ANZCTR - Registration

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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

20/01/2022

Date data sharing statement initially provided

16/04/2019

Date results information initially provided

20/01/2022

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]

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

Condition category

Condition code

Anaesthesiology

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]

Treatment: Drugs

Comparator / control treatment

Not applicable. No comparator/ control treatment will be used in the study

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

from the first dose of study drug administration to 7 days later after the last dose of study drug administration

Secondary outcome [1]

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]

from the first dose of study drug administration to 7 days later after the last dose of study drug administration

Secondary outcome [2]

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]

From the first dose of study drug administration to 7 days later after the last dose of study drug administration

Secondary outcome [3]

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]

from the first dose of study drug administration to 7 days later after the last dose of study drug administration

Secondary outcome [4]

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]

from the first dose of study drug administration to 7 days later after the last dose of study drug administration

Secondary outcome [5]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

24/06/2019

Actual

22/07/2019

Date of last participant enrolment

Anticipated

23/01/2020

Actual

30/06/2020

Date of last data collection

Anticipated

20/02/2020

Actual

28/07/2020

Sample size

Target

225

Accrual to date

Final

232

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Country [2]

United States of America

State/province [2]

Country [3]

United States of America

State/province [3]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

AFT Pharmaceuticals Ltd

Address [1]

Level 1, 129 Hurstmere Road, Takapuna, Auckland, New Zealand 0622

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

03/05/2019

Approval date [1]

05/08/2019

Ethics approval number [1]

Ethics committee name [2]

Advarra IRB

Ethics committee address [2]

6940 Columbia Gateway Dr., Suite 100, Columbia , MD 21046

Ethics committee country [2]

United States of America

Date submitted for ethics approval [2]

17/06/2019

Approval date [2]

10/07/2019

Ethics approval number [2]

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

Dr Simon Carson

Address

Southern Clinical Trials Group Ltd
Forte 2, Level 2, 132 Peterborough Street, Christchurch Central, Christchurch 8013, New Zealand

Country

New Zealand

Phone

+64 3 337 1979

Fax

+64 3 337 1974

[email protected]

Contact person for public queries

Name

Dr Jennifer Zhang

Address

AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
New Zealand

Country

New Zealand

Phone

+64 9 488 0232 ext 710

Fax

+ 64 9 488 0234

[email protected]

Contact person for scientific queries

Name

Dr Jennifer Zhang

Address

AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road, Takapuna, Auckland 0622
New Zealand

Country

New Zealand

Phone

+64 9 488 0232 ext 710

Fax

+ 64 9 488 0234

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		13 May 2021 Gottlieb IJ, Gilchrist N, Carson S, S... [More Details]	368213-(Uploaded-12-08-2021-12-20-20)-Journal results publication.pdf

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Extending the safety profile of the post-operative administration of an intravenous acetaminophen/ibuprofen fixed dose combination: An open-label, multi-center, single arm, multiple dose study.	2021	https://dx.doi.org/10.1016/j.biopha.2021.111710

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically