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

Postoperative Pain Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02077140
• Other study ID #: P13-01
• Status: Completed
• Phase: Phase 2
• First received: February 26, 2014
• Last updated: September 12, 2017
• Start date: February 2014
• Est. completion date: February 2016

Study information

• Verified date: September 2017
• Source: Medtronic Spinal and Biologics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 192
• Est. completion date: February 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Pain, Postoperative
• Postoperative Pain

Intervention

Drug:
• MDT-10013

• Standard of care for pain

Locations

Country	Name	City	State
United States	Research Site	Austin	Texas
United States	Research Site	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Medtronic Spinal and Biologics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-8)	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Maximum Observed Plasma Concentration (Cmax)	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Time to Maximum Plasma Concentration Observed (Tmax)	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Lag Time Before First Measurable Drug Concentration (Tlag)	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Terminal Plasma Half-life (t½)	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.	up to 10 days
Other	Pharmacokinetic (PK) Parameters of MDT-10013: Terminal Phase Rate Constant (?z)	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.	up to 10 days
Other	Summed Pain Intensity Scores (Exploratory Analysis)	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).	over 1 to 24hr, 1 to 48 hrs, 1 to 72hrs, and 1 to 96hrs
Other	Total Use of Opioid Analgesia (Exploratory Analysis).		over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs
Other	Time to First Use of Opioid Analgesia (Exploratory Analysis)		up to 96hrs
Other	Subject's Satisfaction With Study Treatment (Exploratory Analysis)	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	up to 72hrs
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.	over 1 to 48hrs
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.	over 1 to 48hrs
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.	over 1 to 48hrs
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.	over 1 to 48hrs
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).	over 1 to 24hrs, 1 to 72hrs, and 1 to 96hrs
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.	over 0 to 24hrs, 0 to 48hrs, 0 to 72hrs, and 0 to 96hrs
Secondary	Time to First Use of Opioid Analgesia		up to 96hrs
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	up to 72hrs