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Trial registered on ANZCTR


Registration number
ACTRN12619000587101
Ethics application status
Approved
Date submitted
23/11/2018
Date registered
16/04/2019
Date last updated
30/08/2019
Date data sharing statement initially provided
16/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to investigate the clinical safety of Maxigesic IV intravenous infusion among patients with Acute Pain from Orthopedic, General or Plastic surgery
Scientific title
Maxigesic IV Exposure Study: A Phase 3, Open-Label, Multiple-Dose, Single-Arm Exposure Study of Maxigesic® IV in Patients with Acute Pain Following Orthopedic, General or Plastic Surgery
Secondary ID [1] 296689 0
AFT-MXIV-11
Universal Trial Number (UTN)
U1111-1224-4435
Trial acronym
Not applicable
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Post Operative Pain Relief 310533 0
Condition category
Condition code
Anaesthesiology 309244 309244 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Maxigesic® intravenous infusion (acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution for infusion) administered by injection into a dedicated indwelling venous cannula, infused over 15 minutes every 6 hours for a minimum of 48 hours (8 doses). The maximum duration of exposure will be at the discretion of the Investigator.
The administration of each dose will be documented in the Case Report Form (CRF) by a study nurse.
Intervention code [1] 313000 0
Treatment: Drugs
Comparator / control treatment
Not applicable. No comparator/ control treatment will be used in the study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308215 0
Incidence of TEAEs (Treatment-Emergent Adverse Events) at any time during the treatment period including the report from the study participants, the observation by the study staff and hospital records. After discharge from the hospital, study participants will be required to document any adverse events experienced on their patient diary and it will be handed in during their last follow up visit at 7 days following the last treatment.
Some known adverse reactions of this product including:
• Nausea
• Stomach pain
• Loss of appetite
• Itching
• Rash
• Headache
• Dark urine
• Clay-colored stools
• Jaundice (yellowing of skin or eyes)
• Upset stomach or mild heartburn
• Bloating, gas
• Dizziness
• Vomiting
• Diarrhea
• Constipation
• Skin rash
• Headache
• Drowsiness
• Blurred vision
• Ringing in your ears
• Localized irritation at the intravenous infusion site
Timepoint [1] 308215 0
from the first dose of study drug administration to 7 days later after the last dose of study drug administration
Secondary outcome [1] 354247 0
The time course of TEAEs (Treatment-Emergent AEs) including the report from the study participant, the observation by the study staff and hospital records. After discharge from the hospital, study participants will be required to document any adverse events experienced on their patient diary and it will be handed in during their last follow up visit at 7 days following the last treatment.
Timepoint [1] 354247 0
from the first dose of study drug administration to 7 days later after the last dose of study drug administration
Secondary outcome [2] 354248 0
Incidence of Treatment-related Adverse Events (TRAEs) at any time during the treatment period. Treatment-Emergent Adverse Events (TEAEs) considered by the investigator to be " probably" or " definitely" are treatment-related AEs (TRAEs).
This will include any report from the study participant, the observation by the study staff and hospital records. After discharge from the hospital, study participants will be required to document any adverse events experienced on their patient diary and it will be handed in during their last follow up visit at 7 days following the last treatment.
Timepoint [2] 354248 0
From the first dose of study drug administration to 7 days later after the last dose of study drug administration
Secondary outcome [3] 354249 0
Changes in vital sign measurements (hear rate, blood pressure, temperature, respiratory rate) as a composite secondary outcome
There vital signs will be obtained from the hospital records during the participants' hospital stay following their surgery. Methods used to obtain these vital signs are compliant with the hospital routine procedures.
Timepoint [3] 354249 0
from the first dose of study drug administration to 7 days later after the last dose of study drug administration
Secondary outcome [4] 354250 0
Change in clinical laboratory values (as a composite secondary endpoint) including the following:
Hematology: Hemoglobin, Hematocrit, Platelet count, Red Blood Cell (RBC) count, White Blood Cell (WBC) count, Differential Leukocyte Count (DLC)
Biochemistry: Sodium, Potassium,Urea, Creatinine, Phosphate, Glucose, Albumin, Total protein, Alkaline phosphates, Gamma-glutamyl transferase, Aspartate transaminase
Alanine transaminase, Bilirubin
Changes evaluated as " clinically significant" from baseline will be classified as adverse events and included in all analysis of adverse events.
All these clinical laboratory values will be obtained through plasma sample assay. Blood samples will be taken prior to surgery and after the last dose prior to the hospital discharge.
Timepoint [4] 354250 0
from the first dose of study drug administration to 7 days later after the last dose of study drug administration
Secondary outcome [5] 354251 0
Patient's global evaluation of the study drug will be conducted either at the end of the treatment period or at early withdrawal.
Study participants will be asked " How to you rate your study medication?" by the study staff and tick one of those below:
1 = Poor;
2 = Fair;
3 = Good;
4 = Very Good;
5 = Excellent

Timepoint [5] 354251 0
At the end of last dose treatment or at early withdrawal

Eligibility
Key inclusion criteria
Male or female greater than or equal to 18 years of age
Is classified by the anesthesiologist as P1 to P2 in the American Society of Anesthesiologists (ASA) Physical Status Classification System
Requires multiple doses of parenterally administered nonopioid analgesics over multiple days as a result of surgery (non-laparoscopic general, plastic or orthopedic surgery)
Has an expected hospital stay greater than or equal to 48 hours
Has a body weight greater than or equal to 45 kg
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Has a known history of allergic reaction or clinically significant intolerance to acetaminophen, aspirin, opioids, or any nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen); history of NSAID-induced bronchospasm (subjects with the triad of asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should be considered carefully); or hypersensitivity, allergy, or significant reaction to sulfa (including sulfonamide) medicines, ingredients of the study drug, or any other drugs used in the study including anesthetics and antibiotics that may be required on the day of surgery.
2. Has experienced any surgical complications or other issues that, in the opinion of the Investigator, could compromise the safety of the subject if he or she participates in the study or could confound the results of the study.
3. Has known or suspected history of alcoholism or drug abuse or misuse within 2 years of screening or evidence of tolerance or physical dependence before dosing with study drug.
4. Has any clinically significant unstable cardiac, respiratory, neurological, immunological, hematological, or renal disease or any other condition that, in the opinion of the Investigator, could compromise the subject’s welfare, ability to communicate with the study staff, or otherwise contraindicate study participation.
5. Has a history or current diagnosis of a significant psychiatric disorder that, in the opinion of the Investigator, would affect the subject’s ability to comply with the study requirements.
6. Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. Subjects who test positive and can produce a prescription for the medication from their physician may be considered for study enrolment at the discretion of the Investigator.
7. Has a history of a clinically significant (Investigator opinion) gastrointestinal (GI) event within 6 months before screening or has any history of peptic or gastric ulcers or GI bleeding.
8. Has a surgical or medical condition of the GI or renal system that might significantly alter the absorption, distribution, or excretion of any drug substance.
9. Is considered by the Investigator, for any reason (including, but not limited to, the risks described as precautions, warnings, and contraindications in the current version of the Investigator’s Brochure (IB) for Maxigesic® IV to be an unsuitable candidate to receive the study drug.
10. Is receiving systemic chemotherapy, has an active malignancy of any type, or has been diagnosed with cancer within 5 years before Screening (excluding treated squamous or basal cell carcinoma of the skin).
11. Is currently receiving anticoagulants (e.g. heparin or warfarin).
12. Has received a course of systemic corticosteroids (either oral or parenteral) within 3 months before screening (inhaled nasal steroids and regional/limited area application of topical corticosteroids (Investigator discretion) are allowed).
13. Has a history of chronic use (defined as daily use for > 2 weeks) of NSAIDs, opiates, or glucocorticoids (except inhaled nasal steroids and regional/limited topical corticosteroids), for any condition within 6 months before study drug administration. Aspirin at a daily dose of less than or equal to 325 mg is allowed for cardiovascular prophylaxis if the subject has been on a stable dose regimen for greater than or equal to 30 days before screening and has not experienced any relevant medical problem.
14. Has a significant renal or hepatic disease, as indicated by clinical laboratory assessment (results of greater than or equal to 3 times the upper limit of normal [ULN] for any liver function test, including aspartate aminotransferase [AST], alanine aminotransferase [ALT], or creatinine greater than or equal to 1.5 times the ULN).
15. Has any clinically significant laboratory finding at screening that, in the opinion of the Investigator, contraindicates study participation.
16. Previously participated in another clinical study of Maxigesic® IV or received any investigational drug or device or investigational therapy within 30 days before Screening.


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed. This is an open label study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Nil
Phase
Phase 3
Type of endpoint(s)
Safety
Statistical methods / analysis
All subjects who receive at least one dose of the study drug will be included in the safety population. The safety population will be used for all summaries of study endpoints. Early withdrawals for any reason will be tabulated.

The demographic and clinical characteristics of the study population at study entry, including age, gender, race, ethnicity, indication (type of surgery, compound fracture), use of concomitant medications (e.g. opioids), vitals and laboratory results will be summarized as means, medians, standard deviations, ranges and frequencies and percentages as appropriate.

Treatment-emergent adverse events are defined as events first occurring or worsening during the course of the study, regardless of their relationship to the study drug. Treatment-emergent adverse events will be coded to MedDRA System Organ Class Code and Preferred Term and tabulated as frequencies and percentages in the following time periods: At any timepoint during the observational period; at any timepoint during the treatment period; on Day 1; Day 2; Day 3; Day 4; Day 5; Day 6+; and during follow-up. Clinically significant changes from baseline in vital sign measurements All subjects who receive at least one dose of the study drug will be included in the safety population. The safety population will be used for all summaries of study endpoints. Early withdrawals for any reason will be tabulated.

The demographic and clinical characteristics of the study population at study entry, including age, gender, race, ethnicity, indication (type of surgery, compound fracture), use of concomitant medications (e.g. opioids), vitals and laboratory results will be summarized as means, medians, standard deviations, ranges and frequencies and percentages as appropriate.

Treatment-emergent adverse events are defined as events first occurring or worsening during the course of the study, regardless of their relationship to the study drug. Treatment-emergent adverse events will be coded to MedDRA System Organ Class Code and Preferred Term and tabulated as frequencies and percentages in the following time periods: At any timepoint during the observational period; at any timepoint during the treatment period; on Day 1; Day 2; Day 3; Day 4; Day 5; Day 6+; and during follow-up. Clinically significant changes from baseline in vital sign measurements or laboratory test results will be classified as adverse events.

The proportion of TEAEs that are considered by the Investigator to be “probably” or “definitely” related to study medication (treatment-related AEs- TRAEs) will be summarized.

All cardiovascular, gastrointestinal, renal, hepatic, administration site conditions and bleeding-related AEs will be summarized and the proportion of these that are considered treatment-related will be tabulated.

The incidence of TEAEs will be summarized by gender, race, age (<65, 65-75, >75 years), duration of exposure (dosed for less than or equal to 48 hours, dosed for 48 hours – 4 days, dosed for greater than or equal to 5 days) and indication (surgery type, compound fracture). This analysis is subject to recruitment of sufficient participants within each subgroup.

Vital sign measurements and clinical laboratory values at each scheduled timepoint will be summarized with standard descriptive statistics, including means, standard deviations and ranges. Summary shift tables will be produced overall and by duration of treatment (dosed for less than or equal to 48 hours, dosed for 48 hours – 4 days, dosed for greater than or equal to 5 days) of the number of cases with normal baseline laboratory tests changed to abnormal at the end of the treatment period, and abnormal baseline laboratory tests worsened at the end of the treatment period, with the severity of changes summarized as proportional effects.

The use of concomitant medications following study drug administration will be summarized as frequencies and percentages within ATC-coded drug groups.

The frequency and percentage of subjects rating the study drug as ‘poor’, ‘fair’, ‘good’, ‘very good’ and ‘excellent’ will be summarized.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21061 0
New Zealand
State/province [1] 21061 0
Auckland
Country [2] 21062 0
United States of America
State/province [2] 21062 0
MD
Country [3] 21821 0
United States of America
State/province [3] 21821 0
NC

Funding & Sponsors
Funding source category [1] 301266 0
Commercial sector/Industry
Name [1] 301266 0
AFT Pharmaceuticals Ltd
Address [1] 301266 0
Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country [1] 301266 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd.
Address
Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622
Country
New Zealand
Secondary sponsor category [1] 300908 0
None
Name [1] 300908 0
Address [1] 300908 0
Country [1] 300908 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302017 0
Health and Disability Ethics Committee
Ethics committee address [1] 302017 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 302017 0
New Zealand
Date submitted for ethics approval [1] 302017 0
04/02/2019
Approval date [1] 302017 0
05/08/2019
Ethics approval number [1] 302017 0

Summary
Brief summary
The study hypothesis is that Maxigesic® intravenous infusion (intravenous acetaminophen 1000 mg + intravenous ibuprofen 300 mg/ 100 ml solution for infusion) is well tolerated over a treatment period of 5 days, and that the safety profile does not markedly change with extended exposure of 5 days.
Trial website
Not applicable
Trial related presentations / publications
Not applicable
Public notes
Not applicable

Contacts
Principal investigator
Name 55910 0
Dr Simon Carson
Address 55910 0
Southern Clinical Trials Group Ltd
Forte 2, Level 2, 132 Peterborough Street, Christchurch Central, Christchurch 8013, New Zealand
Country 55910 0
New Zealand
Phone 55910 0
+64 3 337 1979
Fax 55910 0
+64 3 337 1974
Email 55910 0
simon@sctrials.co.nz
Contact person for public queries
Name 55911 0
Dr Jennifer Zhang
Address 55911 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
New Zealand
Country 55911 0
New Zealand
Phone 55911 0
+64 9 488 0232 ext 710
Fax 55911 0
+ 64 9 488 0234
Email 55911 0
jenniferz@aftpharm.com
Contact person for scientific queries
Name 55912 0
Dr Jennifer Zhang
Address 55912 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
New Zealand
Country 55912 0
New Zealand
Phone 55912 0
+64 9 488 0232 ext 710
Fax 55912 0
+ 64 9 488 0234
Email 55912 0
jenniferz@aftpharm.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The study results will be obtained from all the study participants in order to reach the statistical significance rather than the individual participant data. Therefore, sharing the individual participant data is not deemed as necessary.
What supporting documents are/will be available?
No other documents available
Summary results
No Results