A Study of MDT-10013 in the Treatment of Acute Postoperative Pain Following Bunionectomy

A Phase II, Dose-escalating, Randomized, Double-blind, Multicenter Study to Evaluate the Efficacy, Safety and Pharmacokinetic Profile of MDT-10013 Versus Standard of Care in the Treatment of Acute Postoperative Pain Following Bunionectomy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02077140

Enrollment

192

Registered

2014-03-04

Start date

2014-02-28

Completion date

2016-02-29

Last updated

2017-10-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Postoperative Pain

Brief summary

The purpose of this study is to evaluate the efficacy and safety of MDT-10013 in men and women 18 to 80 years of age who are undergoing bunionectomy. The primary objective is to determine the analgesic efficacy of MDT-10013 compared with standard of care in the treatment of acute postoperative pain after subjects undergo bunionectomy.

Interventions

DRUGMDT-10013

DRUGStandard of care for pain

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

1. Is male or female aged 18 to 80 years. 2. Has a body mass index from 18 kg/m2 to 40 kg/m2. 3. Is scheduled to undergo primary, unilateral, first metatarsal bunionectomy (osteotomy and internal fixation) with no additional collateral procedures. 4. Is classified by American Society of Anesthesiologists Physical Status Classification System as Class I or II. 5. Must meet the following criteria if female: * Is of non-childbearing potential, defined as any woman who has undergone surgical sterilization or is more than 2 years postmenopausal * If of childbearing potential, may be enrolled on the condition that results of a pregnancy test are negative at baseline (at Screening and before surgery) and that she is routinely using an effective method of birth control with a low failure rate (i.e., hormonal contraception, intrauterine device, condoms in combination with a spermicidal cream, or total sexual abstinence) 6. Has read, understood, and signed the informed consent prior to study entry. 7. Is mentally competent, reliable, and cooperative to undergo all visits and procedures scheduled in the study protocol and to record the required information. 8. Has medical history, physical examination, vital signs, laboratory tests, and 12-lead electrocardiograms (ECGs) that are normal or without clinically relevant abnormalities as per investigator's judgment.

Exclusion criteria

1. Is a female who is pregnant or breastfeeding. 2. Is not indicated for surgery because of an inflammatory process or risk of infection or delayed wound healing (e.g., autoimmune disorder). 3. Has a history of allergy or hypersensitivity to the components in the investigational product or to the opioid medication (oxycodone). 4. Before surgery, has current orthostatic hypotension (defined as systolic blood pressure decrease of at least 20 mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg or an increase in heart rate by 20 beats per minute within 3 minutes of sitting up or standing). 5. Has severe asthma, defined as requiring frequent or ongoing treatment to control symptoms. Exercise-induced asthma or mild asthma not requiring ongoing treatment may not be exclusionary at the discretion of the investigator. 6. Has a current gastrointestinal disorder associated with bleeding, a history of such a disorder, or gastrointestinal inflammatory diseases as Crohn's disease or ulcerative colitis. 7. Has any clinically significant cardiovascular condition as evidenced by physical examination, medical history, and/or baseline ECG. 8. Has evidence of bradycardia as shown by heart rate of \<50 beats per minute via screening ECG. 9. Has a known infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus. 10. Has a chronic pain condition that may interfere with the subject's assessment of pain postoperatively, as determined by the investigator. 11. Has any poorly controlled or serious medical conditions, psychiatric illnesses, or clinically significant laboratory values that, in the opinion of the investigator, could compromise the safety of the subject or the scientific integrity of the study (e.g., uncontrolled hypertension, autoimmune disease, or clinically relevant symptoms of thyroid dysfunction). 12. Has presence or history of local or systemic malignant disease in the past 5 years (history of basal cell carcinoma will be allowed). 13. Has impaired renal function (creatinine \>1.5 times upper limit of normal). 14. Has chronic impairment liver function (aspartate aminotransferase or alanine aminotransferase \>3 times upper limit of normal). 15. Has insulin-dependent diabetes or uncontrolled diabetes mellitus (glycosylated hemoglobin \>7%). 16. Has leukopenia (\<3500 leukocytes/μL). 17. Has current treatment with any of the following medications: 1. Systemic corticosteroids (intranasal/inhaled steroids are acceptable). 2. Immunosuppressant therapy to treat autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, sarcoidosis, focal segmental glomerulosclerosis, Crohn's disease, Behcet's Disease, pemphigus, and ulcerative colitis). 3. Oral or topical products that contain clonidine (e.g., Catapres). 4. Herbal supplements that contain yohimbine. 5. Anticoagulant/antiplatelet therapy (prophylactic aspirin at 81 mg/day is acceptable). If applicable, aspirin therapy should be held before and after the study procedure on the basis of the investigator's discretion. 6. Antiepileptic drugs, antipsychotics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and sulfonamides. 7. Calcium channel blocker, digoxin, or beta-adrenergic blockers. 18. Has chronic use of opioids (including tramadol), defined as use 20 out of the last 30 days before study screening. 19. Has a history of or current diagnosis of epilepsy. 20. Has a known or suspected history of drug or alcohol abuse (as determined by the investigator). 21. Is judged by the investigator not to be a suitable candidate for study treatment and pain relief medication on the basis of medical history, concomitant medication, and concurrent systemic disease. 22. Is not stabilized on the following medications for at least 8 weeks prior to dosing: selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). 23. Is unable to refrain from taking nonsteroidal anti inflammatory drugs (NSAIDs) or opioids within the 24-hour period prior to surgery. 24. Has participated in any other clinical trial in the 4 weeks prior to Screening. 25. Experiences any surgical complication that, in the opinion of the investigator, precludes implantation of MDT-10013.

Design outcomes

Primary

Measure	Time frame	Description
Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)	over 1 to 48hrs	Similar to SPI-48, the theoretical range for this WOCF adjustment for rescue medication is 0-470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). The calculation is identical in terms of area-under the curve using the trapezoidal rule. However, the NRS score at the final assessment prior to each instance of rescue medication is carried forward through for a window based on the approximate half-life of the drug, replacing the raw NRS scores post-rescue for each patient until the end of the pharmacological activity window, at which point calculations revert to raw NRS as applicable. Note that WOCF SPI-48 may include multiple adjustment windows for each patient, depending on the number or rescue events and the active life of the medication selected.
Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3	over 1 to 48hrs	Summed pain intensity is a time-weighted average pain score in numeric rating scale (NRS) over 1 to 48hrs (SPI-48). Summed pain intensity is calculated as area under the curve, using the trapezoidal rule to bridge adjacent time points. Specifically, NRS scores for two adjacent time points are averaged and then multiplied by the time span between points (in hours). The theoretical range for SPI-48 is 0 to 470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). Time 0 was defined as the time the capsule was closed.
Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)	over 1 to 48hrs	Similar to SPI-48, the theoretical range for this LOCF adjustment for rescue medication is 0-470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). The calculation is identical to SPI-48 in terms of area-under the curve using the trapezoidal rule. However, the NRS score at the final assessment prior to rescue is carried forward through 48 hours, replacing the raw NRS scores post-rescue for each patient as applicable.
Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method	over 1 to 48hrs	This sensitivity analysis is an integrated assessment of summed pain intensity over 1 to 48hrs (SPI-48) and total opioid intake (ME0-48) in first 48hrs. Briefly, subjects were ranked according to SPI-48 regardless of the treatment received (including Standard of Care, SOC). The mean of all the ranks for this variable was calculated. Then, the percent difference for each individual rank from the pooled mean rank was computed. This process was repeated for total opioid intake in the first 48hrs (ME0-48). The integrated endpoint for each subject was the sum of the rank order percent differences for SPI-48 and ME0-48. The theoretical minimum and maximum on the integrated endpoint are -197% and +197% in this study. Lower scores are better, indicative of less pain and/or less opioid intake.

Secondary

Measure	Time frame	Description
Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	over 1 to 24hrs, 1 to 72hrs, and 1 to 96hrs	The theoretical range for SPI-24, SPI-72, and SPI-96 is 0 to 230, 0-710, and 0-960, respectively, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). Summed pain intensity is calculated as area under the curve, using the trapezoidal rule to bridge adjacent time points. Specifically, NRS scores for two adjacent time points are averaged and then multiplied by the time span between points (in hours).
Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs	Total use of opioid analgesia over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs. The analgesia administered was converted to a morphine equivalent by using a standard conversion table.
Time to First Use of Opioid Analgesia	up to 96hrs	—
Subject's Satisfaction With Study Treatment	up to 72hrs	Subject's satisfaction with study treatment as measured by a 5-point categorical scale where 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent

Other

Measure	Time frame	Description
Total Use of Opioid Analgesia (Exploratory Analysis).	over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs	—
Pharmacokinetic (PK) Parameters of MDT-10013: Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.
Subject's Satisfaction With Study Treatment (Exploratory Analysis)	up to 72hrs	Subject's satisfaction with study treatment as measured by a 5-point categorical scale where 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent
Time to First Use of Opioid Analgesia (Exploratory Analysis)	up to 96hrs	—
Pharmacokinetic (PK) Parameters of MDT-10013: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-∞)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.
Pharmacokinetic (PK) Parameters of MDT-10013: Maximum Observed Plasma Concentration (Cmax)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.
Pharmacokinetic (PK) Parameters of MDT-10013: Time to Maximum Plasma Concentration Observed (Tmax)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.
Pharmacokinetic (PK) Parameters of MDT-10013: Lag Time Before First Measurable Drug Concentration (Tlag)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.
Pharmacokinetic (PK) Parameters of MDT-10013: Terminal Plasma Half-life (t½)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed.
Pharmacokinetic (PK) Parameters of MDT-10013: Terminal Phase Rate Constant (λz)	up to 10 days	Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed.
Summed Pain Intensity Scores (Exploratory Analysis)	over 1 to 24hr, 1 to 48 hrs, 1 to 72hrs, and 1 to 96hrs	The theoretical range for SPI-24, SPI-48, SPI-72, and SPI-96 is 0 to 230, 0-470, 0-710, and 0-960, respectively, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). Summed pain intensity is calculated as area under the curve, using the trapezoidal rule to bridge adjacent time points. Specifically, NRS scores for two adjacent time points are averaged and then multiplied by the time span between points (in hours).

Countries

United States

Participant flow

Recruitment details

The study was planned to enroll 3 sequential cohorts, the 4th cohort was added after data review from Cohort 1-3. In each cohort, 48 subjects were randomized in a 3:1 ratio (investigational vs. control). The investigational subjects were implanted MDT-10013 strips in surgical wound while control subjects received standard of care for pain control.

Participants by arm

Arm	Count
1 MDT-10013 Strip (In Cohort 1) For the investigational subjects of Cohort 1, one MDT-10013 strip was sutured to the exterior of the capsule wall.	36
2 MDT-10013 Strips (In Cohort 2) For the investigational subjects of Cohort 2, one MDT-10013 strip was sutured to the exterior of the capsule and 1 strip was sutured to the interior capsule wall.	36
3 MDT-10013 Strips (In Cohort 3) For the investigational subjects of Cohort 3, one MDT-10013 strip was sutured to the exterior of the capsule and 2 strips were sutured to the interior capsule wall.	36
2 MDT-10013 Strips (In Cohort 4) For the investigational subjects of Cohort 4, two MDT-10013 strips were sutured to the interior capsule wall.	36
Control (In Cohort 1 to 4) Control subjects in Cohort 1 to 4 received standard of care for pain control.	48
Total	192

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Lost to Follow-up	4	1	2	2	3
Overall Study	Withdrawal by Subject	0	1	0	2	2

Baseline characteristics

Characteristic	1 MDT-10013 Strip (In Cohort 1)	2 MDT-10013 Strips (In Cohort 2)	3 MDT-10013 Strips (In Cohort 3)	2 MDT-10013 Strips (In Cohort 4)	Control (In Cohort 1 to 4)	Total
Age, Continuous	47.6 years STANDARD_DEVIATION 13.22	39.7 years STANDARD_DEVIATION 11.9	40.4 years STANDARD_DEVIATION 12.37	41.1 years STANDARD_DEVIATION 13.49	40.7 years STANDARD_DEVIATION 11.78	41.8 years STANDARD_DEVIATION 12.71
BMI	27.3 kg/m^2 STANDARD_DEVIATION 4.82	27.3 kg/m^2 STANDARD_DEVIATION 4.51	27.4 kg/m^2 STANDARD_DEVIATION 4.07	27.6 kg/m^2 STANDARD_DEVIATION 4.44	28.0 kg/m^2 STANDARD_DEVIATION 4.55	27.6 kg/m^2 STANDARD_DEVIATION 4.45
Height	162.8 cm STANDARD_DEVIATION 8.12	162.5 cm STANDARD_DEVIATION 7.38	163.8 cm STANDARD_DEVIATION 8.92	162.8 cm STANDARD_DEVIATION 9.86	165.2 cm STANDARD_DEVIATION 8.67	163.5 cm STANDARD_DEVIATION 8.61
Race/Ethnicity, Customized American-Indian or Alaska Native	0 Participants	2 Participants	2 Participants	0 Participants	0 Participants	4 Participants
Race/Ethnicity, Customized Asian	0 Participants	2 Participants	1 Participants	0 Participants	0 Participants	3 Participants
Race/Ethnicity, Customized Black or African-American	4 Participants	4 Participants	7 Participants	5 Participants	4 Participants	24 Participants
Race/Ethnicity, Customized Data missing	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Other	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized White	31 Participants	28 Participants	26 Participants	30 Participants	44 Participants	159 Participants
Sex: Female, Male Female	32 Participants	33 Participants	29 Participants	31 Participants	43 Participants	168 Participants
Sex: Female, Male Male	4 Participants	3 Participants	7 Participants	5 Participants	5 Participants	24 Participants
Weight	72.71 lbs STANDARD_DEVIATION 15.41	71.97 lbs STANDARD_DEVIATION 12.79	73.94 lbs STANDARD_DEVIATION 14.51	72.99 lbs STANDARD_DEVIATION 13.3	76.12 lbs STANDARD_DEVIATION 14.24	73.71 lbs STANDARD_DEVIATION 14.02

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 36	0 / 36	0 / 36	0 / 36	0 / 48
other Total, other adverse events	28 / 36	34 / 36	30 / 36	24 / 36	38 / 48
serious Total, serious adverse events	0 / 36	0 / 36	0 / 36	0 / 36	0 / 48

Outcome results

Primary

Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method

This sensitivity analysis is an integrated assessment of summed pain intensity over 1 to 48hrs (SPI-48) and total opioid intake (ME0-48) in first 48hrs. Briefly, subjects were ranked according to SPI-48 regardless of the treatment received (including Standard of Care, SOC). The mean of all the ranks for this variable was calculated. Then, the percent difference for each individual rank from the pooled mean rank was computed. This process was repeated for total opioid intake in the first 48hrs (ME0-48). The integrated endpoint for each subject was the sum of the rank order percent differences for SPI-48 and ME0-48. The theoretical minimum and maximum on the integrated endpoint are -197% and +197% in this study. Lower scores are better, indicative of less pain and/or less opioid intake.

Time frame: over 1 to 48hrs

Population: The primary efficacy analysis was based on the Full Analysis dataset of Cohort 1 to 3. Full Analysis dataset included Safety population (i.e., all subjects who received at least 1 MDT-10013 strip or completed surgery in a standard-of-care group based on the actual treatment a subject received) having at least 1 postoperative pain assessment.

Arm	Measure	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method	23.66 percent difference	Standard Deviation 54.274
2 MDT-10013 Strips (In Cohort 2)	Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method	-4.79 percent difference	Standard Deviation 55.043
3 MDT-10013 Strips (In Cohort 3)	Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method	-17.36 percent difference	Standard Deviation 62.466
Control (In Cohort 1-3)	Integrated Summed Pain Intensity Over 1- 48hrs (SPI-48) and Total Opioid Intake in First 48hrs --Sensitivity Analysis Using Silverman Method	-1.51 percent difference	Standard Deviation 52.306

Primary

Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3

Summed pain intensity is a time-weighted average pain score in numeric rating scale (NRS) over 1 to 48hrs (SPI-48). Summed pain intensity is calculated as area under the curve, using the trapezoidal rule to bridge adjacent time points. Specifically, NRS scores for two adjacent time points are averaged and then multiplied by the time span between points (in hours). The theoretical range for SPI-48 is 0 to 470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). Time 0 was defined as the time the capsule was closed.

Time frame: over 1 to 48hrs

Arm	Measure	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3	252.29 units on a scale	Standard Deviation 74.423
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3	213.28 units on a scale	Standard Deviation 73.33
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3	191.97 units on a scale	Standard Deviation 84.94
Control (In Cohort 1-3)	Summed Pain Intensity Over 1- 48hrs (SPI-48) From Cohort 1 to 3	215.35 units on a scale	Standard Deviation 66.133

Primary

Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)

Similar to SPI-48, the theoretical range for this LOCF adjustment for rescue medication is 0-470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). The calculation is identical to SPI-48 in terms of area-under the curve using the trapezoidal rule. However, the NRS score at the final assessment prior to rescue is carried forward through 48 hours, replacing the raw NRS scores post-rescue for each patient as applicable.

Time frame: over 1 to 48hrs

Arm	Measure	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)	324.82 units on a scale	Standard Deviation 65.141
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)	284.60 units on a scale	Standard Deviation 80.08
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)	281.03 units on a scale	Standard Deviation 82.593
Control (In Cohort 1-3)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Last Observation Carried Forward (LOCF)	281.83 units on a scale	Standard Deviation 91.415

Primary

Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)

Similar to SPI-48, the theoretical range for this WOCF adjustment for rescue medication is 0-470, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). The calculation is identical in terms of area-under the curve using the trapezoidal rule. However, the NRS score at the final assessment prior to each instance of rescue medication is carried forward through for a window based on the approximate half-life of the drug, replacing the raw NRS scores post-rescue for each patient until the end of the pharmacological activity window, at which point calculations revert to raw NRS as applicable. Note that WOCF SPI-48 may include multiple adjustment windows for each patient, depending on the number or rescue events and the active life of the medication selected.

Time frame: over 1 to 48hrs

Arm	Measure	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)	322.08 units on a scale	Standard Deviation 93.298
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)	278.44 units on a scale	Standard Deviation 83.515
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)	257.57 units on a scale	Standard Deviation 100.43
Control (In Cohort 1-3)	Summed Pain Intensity Over 1- 48hrs (SPI-48)--Sensitivity Analysis Using Windowed Worst Observation Carried Forward (WOCF)	302.54 units on a scale	Standard Deviation 82.105

Secondary

Subject's Satisfaction With Study Treatment

Subject's satisfaction with study treatment as measured by a 5-point categorical scale where 0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent

Time frame: up to 72hrs

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
1 MDT-10013 Strip (In Cohort 1)	Subject's Satisfaction With Study Treatment	Very good	8 Participants
1 MDT-10013 Strip (In Cohort 1)	Subject's Satisfaction With Study Treatment	Fair	3 Participants
1 MDT-10013 Strip (In Cohort 1)	Subject's Satisfaction With Study Treatment	Excellent	4 Participants
1 MDT-10013 Strip (In Cohort 1)	Subject's Satisfaction With Study Treatment	Good	10 Participants
1 MDT-10013 Strip (In Cohort 1)	Subject's Satisfaction With Study Treatment	Poor	11 Participants
2 MDT-10013 Strips (In Cohort 2)	Subject's Satisfaction With Study Treatment	Good	9 Participants
2 MDT-10013 Strips (In Cohort 2)	Subject's Satisfaction With Study Treatment	Very good	11 Participants
2 MDT-10013 Strips (In Cohort 2)	Subject's Satisfaction With Study Treatment	Excellent	8 Participants
2 MDT-10013 Strips (In Cohort 2)	Subject's Satisfaction With Study Treatment	Fair	5 Participants
2 MDT-10013 Strips (In Cohort 2)	Subject's Satisfaction With Study Treatment	Poor	3 Participants
3 MDT-10013 Strips (In Cohort 3)	Subject's Satisfaction With Study Treatment	Good	11 Participants
3 MDT-10013 Strips (In Cohort 3)	Subject's Satisfaction With Study Treatment	Poor	3 Participants
3 MDT-10013 Strips (In Cohort 3)	Subject's Satisfaction With Study Treatment	Fair	4 Participants
3 MDT-10013 Strips (In Cohort 3)	Subject's Satisfaction With Study Treatment	Very good	13 Participants
3 MDT-10013 Strips (In Cohort 3)	Subject's Satisfaction With Study Treatment	Excellent	5 Participants
Control (In Cohort 1-3)	Subject's Satisfaction With Study Treatment	Very good	8 Participants
Control (In Cohort 1-3)	Subject's Satisfaction With Study Treatment	Fair	6 Participants
Control (In Cohort 1-3)	Subject's Satisfaction With Study Treatment	Poor	9 Participants
Control (In Cohort 1-3)	Subject's Satisfaction With Study Treatment	Good	10 Participants
Control (In Cohort 1-3)	Subject's Satisfaction With Study Treatment	Excellent	3 Participants

Secondary

Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)

The theoretical range for SPI-24, SPI-72, and SPI-96 is 0 to 230, 0-710, and 0-960, respectively, with lower scores indicative of less pain over this time period (i.e., lower scores are consistent with better analgesia). Summed pain intensity is calculated as area under the curve, using the trapezoidal rule to bridge adjacent time points. Specifically, NRS scores for two adjacent time points are averaged and then multiplied by the time span between points (in hours).

Time frame: over 1 to 24hrs, 1 to 72hrs, and 1 to 96hrs

Arm	Measure	Group	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-24	132.18 units on a scale	Standard Deviation 35.321
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-96	393.29 units on a scale	Standard Deviation 155.314
1 MDT-10013 Strip (In Cohort 1)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-72	325.96 units on a scale	Standard Deviation 113.416
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-24	110.83 units on a scale	Standard Deviation 35.831
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-96	345.50 units on a scale	Standard Deviation 144.692
2 MDT-10013 Strips (In Cohort 2)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-72	285.50 units on a scale	Standard Deviation 109.126
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-72	259.42 units on a scale	Standard Deviation 126.691
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-24	102.42 units on a scale	Standard Deviation 38.324
3 MDT-10013 Strips (In Cohort 3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-96	322.97 units on a scale	Standard Deviation 168.672
Control (In Cohort 1-3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-24	118.13 units on a scale	Standard Deviation 33.591
Control (In Cohort 1-3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-96	344.90 units on a scale	Standard Deviation 147.835
Control (In Cohort 1-3)	Summed Pain Intensity Scores Over 1- 24hrs (SPI-24), 1- 72hrs (SPI-72) and 1- 96hrs (SPI-96)	SPI-72	282.90 units on a scale	Standard Deviation 105.476

Secondary

Time to First Use of Opioid Analgesia

Time frame: up to 96hrs

Arm	Measure	Value (MEDIAN)
1 MDT-10013 Strip (In Cohort 1)	Time to First Use of Opioid Analgesia	4.4 hours
2 MDT-10013 Strips (In Cohort 2)	Time to First Use of Opioid Analgesia	5.3 hours
3 MDT-10013 Strips (In Cohort 3)	Time to First Use of Opioid Analgesia	5.1 hours
Control (In Cohort 1-3)	Time to First Use of Opioid Analgesia	3.7 hours

Secondary

Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.

Total use of opioid analgesia over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs. The analgesia administered was converted to a morphine equivalent by using a standard conversion table.

Time frame: over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs

Arm	Measure	Group	Value (MEAN)	Dispersion
1 MDT-10013 Strip (In Cohort 1)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 24 hrs	51.04 morphine mg equivalent	Standard Deviation 21.798
1 MDT-10013 Strip (In Cohort 1)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 48 hrs	81.67 morphine mg equivalent	Standard Deviation 38.526
1 MDT-10013 Strip (In Cohort 1)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 72 hrs	95.35 morphine mg equivalent	Standard Deviation 50.886
1 MDT-10013 Strip (In Cohort 1)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 96 hrs	106.04 morphine mg equivalent	Standard Deviation 57.744
2 MDT-10013 Strips (In Cohort 2)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 48 hrs	59.10 morphine mg equivalent	Standard Deviation 32.278
2 MDT-10013 Strips (In Cohort 2)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 72 hrs	73.68 morphine mg equivalent	Standard Deviation 45.773
2 MDT-10013 Strips (In Cohort 2)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 96 hrs	81.98 morphine mg equivalent	Standard Deviation 54.366
2 MDT-10013 Strips (In Cohort 2)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 24 hrs	37.64 morphine mg equivalent	Standard Deviation 21.654
3 MDT-10013 Strips (In Cohort 3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 72 hrs	69.58 morphine mg equivalent	Standard Deviation 46.876
3 MDT-10013 Strips (In Cohort 3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 48 hrs	56.04 morphine mg equivalent	Standard Deviation 34.04
3 MDT-10013 Strips (In Cohort 3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 96 hrs	77.92 morphine mg equivalent	Standard Deviation 54.803
3 MDT-10013 Strips (In Cohort 3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 24 hrs	34.17 morphine mg equivalent	Standard Deviation 18.927
Control (In Cohort 1-3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 96 hrs	102.92 morphine mg equivalent	Standard Deviation 51.805
Control (In Cohort 1-3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 48 hrs	82.08 morphine mg equivalent	Standard Deviation 34.203
Control (In Cohort 1-3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 24 hrs	55.42 morphine mg equivalent	Standard Deviation 19.987
Control (In Cohort 1-3)	Total Use of Opioid Analgesia Over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs.	Total opioid analgesia use over 0 to 72 hrs	95.63 morphine mg equivalent	Standard Deviation 45.862

Other Pre-specified

Pharmacokinetic (PK) Parameters of MDT-10013: Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t)

Blood samples were taken for pharmacokinetic parameters of MDT-10013 determinations before surgery on Day 0; at 1, 2, 4, 6, 8, 12, 24, 48, 72, and 96 hours after Time 0 (96-hour sample for Cohort 4 only); and on Days 7 to 10 after Time 0. Time 0 was defined as the time the capsule was closed. Actual sampling times after T0 (to 1/1000th of an hour) were used to calculate PK parameters.

Time frame: up to 10 days