Trial document




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  DRKS00000060

Trial Description

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Title

A Randomized, Double-Blind, Active Controlled Study Comparing the Intravenous Dose of Morphine and Oxycodone Combined in a Ratio of 1:1 Versus Morphine Alone Required to Achieve Effective Pain Control After Total Hip Replacement and the Untoward Effects of Combined Morphine and Oxycodone vs. Morphine Alone

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Trial Acronym

Duale Opioide Studie

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Primary objective is the comparison of the side effects of multiple dose intravenous co-administration of morphine and oxycodone vs. morphine alone in the therapy of moderate to severe postoperative pain after total hip replacement.

Secondary objectives are the comparison of the doses of opioid used and the analgesic efficacy as well as the evaluation of the safety and tolerability of intravenous co administration of morphine and oxycodone compared to morphine alone in all study participants. Additional recording of adverse events (AE), vital parameters, pulse oximetry, the total dose of study medication, serum levels of opioids and the application of additional analgetics allows the objectivation of effects recorded by patients and nursing staff. The investigation of potential effects of the combinated analgesia targets an increase in the effectiveness of pain reduction and reduction of opioid-related side effects via reduced total dosage.

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Brief Summary in Scientific Language

This is a randomized, double-blind, parallel treatment, active controlled, proof of concept study designed to determine whether the intravenous co administration of morphine and oxycodone has fewer opioid related adverse effects (AEs) than morphine alone at doses that result in effective and equi-analgesic pain relief for acute post operative pain, and to determine the doses of morphine and oxycodone co-administered versus morphine required to achieve effective pain relief. The study consists of the following periods.
Screening Period: Patients will be screened for inclusion in this study from the time the Informed Consent Form is signed to the time of arrival at the surgical site on the day of surgery. The Screening Period may last from 1 to 30 days.
Pre Treatment Period: Patients will participate in a Pre Treatment Period from the time they arrive at the surgical site, through the surgical procedure, and during the initial stay in the post-surgical patient-care area (Post-anesthesia care unit, PACU, or equivalent). The Pre treatment Period will end in the post operative period when the patient:
- reports moderate or severe pain (score of >= 4 on the 11 point NPRS)
- has oxygen saturation of at least 95%, by pulse oximetry
- has a respiratory rate of at least 12 breaths/minute
- has a systolic blood pressure ≥ 100 mm Hg, diastolic blood pressure ≥ 60 mm Hg, and pulse not less than 10% of their preoperative resting pulse and ≤ 100 beats/min,
- and is randomized
Baseline Period: from the time a patient confirms his or her pain as moderate or severe and at least a score of 4 on an 11-point NPRS [0=no pain and 10=worst pain imaginable] (see Section 7.2) to randomization and administration of the first dose of study medication. If the time between randomization and delivery of drug is >30 minutes, the NPRS intensity assessments will be repeated. Please note: The interval between time of randomization and delivery of study drug is expected to be less than 10 minutes.
The Pre treatment Period will last for variable lengths of time, all on the day of surgery, but no longer than 6 hours after the completion of surgery and arrival of the patient in the post operative recovery unit. Patients failing to meet the inclusion criteria within 6 hours will be withdrawn from the study and will not be eligible to receive study medication.
Treatment Period: The Treatment Period of the study will be conducted in two parts using a parallel group design. The total duration of the Treatment Period will be approximately 48 hours.
Treatment Part 1. Anaesthesiologist Controlled Analgesia (ACA)
Eligible patients will be randomized in a 1:1 ratio to one of two treatment groups:
- morphine/oxycodone co administered as a series of intravenous infusions at a ratio of 1:1
or
- morphine hydrochloride administered as a series of intravenous infusions using an ACA protocol.
Study medication will be prepared by an unblinded investigator and will be applied by a second blinded investigator in the recovery room. Study medication will be prepared by an unblinded investigator and will be applied by a second blinded investigator in the recovery room. During Treatment Part 1 the patient will be continuously monitored by an anesthesiologist and all drug doses will be given by the anesthesiologist. Five minutes after the first dose and, provided that the subject meets all safety criteria including stable vital signs, injections will be administered every five minutes as described below. In order to maintain blinding the volume per dose of the morphine/oxycodone and morphine solutions will be identical. The first injection will consist of either 1.5mg of morphine co administered with 1.5mg of oxycodone or 3mg of morphine alone.
Subsequent injections administered via ACA will include 0.75mg morphine co administered with 0.75mg oxycodone, or 1.5 mg morphine alone.
Study medication will be administered to patients in both treatment groups at intervals of 5 minutes until the patient;
- reports a score of 2 or less on the 11 point NPRS) (ACA responders) or
- is unable to tolerate additional injections of study medication on the ACA 5-minute schedule (ACA non responders due to toxicity) or
- has received a total of 13 injections (cumulative dose of 10.5mg morphine co administered with 10.5mg oxycodone or 21mg morphine alone) and fails to achieve the analgesic target in 65 minutes (ACA non responders)
Vitals signs (blood pressure, respiration rate, pulse, and SpO2) will be measured and recorded just prior to each dose. To qualify for re-treatment with study drug during Part 1 the patient must have Stable Vital Signs: systolic blood pressure of > 100mm Hg and a diastolic blood pressure of > 60mm Hg, a pulse rate not less than 10% below their preoperative resting pulse rate and < 100 beats/minute, and an oxygen saturation of > 90%. The Visual Analog Scale to rate the level of patient alertness/drowsiness will be completed by the study staff at the same time as the vital signs and pain intensity scores.
The Opioid-Related Symptom Distress Scale Questionnaire and the Patient's Global Assessment of Medication for Pain will be completed by all patients at the end of Part 1.
Treatment Part 2. Patient-Controlled Analgesia
Patients who reach the target pain score (ACA responders), will then enter Part 2 and continue to receive blinded study medication (bolus injections of morphine and oxycodone (0.50mg/0.50mg) or 1.0mg morphine alone) until hour 48 on an "as needed" basis using PCA with a lockout interval of 5 minutes and a maximum allowable 3 injections per hour up to a total of 60 mg of morphine/oxycodone or morphine alone/24 hour period.
Patients who are unable to achieve the target pain score because of opioid related AEs that interfere with completion of the ACA period will be defined as ACA non responders (due to toxicity) and will not receive further study medication during the ACA portion of the study. Patients in this category will be allowed to enter Part 2 and receive their study drug (morphine/oxycodone: 0.50mg/0.50mg; or 1.0mg morphine alone) via PCA if their symptoms sufficiently resolve within 120 minutes after discontinuing study medication during ACA and who can safely resume opioid therapy, in the judgment of the managing clinician . For example, if a patients oxygen saturation falls below 90%, the patient will receive supplemental oxygen and be eligible to re enter the PCA portion of the study once oxygen levels have returned to >=90%.
Post-Treatment Period: From 48 hours after the first dose of study medication until the patient completes all Post-Treatment assessments and is discharged from the study site, at least 2 hours after the final dose of study medication and up to 24 hours.

Follow-Up Period: All patients will be contacted either by telephone, mail or email up to 7 ± 2 days after their last dose of study medication and final safety data will be collected.
Patients unable to achieve the target pain score during the 65 minute ACA period for reasons other than opioid toxicity (ACA non responders) will also be eligible to enter Part 2 and receive their study medication (morphine/oxycodone: 0.50mg/0.50mg; or 1.0mg morphine alone) via PCA.
Because of the relative intensity of treatments and evaluations required to titrate the patient to the target pain score during the ACA period, a fully dedicated investigator or study nurse (instructed and supervised by the Principal Investigator) will be required for the management of each patient, and the dedicated manager should not be assigned more than a single patient.
All patients participating in the study will receive ibuprofen: 600 mg rectally on day 1 at the end of surgery, another 800 mg p.o. with dinner (after study Part 1), and on day 2, 800 mg p.o. at 6h, 12h, and 18h.

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Organizational Data

  •   DRKS00000060
  •   2009/08/07
  •   [---]*
  •   yes
  •   Approved
  •   F-08/2009, Ethik-Kommission der Universität Witten/Herdecke
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Secondary IDs

  •   2008-008527-14 
  •   4035025 
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Health Condition or Problem studied

  •   10054710: Postoperative hip pain
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Interventions/Observational Groups

  •   morphine hydrochloride/oxycodone hydrochloride co-administered as a series of intravenous infusions at a ratio of 1:1
  •   morphine hydrochloride administered as a series of intravenous infusions using an ACA protocol.
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
  •   [---]*
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Primary Outcome

To compare the side effects with multiple dose intravenous co administration of morphine and oxycodone vs. morphine alone at doses that result in effective relief of pain, defined as a score of 2 or less on the 11 point NPRS

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Secondary Outcome

- To compare the doses of opioid used and the analgesic efficacy provided by intravenous morphine plus oxycodone versus morphine alone in all study participants, including patients who do not achieve the target NPRS score (<=2) for comparison of equi-analgesic effects.

- To evaluate the safety and tolerability of intravenous co administration of morphine and oxycodone compared to morphine alone following repeat administration of study medication during the post operative period.

Concomitant recording of Adverse Events (AE), vital parameters, oxygen saturation, cumulative dosage of study medication, serum levels of opioids and the application of supplemental analgesics allow the objectivation of the effects recorded by the patients and the nursing staff. The analysis of potential effects of the combinated analgesia target at an increased effectivity of pain relief and a reduction of opiod-induced adverse effects by means of lower cumulative dosages.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • [---]*
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Recruitment

  •   Actual
  •   2009/07/20
  •   40
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

To qualify for enrollment in this study, the patient must:
-have voluntarily provided written informed consent and HIPAA authorization prior to any study-related procedures are performed;
-be male or female, at least 18 years of age, at the time of enrollment;
- if female, be at least one year post-menopausal (defined as one year without menses), surgically sterile (must be documented), or practicing effective contraception, in the opinion of the Investigator, and be willing to continue to use effective contraception for the duration of participation in the study (Double barrier methods, hormonal contraceptives, and abstinence are acceptable birth control methods for this study)
-have undergone a primary unilateral total hip replacement performed under standardized general, spinal, or epidural anesthesia;
-be scored I-III on the American Society of Anesthesiologists (ASA) physical status classification system;
- have developed moderate or severe pain on a 11-point NPRS (>=4) scale within 6 hours post end of surgery (time of last stitch)on the day of surgery

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Exclusion Criteria

A patient will be excluded from enrollment in this study if the patient:
-has a history of acute or severe asthma, chronic pulmonary disease, renal disease, Addisons disease (chronic adrenal insufficiency), head injury, elevated intracranial pressure, convulsive states, congestive heart failure current cardiac arrhythmia, current transient cerebral ischemic attacks, current uncontrolled unstable co-existent systemic disease, other medical condition, laboratory abnormality, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the study;
-has allergy, hypersensitivity, or contraindications to opioids or acetaminophen;
-has positive HIV serology or signs of HIV infection or AIDs;
-has positive HBsAg or HCV antibody;
-has undergone any other surgical procedure, either related or unrelated, during the same surgery session;
-has a total hip replacement procedure time greater than 6 hours;
-has a history of drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere with adherence to study requirements;
-has current evidence of alcohol abuse.

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Addresses

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    • Private Universität Witten/Herdecke gGmbH
    • Alfred-Herrhausen-Straße 50
    • 58448  Witten
    • Germany
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    • Klinik für Anaesthesiologie und operative Intensivmedizin Kliniken der Stadt Köln gGmbH, Klinikum Merheim
    • Mr.  Dr.  Robin  Joppich 
    • Ostmerheimer Str. 200 (Haus32A)
    • 51109  Köln
    • Germany
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    • Klinik für Anaesthesiologie und operative Intensivmedizin Kliniken der Stadt Köln gGmbH, Kliniken Merheim
    • Mr.  Dr.  Robin  Joppich 
    • Ostmerheimer Str. 200 (Haus 32A)
    • 51109  Köln
    • Germany
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Sources of Monetary or Material Support

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    • QRxPharma, Inc.
    • 1430 US Highway 206 Suite 230
    • 07921  Bedminster NJ
    • United States
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    •   [---]*
    •   [---]*
    •   [---]*
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Status

  •   Recruiting complete, follow-up complete
  •   2010/05/24
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Trial Publications, Results and other Documents

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