Efficacy and Safety in a randomised acute pain study of MR308.

• Register: EUCTR
• Last refreshed on: 20 August 2018
• Main ID: EUCTR2016-000593-38-LV
• Date of registration: 19/12/2016
• Prospective Registration: Yes
• Primary sponsor: Mundipharma Research GmbH & Co. KG
• Public title: Efficacy and Safety in a randomised acute pain study of MR308.
• Scientific title: A Randomized, Double-Blind, Multicenter, Placebo- and active Comparator-Controlled Study to evaluate Efficacy and Safety of MR308 in the Treatment of Acute Pain After Abdominal Hysterectomy Surgery under General Anaesthesia (STARDOM2). - STARDOM2
• Date of first enrolment: 20/02/2017
• Target sample size: 1100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000593-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 6
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belarus, Bulgaria, Canada, Czech Republic, Germany, Hungary, Japan, Latvia, Lithuania, Poland, Romania, Russian Federation, Slovakia, Spain

Contacts

• Name: Clinical trial contact
• Affiliation: Mundipharma Research GmbH & Co. KG

• Name: Clinical trial contact
• Affiliation: Mundipharma Research GmbH & Co. KG

Key inclusion & exclusion criteria

Inclusion criteria:
Only subjects meeting all of the following inclusion criteria will be considered for study inclusion:
1. Female subjects = 18 years on the day of consent.
2. Willing and able to provide written informed consent for this study.
3. Subjects are scheduled to have a total or subtotal abdominal hysterectomy under general anasethesia via a Pfannenstiel incision.
4. The elective procedure (total or subtotal hysterectomy with or without salpingo-oophorectomy) must be for benign conditions within 28 days of screening. Subjects with stage 0 carcinoma in situ of cervix, endometrial hyperplasia or clinically staged 1A or 1B endometrial cancer are allowed to participate.
5. American Society Anaesthesiology physical status of I or II.
6. If a female is of child-bearing potential, she must be using highly effective methods of contraception throughout the study, not breastfeeding, and have negative pregnancy tests prior to receiving IMP. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner).
7. Good general health as judged by Investigators on the basis of medical history and physical examination.
8. Willingness to comply with the study procedures and requirements.

Additional Inclusion Criteria after Surgery:

1. Abdominal hysterectomy completed without any immediate complication.
2. Tolerating oral fluids, no uncontrolled nausea/vomiting and ready to take oral analgesia.
3. The subject is alert and calm, spontaneously pays attention to caregiver, e.g. RASS = 0 (Sessler et al., 2002 & Ely et al., 2003).
4. Subjects will be capable to sit up from supine, stand up from a sitting position and walk 10 meters without assistance in the morning of the day following surgery.
5. Subjects with moderate or severe pain (qualifying PI-VAS score = 45mm and < 70mm or = 70mm and = 90mm) as a result of a surgical procedure (abdominal hysterectomy) under general anaesthesia. This must be measured within a maximum of 24 hours after leaving the recovery room and subjects can only be randomised on the day after surgery, after cessation of the post-operative analgesia*.

*Randomisation within one pain group may be temporarily closed, please see section 11.4 for further Details.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1100
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
Subjects having any of the following criteria must not be included in the study.
1. Any abnormal laboratory value that is clinically significant in the opinion of Investigator that would compromise the safety of the subject in the study.
2. Any recent history of frequent nausea or vomiting, dizziness within the last 3 months regardless of etiology.
3. Subjects having any medical condition or treatment that is either a warning or contraindication as per the SmPC of tramadol (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, MAO inhibitors (within 14 days before taking IMP), antipsychotics, anticonvulsant and other seizure threshold-lowering medicinal products), celecoxib (e.g. increased risk of post-operative bleeding, active peptic ulceration, GI bleeding or inflammatory bowel disease) or paracetamol.
4. Known sensitivity and/or contraindication to tramadol, celecoxib, paracetamol, sulfonamides, opioids, NSAIDS, COX-2 inhibitors, or related compounds or formulation excipients as well as severe hypersensitivity reactions (e.g. angioedema) to any drugs.
5. Subjects who are known to have had inadequate pain relief from paracetamol, tramadol or celecoxib.
6. Subjects requiring any medication which is prohibited as per section prohibited medication.
7. Subjects who are in the Investigator’s opinion considered at increased risk of operative (those associated with the surgical procedure and general anaesthesia) and post-operative complications, e.g.excessive post-operative bleeding, infection.
8. Any history of drug or alcohol abuse, misuse, physical or psychological dependence, mood changes, sleep disturbance and functional capacity which have an impact on pain perception.
9. Significant neurological or psychiatric disorders including mental instability (unrelated to the pain) that could interfere with pain assessment; other pain that might impair the assessment of the nociceptive pain.
10. Any medical history of significant and/or inadequately controlled cardiovascular (uncontrolled high blood pressure, high risk of cardiovascular events, severe heart failure), pulmonary, hematologic, (including coagulopathy/bleeding disorders), neurological (e.g. subjects with epilepsy or those susceptible to seizures), liver disease (e.g. severe hepatic impairment), kidney disease (e.g. serum creatinine level greater than 1.5 times the upper limit of normal, impaired renal function in subjects taking diuretics, ACE-inhibitors, or angiotensin II antagonists), endocrine, immunologic, dermatologic painful conditions or any other conditions that may compromise the ability of the subject to participate in the study or might interfere with drug absorption, distribution, metabolism or excretion.
11. Previous randomisation in this study.
12. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).
13. Subjects who were treated regularly with opioid analgesic or NSAIDs within 30 days prior to screening or who have received a long-acting NSAID within three days prior to the start of the surgery.
14. Subjects who are incapable of complying with the protocol.
15. Epidural or spinal anaesthesia or infiltration of the wound with an infusion of a local anaesthetic agent is not allowed. A single perioperative dose is allowed.
16. History or ongoing chronic

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Acute pain after open total or subtotal abdominal hysterectomy
MedDRA version: 19.0 Level: LLT Classification code 10066714 Term: Acute pain System Organ Class: 100000004867

Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

Intervention(s)

Product Name: MR308 Tablet 100 mg
Pharmaceutical Form: Tablet
INN or Proposed INN: Tramadol hydrochloride Celecoxib
Current Sponsor code: MR308 Co-crystal
Other descriptive name: CTC cocrystal
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: MR308 Tablet 150 mg
Pharmaceutical Form: Tablet
INN or Proposed INN: Tramadol hydrochloride Celecoxib
Current Sponsor code: MR308 Co-crystal
Other descriptive name: CTC cocrystal
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Zydol 50 mg capsules
Pharmaceutical Form: Capsule
INN or Proposed INN: Tramadol hydrochloride
Other descriptive name: TRAMADOL HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Celebrex 100mg capsule
Product Name: Celebrex 100 mg capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Celecoxib
Other descriptive name: CELECOXIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint is the Sum of Pain Intensity Differences over 0-4 hours (SPID4). SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain – current pain), measured at different time points via the PI-VAS. Time between two consecutive measurements will be used for weighting. Larger values indicate larger pain relief.

Main Objective: To demonstrate the efficacy of MR308 doses in the Treatment of acute moderate to severe pain. Efficacy will be assessed by showing superiority of MR308 doses over Placebo and non-inferiority compared with Tramadol, followed by superiority over Tramadol based on the sum of pain intesity differences over 0-4 hours (SPID4).

Timepoint(s) of evaluation of this end point: 0-4 hours (SPID4)

Secondary Objective: To compare the effficacy of MR308 doses versus Tramadol and Placebo based on the secondary efficacy endpoints.
To compare the safety and tolerability of MR308 doses versus Tramadol and Placebo.

Secondary Outcome(s)

Secondary end point(s): Key secondary endpoints:
1. 50% responder at 4 hours, defined as subjects with a reduction in pain intensity (PI-VAS) from 0 hours at 4 hours of at least 50%.
2. Use of at least one dose of rescue medication during the first 4 hours.

Other secondary endpoints:
1. SPID over 0-12 hours, 0-24 hours, 0-48 hours 0-72 hours, 0-96 hours and 0-120 hours.
2. Pain (PI-VAS) at each post-dose time point.
3. Pain Relief (PAR) at each post-dose time point.
4. Total Pain Relief (TOTPAR) over 0-4 hours, 0-12 hours, 0-24 hours, 0-48 hours, 0- 72 hours, 0-96 hours and 0-120 hours, defined as the sum of respective PAR, weighted with the time between two consecutive measurements.
5. Worst pain as per PI-VAS experienced by subjects in 24 and 48 hours from first IMP intake.
6. Responder based on PI-VAS
• 50% responder, based on PI-VAS at 12, 24, 48, 72, 96 and 120 hours.
• 30% responder, based on PI-VAS at 4, 12, 24, 48, 72, 96 and 120 hours.
7. Time to 30% and time to 50% response based on PI-VAS.
8. Time to perceptible pain relief and time to meaningful pain relief.
9. Rescue medication use.
• Average dose of rescue medication per 24 hours.
• Time to first intake of rescue medication.
10. EQ-5D-5L at 4, 24, 48, 72, 96 and 120 hours.
11. Mobilisation PI-VAS:
• Daily elicited pain at lying, sitting, standing and walking on Day 1 to 5.
• Average elicited pain over Day 1 to 5 at lying, sitting, standing and walking.

Timepoint(s) of evaluation of this end point: see above

Secondary ID(s)

MR308-3502

2016-000593-38-ES

Source(s) of Monetary Support

Mundipharma Research GmbH & Co. KG