For safety 
analyses, subjects will be analyzed according to the actual treatment received. 
 
Data will be listed by treatment and subject. In general, listings will be sorted in the order that 
columns are displayed, starting with the first column on the left (treatment). Subject listings 
of data will be presented for all randomized subjects unless specified otherwise. 


Unless otherwise specified, summaries will include the following study arms:  
x MECC-SA 15 mg QD 
x MECC-SA 10 mg QD 
x MECC-SA 15 mg BID 
x MECC-SA 10 mg BID 
x Placebo 
 
SAS statistical software, version 9.4 or higher, will be used for all analyses.  
4.1. 
Assessment Time Windows 
Assessments should be performed within the windows stated in the protocol and will be 
analyzed by the visit/time point under which they are entered into the case report form (CRF). 
For assessments other than the NPRS pain, if an assessment is missing and an unscheduled or 
early termination assessment falls within the protocol-specified window, it will be assigned to 
that visit/time point for the purposes of summarization. If more than one unscheduled visit/ 
early termination visit falls into a window, the one closest to the scheduled time point will be 
used (with the earlier one used in case of a tie); again, scheduled visits will always take 
precedence, regardless of timing. 
NPRS assessments will use the actual times of collection; see section 8.2.1 for additional 
details. 
 


5. 
ANALYSIS SETS 
The following 6 analysis populations are planned for this study: 
x All Subjects Analysis Set: This includes all subjects consented and screened and will 
be used for the reporting of subject populations and dispositions. 
x Safety Analysis Set: The safety analysis set (SS) will include all subjects who 
received at least one dose of study drug. Data will be summarized according to the 
treatment a subject actually received. 
x Modified Intent-to-treat (mITT) Analysis Set: The mITT analysis set includes all 
randomized subjects who received study drug and report at least one post-baseline 
pain intensity, including subjects who discontinued study treatment or received 
protocol allowed rescue medication. This will be used for all efficacy analyses; data 
will be summarized and analyzed according to the treatment a subject was 
randomized to receive. 
x Intent-to-treat (ITT) Analysis Set: The ITT analysis set includes all randomized 
subjects who received study drug, including subjects who discontinued study 
treatment or received protocol allowed rescue medication.  Data will be summarized 
and analyzed according to the treatment a subject was randomized to receive.  This 
population is the anticipated phase III population and will be utilized for planning and 
power calculations for the phase III studies. 
x Per Protocol Analysis Set: The per protocol analysis set (PP) will include all subjects 
in the ITT who had no major protocol violation that would impact on the primary 
efficacy endpoint. Significant protocol deviations are defined in Section 9.4 of the 
protocol. The list of major protocol deviations will be finalized prior to database lock 
and unblinding as part of the final blinded data review (BDR). Data will be 
summarized and analyzed according to the treatment a subject actually received at 
randomization. 
x PK Analysis Set: The pharmacokinetic analysis set (PK) will include all subjects who 
receive a dose of study medication and who provide at least one post dose 
concentration sample for the Population PK analysis. 
 


6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
The number and percentage of subjects screened, enrolled (marked as meeting inclusion 
criteria and not a screen failure), randomized, received treatment, completed the study, and 
discontinued from the study, will be reported, along with the reason for discontinuation 
(counts only will be reported for screened and enrolled subjects).  Percentages will be out of 
the number of subjects randomized. Additionally, the number and percentage of subjects that 
complete the in-clinic portion (through day 2) will be reported.  Subjects screened and 
enrolled will be reported overall; the remaining items will be reported by treatment group and 
overall.  Subjects randomized will include all subjects for whom randomization is checked on 
the CRF; subjects receiving treatment will include all subjects that had any IP administered; 
subjects completing the study will be based on the recorded disposition; subjects completing 
the confinement period will include those that have a termination date on or after day 2. 
Reasons for discontinuation include the following: 
x Adverse Event 
x Death 
x Lack of Efficacy 
x Lost to Follow-Up 
x Non-Compliance with Study Drug 
x Physician Decision 
x Pregnancy 
x Protocol Deviation 
x Site Terminated by Sponsor 
x Study Terminated by Sponsor 
x Withdrawal by Subject 
x Other 
 
Additionally, the number and percent of subjects in each analysis population will be reported 
by treatment. Screen failures will also be included in a by-subject listing.  
6.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be collected during the Screening Visit. 
Descriptive statistics will be provided for all demographic and baseline characteristics based 
on the Safety Population; if the mITT population is different, demographics will be presented 
for it as well. For categorical variables, the number and percentage of subjects in each 
category will be presented. For continuous variables, summaries will include the number of 
subjects with data, mean, median, standard deviation, minimum, and maximum.  
Variables to be summarized include:  
x Age at screening (years) as recorded on the CRF 
x Sex 
x Ethnicity  
x Race  
x Weight (kg) 
x Height (cm) 
x BMI (kg/m2) 


All demographic and other baseline characteristics will be provided in a listing.  Additionally, 
the substance use and surgery info collected will be provided in a listing. 
6.3. 
Prior and Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to post-
study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the CRF. All subjects will be questioned about concomitant medication at 
each clinic visit and at follow up. 
Medications taken prior to dosing with study medication will be documented as a prior 
medication. Medications taken after dosing with study medication will be documented as 
concomitant medications. All medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) Version GLOBALB3Sep20. 
Rescue medication of immediate release hydrocodone/acetaminophen (5/500 mg) will be 
allowed to treat breakthrough pain, subjects will be encouraged to refrain from rescue 
medication until at least 1-hour post-dose. A dose of rescue medication will be allowed as 
needed up to once every two hours. A maximum of 6 tablets (equivalent to 3000 mg 
acetaminophen) will be allowed; if a subject requires greater than this the subject should be 
withdrawn from the study. 
Pain Intensity will be measured immediately before any rescue medication is administered.  
Rescue medications and the associated pain intensities will be recorded on a separate CRF 
page. 
6.3.1. 
Prior Medications 
Prior medications are defined as all medications recorded in the CRF initiated prior to the 
administration of IP. Prior medications will be summarized in a table by treatment group 
using the Safety Analysis Set. Medications will be reported by drug class (Anatomical 
Therapeutic Chemical [ATC] Level 3) and preferred term; a subject will be counted only 
once for each medication.  
6.3.2. 
Concomitant Medications 
Concomitant medications are defined as all medications recorded in the CRF taken after the 
administration of IP, including those that were initiated prior to administration of IP and 
ongoing. Concomitant medications will be summarized in a table by treatment group using 
the Safety Analysis Set. Medications will be reported by drug class (Anatomical Therapeutic 
Chemical [ATC] Level 3) and preferred term; a subject will be counted only once for each 
medication.  
 
6.4. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.1. Conditions will be listed, including the verbatim investigator description of the 
relevant medical condition, the coded terms (system organ class, preferred term), start date, 
end date, and whether or not the condition is ongoing. 


7. 
STUDY OPERATIONS 
7.1. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) requirements. The noncompliance may be either on the 
part of the participant, the investigator, or the study site staff. Protocol deviations will be 
recorded on the source documents and with an explanation for the deviation. All protocol 
deviations will also be recorded as specified in the monitoring plan. 
Protocol deviations will be identified by site staff, through medical reviews, and by clinical 
research associates during site monitoring. Deviations will be classified as minor or major 
prior to the database lock. Major protocol deviations are defined as those that result in harm 
to the study patients or significantly affect the scientific value of the reported results of the 
study. Other deviations will be considered minor. 
Major protocol deviations will be summarized in a table; all deviations will be presented in a 
listing, including their assigned severity (major/minor). 
7.2. 
Randomization 
Assignment of Subject Identification (SID) number, randomization number and study 
medication, as well as site drug inventory control will be managed by an automated 
Interactive Web Response system (IWRS). A manual containing complete instructions for 
internet or telephone access and use will be provided to each site prior to study start. At their 
first clinic visit, the IVRS/IWRS will assign a SID. Each SID will be unique and serve as the 
primary subject identifier throughout all phases of the study. The SID must appear on all CRF 
pages, source documents, laboratory data, ECG and diary data. Subjects qualifying to enter 
the study drug treatment phase, will be assigned an additional “randomization number” by the 
IWRS at randomization.  
A total of 110 subjects are planned to be randomized in a 1:1:1:1:1 ratio of 22 subjects to 
each of the five study arms: 
x MECC-SA 15 mg QD 
x MECC-SA 10 mg QD 
x MECC-SA 15 mg BID 
x MECC-SA 10 mg BID 
x Placebo BID 
A by-subject listing of randomized treatment group and randomization number will be 
presented. 
7.3. 
Measures of Treatment Compliance 
Subjects will receive a two doses in the clinic on Visit 2 (Day 1); the first will be denoted 
time zero; the second will occur 12 hours later.  A visual check of the subject’s mouth and 
hands will be made to ensure compliance of dosing.  The number and percentage of subjects 
in the safety population that received first dose, the second dose and both doses will be 
reported.  Additionally, the date and time of the first and second doses will be presented in a 


listing and the target date and time for the second dose will be listed.  First doses that do not 
occur within 15 minutes of the baseline pain assessment will be flagged on the listing. 
 


8. 
ENDPOINT EVALUATION 
8.1. 
Overview of Efficacy Analysis Methods 
8.1.1. 
Multicenter Studies 
This is a single-center study and no special considerations are required for pooling of data. 
8.1.2. 
Timing of Analyses 
All final, planned analyses will be performed after the last participant has completed all study 
assessments, all relevant study data have been processed and integrated into the analysis 
database, and the database has been locked.  
Any post-hoc, exploratory analyses completed to support planned study analysis, which were 
not identified in this SAP, will be documented and reported in appendices to the CSR. Any 
results from these unplanned analyses (post-hoc) will also be clearly identified in the text of 
the CSR. 
8.1.3. 
Multiple Comparisons/Multiplicity 
All hypotheses will be tested at a two-sided significance level of 0.05. Nominal p-values will 
be presented for all secondary endpoints without adjustment for multiple comparisons (since 
this is a Phase 2 study). 
8.2. 
Primary Efficacy Endpoint 
The primary endpoint is the summed pain intensity difference (SPID) over 0 to 24 hours 
(SPID0-24). 
8.2.1. 
Computation of the Primary Endpoint 
First, the pre-dose NPRS will be subtracted from each pain score for a pain intensity 
difference (PID).  The SPID will be calculated using these values and actual times of 
collection with the trapezoidal rule; the primary analysis will include the NPRS scores 
recorded at the time of perceptible pain relief and at the time of meaningful pain relief. Due 
to the short duration of the study, missing data is expected to be minimal. 
Missing data will be imputed based on the reason for missingness: 
x Missing pain assessments for subjects who discontinued early due to lack of efficacy 
(including subjects that discontinue as a result of requiring more than 6 tablets of 
rescue medication), or an AE will be imputed using a baseline observation carried 
forward (BOCF) approach.  These values will be placed at the planned times of 
assessments for the purpose of computing the SPID. 
x Missing pain assessments due to other reasons for discontinuing will be imputed using 
a last observation carried forward (LOCF) approach. These values will be placed the 
planned times of assessments for the purpose of computing the SPID.  Subjects that 
discontinue while in a period of censoring for rescue will have the pre-rescue value 
carried forward. 
x Intermittent missing pain assessments between two non-missing scores will be 
imputed using linear interpolation.    


Additionally, NPRS scores will be recorded just prior to administration of rescue 
medications.  For the primary analysis of the primary efficacy endpoint a 2-hour windowed 
last observation carried forward (W2LOCF) approach will be used whereby the NPRS score 
obtained before a given rescue medication will be carried forward to replace the NPRS scores 
collected at each observation time point within 2 hours following the rescue dose. For the 
purposes of calculating the SPID, these values will be placed at the time of the assessments 
that they are replacing.  If there is no assessment at a planned time point that falls within the 
censoring period, then the W2LOCF value will be placed at the planned time.  If a NPRS 
score is not obtained as planned just prior to the rescue administration, then the last NPRS 
value available prior to the rescue will be utilized. 
Once the above imputation process is complete, it is expected that there will be slight 
variations in the time contributing to the SPID; these will all be normalized to be precisely 24 
hours. 
8.2.2. 
Primary Analysis of the Primary Endpoint 
A 3-parameter Emax model will be fitted to the SPID0-24 standardized means (observed mean 
for each dose and placebo divided by the pooled standard deviation) for placebo and each 
dose of MECC-SA, using SAS proc NLMIXED. Standardized effect sizes will be estimated 
from the Emax model together with their 95% confidence intervals and p-values. Baseline 
pain intensity score (PI) will be used as a covariate in the Emax model; it will be centered by 
subtracting the mean baseline across all treatment groups from each subject’s baseline. 
The model will take the following form: 
ܵܲܫܦ଴ିଶସ௛௥ൌܴܰܲܵ଴൅ܧ଴൅
ா೘ೌೣ஽௢௦௘
ா஽ఱబା஽௢௦௘+ ε 
Where E0 is the placebo response, Emax is the asymptotic maximum dose effect and ED50 is 
the dose that produces 50% of the maximal effect and ε is the random error term. 
For the purposes of fitting the Emax model, the doses assigned will reflect the actual dose the 
subject received and dose will be considered as a numerical (not class) variable.  This 
departure from the ITT principle will apply solely to fitting of the Emax model and reporting 
results based on the model.  The numerical dose values will be 10, 15, 20, 30 and 0 for 10 mg 
QD, 15 mg QD, 10 mg BID, 15 mg BID and placebo respectively. 
Descriptive statistics and other analyses of the SPIDs on the mITT population will analyze 
subjects based on the randomized treatment group. 
If the Emax model fails to converge, additional models will be investigated using a Multiple 
Comparison Procedure – Modeling (MCP-Mod) approach (Branson, 2003). If no other 
suitable models are identified using MCP-Mod, an Analysis of covariance (ANCOVA) will 
be used to assess the difference between treatment groups for SPID0-24. The ANCOVA model 
will include treatment as a fixed effect and baseline PI score as a covariate. The difference 
between MECC-SA and placebo will be estimated from the least squares means (LS means) 
along with the 95% confidence interval (CI) and associated 2-sided p-values. In addition, the 
standardized effect sizes for each dose will be calculated by dividing the differences in LS 
means for each dose and placebo by the pooled standard deviation. 
 


8.2.3. 
Sensitivity Analyses of the Primary Analysis 
As a sensitivity analysis of the W2LOCF approach, a W4LOCF will also be used whereby 
the PI score obtained before a given rescue medication will be carried forward to replace the 
PI scores collected at each observation within 4 hours following the rescue dose. The analysis 
will be conducted in both the mITT and the PP analysis sets. 
In addition to the BOCF/LOCF approaches outlined above, missing data may be imputed 
using multiple imputation (MI) methods.  This will be executed in three stages:  
x Censoring and replacement of values within the two-hour rescue window will be 
performed via W2LOCF. 
x Intermittent missing values will be imputed assuming missing at random with 20 
replicates; covariates will include all non-missing NPRS assessments (including the 
pre-dose value) and imputation will be done within treatment arm. 
x For the third stage subjects who discontinued early due to lack of efficacy or an AE 
related to study drug will be imputed using the pre-dose distribution by sampling from 
a trimmed normal that has the mean and standard deviation of the baseline values 
across all arms.  The distribution will be trimmed to a value of 5-10.  For subjects that 
discontinue for any other reason, values will be imputed assuming missing at random 
with 20 replicates; covariates will include all non-missing NPRS assessments 
(including the pre-dose value) and imputation will be done within treatment arm. 
For the multiple imputation stages, values will be imputed using the Markov Chain Monte 
Carlo (MCMC) method implemented with the SAS MI procedure.  If the missing data is 
minimal, this analysis may not be performed.  This MI analysis will be performed on both the 
mITT and ITT populations (if they differ). 
 
Additionally, the primary analysis will be repeated excluding the NPRS scores recorded at 
the time of perceptible pain relief and at the time of meaningful pain relief. 
8.3. 
Secondary Endpoints 
All hypotheses will be tested at a two-sided significance level of 0.05.  Since this is a phase 2 
study, nominal p-values will be presented for all secondary endpoints without adjustment for 
multiple comparisons. 
8.3.1. 
Secondary SPID Endpoints  
An approach identical to the primary computation for the SPID0-24 above will be employed 
for the cumulative SPID for hours 0-2, 0-4, 0-8, and 0-12.  Additionally, the interval 12-24 
will be calculated by subtracting the 0-12 SPID from the 0-24 SPID.   
For each, summary statistics will be presented as well as the ANCOVA LS means model 
results from a model identical to the one specified for the primary.  If it converges, results 
from the 3 parameter Emax model will also be presented for each interval. 
8.3.2. 
Total Pain Relief (TOTPAR) 
TOTPAR will have AUCs calculated in a manner identical to the primary SPID analysis with 
the exception that it is not collected pre-dose, therefore, there is no comparison to the pre-
dose value.  AUCs will be calculated for the intervals 0-2, 0-4, 0-8, 0-12, 0-24 and 12-24.   
For each, summary statistics will be presented as well as the ANCOVA LS means model 
results from a model identical to the one specified for the primary.  If it converges, results 


from the 3 parameter Emax model will also be presented for each interval.  Note that these 
models will utilize the baseline pain intensity NPRS value as a covariate. 
8.3.3. 
Pain Intensity Differences over Time 
Summary statistics will be presented for the pain intensity differences (pre-dose value minus 
NPRS) at each collection time point.  Additionally, a longitudinal mixed model for repeated 
measures (MMRM) with fixed effects for treatment, time, treatment by time interaction and 
baseline PI score will be fit. No imputations will be performed and data will be assumed to be 
missing at random. An unstructured covariance matrix will be fit to the subjects’ repeated 
measures; if this fails to converge, compound symmetric will be used instead.  Degrees of 
freedom will utilize the DDFM=KR option in Proc MIXED.  Least square means for each 
time point and 95% CIs will be presented for each study arm and the MECC-SA arms pooled 
(via an estimate statement).  Likewise, the differences from placebo at each time point will be 
presented for the individual MECC-SA arms and overall with LS means, 95% CIs and p-
values.  
Least squares means will be plotted by time to show the pain-relieving efficacy of both 
MECC-SA and placebo over 24 hours. 
8.3.4. 
Time to Event outcomes 
The three time to event outcomes will be analyzed in an identical manner.  These include: 
x Time to perceptible relief (as measured by double-stopwatch technique) after first 
dose. 
x Time to meaningful pain relief (as measured by double-stopwatch technique) after 
first dose. 
x Elapsed time from the start of study medication to first rescue medication 
administration. 
 
Each will be analyzed using the Kaplan-Meier method with strata for all arms to present 
quantiles (25%, median, 75%), if estimable.  The log-rank test will be used to test the 
hypothesis of overall treatment difference, pooling the MECC-SA arms.  If significant, the 
individual arms will be compared to placebo in a pairwise manner.  
Plots of the Kaplan-Meier curves will also be presented. 
8.3.5. 
Responder endpoints 
The four responder endpoints will be analyzed in an identical manner.  These include: 
x Proportion of subjects with overall pain reductions from baseline of ≥30% and ≥50% 
within 4 hours following the first dose based on the PI scores. Both these analyses 
will be presented for both methods of handling rescue medication use (W2LOCF and 
W4LOCF approaches).  This will include the 4-hour nominal time point, even if it 
falls slightly after four hours. 
x Proportion of subjects using rescue medication during 0-24 hours.  This will be cut off 
at precisely 24 hours from first dose. 
x Proportion of subjects using rescue medication prior to second dose.  Subjects that do 
not have a second dose will be cut off at precisely 12 hours from first dose.  This 
analysis will be repeated pooling the matching first dose for BID and QD treatments. 


x Patient’s Global Assessment of pain control for 0-24 hours after the initial dose 
scored on the 5-point scale will be dichotomized and the percentage of subjects 
reporting a PGA score of 2 (good) or better defined as a responder. This will include 
the 24-hour nominal time point, even if it falls slightly after 24 hours. 
The number and percentage of responders in each treatment group will be summarized. 
Comparisons between MECC-SA and placebo will be evaluated with the odds ratio and 
corresponding 95% CI from a logistic regression model with treatment group and baseline PI 
as a covariate.  Pairwise tests will be performed via an estimate statement. For the proportion 
of subjects using rescue medication prior to second dose, an additional analysis of treatment 
groups combined vs. Placebo will be performed. 
8.3.6. 
Frequency of Rescue Medication Use 
The frequency of rescue medication use in the 0-24 hours period after the first dose of study 
treatment will be summed for each subject and this will be summarized and graphically 
presented.  A Wilcoxon Test Rank Sum will perform pairwise comparisons of the rescue use 
in each arm versus placebo. 
8.3.7. 
Pharmacokinetics 
For all pharmacokinetic data analyses, the PK population will be used. 
Samples for PK determination of drug concentrations of meloxicam and salicylic acid, in 
plasma will be determined by a bioanalytical laboratory using validated bioanalytical 
methods. Details of the validated bioanalytical method used will be provided in a separate 
bioanalytical report.  
The plasma concentration data for meloxicam will be listed, summarized on the basis of time 
intervals, and plotted using a scatter plot with time relative to the preceding meloxicam 
dosing time. Actual times will be displayed in listings, when plotting individual data, and for 
the derivations of PK parameters; summaries by time point will group values by the nominal 
times.  Summary statistics (mean, standard deviation, minimum, maximum, number of 
subjects, and coefficient of variation) will be calculated for plasma concentrations for each 
time interval and by treatment group. 
Additional population PK (PPK) analyses of meloxicam concentrations will be performed; 
these analyses will be conducted and reported separately. These analyses may include 
explorations of: 
x Plasma AUCs and corresponding SPIDs for matching time periods (AUC0-4 vs SPID0-
4, for example) 
x Rescue medication use through 24hr and AUC0-24 
x Tmax and time to perceptible relief/time to meaningful pain relief 
x Scatter plots of pain intensity vs corresponding plasma concentration at the same time 
x Scatter plots of time to perceptible relief/time to meaningful pain relief vs 
corresponding plasma concentration at nearest collection 
x Additional PK:PD relationships 
Full details of the PPK model building will be described in a separate PPK analysis plan. 


8.4. 
Examination of Subgroups 
There are no preplanned analyses of subgroups; exploratory analyses of subgroups may be 
performed, but will be post-hoc. 
 


9. 
SAFETY EVALUATION 
 
9.1. 
Overview of Safety Analysis Methods 
Analysis of all safety data will be performed on the Safety Population and will be presented 
by the treatment received. 
 
9.2. 
Adverse Events 
Subjects will be routinely queried in regard to the presence or absence of AEs using open 
ended questions. When assessing AEs, the subject will be specifically asked regarding the 
presence of any GI symptoms. The clinic will provide documentation of any adverse events 
in the subject’s CRF. The AE source documentation will minimally include the following 
information: date and time of assessment, the outcome of the response, and identification of 
the clinic staff member collecting the information. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in 
the frequency or severity, or a change in the quality, of the disease or condition. (Worsening 
of a pre-existing condition is considered an AE.) 
Events that occur in subjects treated with placebo are also considered AEs. 
An AE is considered to be a treatment-emergent adverse event (TEAE) if the first onset or 
worsening is after administration of the IP (MECC-SA or placebo) and not more than 30 days 
after administration of IP. 
All AEs will be coded using MedDRA Version 23.1. 
 
An AE summary table presenting the total number of AEs will be presented for the 
following: 
x TEAEs 
x TEAEs by severity 
x TEAEs leading to study discontinuation  
x TEAEs by relationship 
x Serious AEs (defined below) 
Summaries of incidence rates (frequencies and percentages) of individual AEs by MedDRA 
System organ class (SOC) and preferred term will be prepared. Such summaries will be 
displayed for all TEAEs, TEAEs by maximum severity, and TEAEs by strongest relationship 
to study drug.  If missing, severity will be imputed as severe and relationship will be imputed 
as related. 
Each participant will be counted only once within each summation level (SOC; preferred 
term). If a participant experiences more than one TEAE within each summation level only, 
the TEAE with the strongest relationship or the maximum severity, as appropriate, will be 
included in the summaries of relationship and severity. 
In the AE data listings, all AEs will be displayed. AEs that are treatment-emergent will be 
flagged. 


9.3. 
Deaths, Serious Adverse Events (SAE), and Other Significant 
Adverse Events 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE 
that is: 
x Fatal 
x Life-threatening 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
Section 7.3.1 of the protocol provides additional detail and exceptions to the above criteria. 
 
A summary of incidence rates (frequencies and percentages) of SAEs by treatment group, 
SOC, and preferred term will be prepared for the Safety Population. A data listing of SAEs 
will also be provided, displaying details of the event(s) captured on the CRF. Likewise, AEs 
resulting in study discontinuation and AEs resulting in death will be listed separately.  
 
Adverse events of special interest given that MECC-SA is an NSAID will include the 
following: 
x Myocardial Infarction/Unstable Angina 
x Stroke/transient ischemic attack (TIA) 
x Heart Failure 
x Cardiac Arrhythmia (Atrial & Ventricular) 
x Gastrointestinal haemorrhages NEC 
x Gastrointestinal ulceration and perforation 
 
Additionally, a summary of incidence rates (frequencies and percentages) of adverse events 
of special interest by treatment group, SOC, and preferred term will be prepared for the 
Safety Population.  
9.4. 
Clinical Laboratory Evaluation 
Clinical laboratory values will be collected at the Screening Visit and after the final pain 
assessment (24 hours post-dose).  Values collected at Screening will serve as the baseline. 
Clinical laboratory results will be listed only. Only laboratory values that are outside the 
normal range will be flagged in the data listings and presented with the corresponding normal 
ranges. The original units for normal ranges provided the study’s local lab will be utilized in 
determining whether parameters are in range; that is, no conversions or rounding will be 
performed prior to this determination. Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
Pregnancy tests, and urine drug screens will be presented in separate listings. 
 
9.5. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1. 
Vital Signs 
Blood Pressure and pulse rate will be listed and descriptively summarized (N, mean, SD, 
minimum and maximum) by treatment group and visit. Baseline (defined as the pre-dose 
value collected on Visit 2 (Day 1) and changes from baseline will be similarly summarized. 


9.5.2. 
ECGs 
ECG data; QT, QTcF (Fridericia’s), heart rate (HR), QRS duration, PR and RR interval will 
be listed. 
Baseline (defined as the pre-dose value collected on Visit 2 (Day 1)) and change from 
baseline for QT, QTcF, HR, QRS, RR and PR will be summarized using descriptive statistics 
(N, mean, SD, minimum and maximum) by treatment and time point. 
For QTcF a classification of absolute values and increases from baseline will be performed. 
The number of subjects with maximum absolute QTcF <450 msec, 450 msec ≤QTcF <480 
msec, 480 msec ≤QTcF <500 msec and QTcF values ≥500 msec will be tabulated by 
treatment and visit. The number of subjects with maximum increase from baseline QTcF <30 
msec, 30 msec ≤QTcF <60 msec and QTcF ≥60 msec will be tabulated by treatment and time 
point. 
All ECG results will be presented in a listing, including the interpretation. 
9.5.3. 
Physical Exams 
Physical Exam findings are recorded in medical history or adverse events CRFs as 
appropriate; dates they were performed and whether significant findings were present will be 
presented in a listing. 
 


10. 
INTERIM ANALYSES AND DATA MONITORING 
No interim analyses are planned. 


11. 
CHANGES TO THE ANALYSES 
11.1. 
Changes to the Analyses Planned in the protocol 
The following are changes from the protocol-planned analyses: 
The protocol specifies an ITT set for the efficacy analyses; in the context of the objectives of 
this study, subjects with no post baseline data do not inform the dose-response relationship 
and are excluded from the mITT population that this SAP specifies for the efficacy analyses.  
However, it is expected that an ITT population will be used in the phase III and dropouts 
prior to the first efficacy assessment there may be informative of the effectiveness of the 
drug; hence, it is planned to use the ITT population for phase III study planning and 
calculation of effect sizes for power and sample size.  
The protocol includes a site covariate in many of the model descriptions; since this is a 
single-site study, it is not necessary.   
The protocol described several models as ANOVA; these have been updated to ANCOVA.  
For the protocol’s MMRM model for the analysis of pain intensity over time included a 
random effect for subject; instead, subject correlated data will be handled via a repeated 
statement.   
Intolerance to study drug was listed among the reasons for withdrawal that would result in 
BOCF imputation; this is not among the choices for reason for withdrawal, but should be 
recorded as an AE withdrawal. 
 
A test comparing the number of RM uses was added. 
 
Laboratory results are to be listed only. 
11.2. 
Analyses Changed or Added from the Initial Draft 
 
 
 
 
 
 
 
 
 
 
A test comparing the number of RM uses was added. 
 
Laboratory results are to be listed only. 


Minor editorial corrections for typos and grammar. 
 


12. 
REFERENCES 
Branson, M., J. Pinheiro, and F. Bretz, Searching for an adequate dose: Combining Multiple 
Comparisons and Modeling Techniques in Dose-Response Studies. Novartis Biometrics 
Technical Report, 2003. Number 2003-08-20. 


13. 
APPENDIX 
13.1. 
Schedule of Events 
VISIT 
1 
(Screen) 
2 
(In-
clinic) 
2 
(In-
clinic) 
Follow up 
Telephone 
Call 
DAY 
-30 to -2 
1 
2 
5-7 
Written informed consent 
X 
 
 
 
IVRS/IWRS registration 
X 
 
 
 
Demography and medical history 
X 
 
 
 
Review concomitant medications 
X 
X 
X 
X 
General physical examination1 
X 
 
X15 
 
Height  
X 
 
 
 
Weight 
X 
 
 
 
Temperature 
 
X2 
 
 
Vital Signs (supine/semi-recumbent blood pressure, pulse 
rate) 
X 
X3 
X15 
 
12-lead ECG (supine/semi-recumbent) 
X 
X4 
X15 
 
Serum or urine pregnancy test5 
X 
X2 
X15 
 
Urinalysis6 
X 
 
X15 
 
Urine drug screen 
X 
X2 
 
 
Blood safety labs (hematology, chemistry) including 
FSH (V1)7 
X 
 
X15 
 
PK Sample8 
 
X 
X 
 
Diary training 
 
X2 
 
 
Review AEs9 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
 
 
Dispense diary for pain assessment recordings 
 
X 
 
 
Subject records AEs at home 
X 
 
 
X 
Subject records AEs in the clinic 
 
X 
X 
 
Perform dental surgery 
 
X 
 
 
Pain Assessments (Pain Intensity, Categorical Pain 
Rating) (prior to randomization) 
 
X10 
 
 
Randomize to study via IVRS/IWRS 
 
X 
 
 
Dispense study drug 
 
X11 
 
 
Administer study drug (within 15 minutes of eligible 
pain assessments) 
 
X12 
 
 
Administer study drug (12 hours after first dose) 
 
X 
 
 
Pain Intensity Assessments (post-randomization) 
 
X13 
X13 
 
Pain Relief Assessments (post-randomization) 
 
X13 
X 
 
Patient Global Assessment of Pain Control 
 
 
X14 
 
Record Rescue Medication Use 
 
X 
X 
X 


 
1 
Including respiratory, cardiovascular, gastrointestinal, musculoskeletal, neurological systems, 
lymph nodes, skin, extremities, head, ears, eyes, nose, and thyroid gland. 
2 
Prior to surgery. 
3 
Vital signs (blood pressure and pulse rate) are taken prior to surgery, pre-dose and 24 hours 
post-dose performed after ECG measurements taken at the same nominal time. 
4 
12-lead ECG will be performed both pre-dose and 24 hours post-dose as single measures. 
5 
Serum pregnancy test at screening, urine at other visits. 
6 
Urinalysis for blood, protein, nitrites, leukocyte esterase, pH, glucose and ketones. If positive 
for blood, protein, nitrites or leukocytes esterase a sample for microscopy/culture should be 
analyzed by the central laboratory. 
7 
FSH to be measured in females who have been amenorrheic for at least 2 years, to confirm 
non-child bearing potential. 
8 
PK sample taken pre-dose and 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 16, 
20 and 24 hours after the first dose of study medication. 
9 
All AEs will be recorded from time of consent until the telephone follow up/End of Study 
(EOS) Visit. The Investigator is also responsible for notifying the sponsor if they become 
aware of any AE after the study period has ended and it is considered related to the study 
medication. When assessing AEs, the subject will be specifically asked regarding the presence 
of any GI symptoms.  
10 Pain assessments (Pain Intensity and Categorical Pain Rating) performed for up to 5 hours post 
completion of surgery. Subjects with NPRS ≥5 and a rating of moderate or severe pain on a 
4-point categorical pain rating scale (i.e., none, mild, moderate, severe) during this time they 
will be eligible for randomization. 
11 Drug is dispensed at ‘time zero’ and 12 hours later. 
12 Dosing of study medication must be within 15 minutes of the eligible pain assessments. 
13 Post-dose pain assessments made at 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 14, 
16, 20 and 24 hours after the first dose of study medication, and immediately before any dose 
of rescue medication. Assessments will also be made immediately following the time of first 
relief and time of meaningful relief. 
14 Patient’s Global Assessment of Pain Control measured at 24 hours post-dose, or at time of 
early termination if applicable. 
15 Procedures performed after the final pain assessment (24 hours post-dose).


Mylan Inc 
MECC-TBZ-2001 
Page 34 of 35 
Version Date: 2020-10-05 
Version: <1.0>  
 
 
13.2. 
Random Seeds 
The following list of number will be used in order for programming tasks that require random 
seeds. If additional numbers are required, programming will return to the start of the list and add 
one to each value for additional seeds. 
95757437 
73846758 
65831589 
86284444 
90876999 
43543977 
78974612 
22334268 
66674922 
78467583 
 


Mylan Inc 
MECC-TBZ-2001 
Page 35 of 35 
Version Date: 2020-10-05 
Version: <1.0>  
 
14. 
ATTACHMENTS