Maxigesic IV Phase 3 Bunionectomy Study | NCT02689063

NCT02689063

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Detailed Description

AFT Pharmaceuticals Ltd. has been developing a fixed-dose combination of acetaminophen 1000mg and ibuprofen 300mg/100mL solution for infusion (Maxigesic IV) for the temporary relief of postoperative pain, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration not possible.

A phase 3 efficacy study (AFT-MXIV-07) is proposed to determine the analgesic effects of the fixed dose combination product Maxigesic IV versus its individual components (acetaminophen IV and ibuprofen IV) and placebo in participants with acute post-operative pain after bunionectomy.

The primary efficacy objective is to determine the efficacy of Maxigesic IV, acetaminophen IV, Ibuprofen IV versus placebo IV as measured by the summed pain intensity difference (SPID) (calculated as a time-weighted average) over 0-48 hours (SPID-48) after time 0.

Other secondary efficacy endpoints are:

VAS Pain intensity difference (PID) at each scheduled assessment time point after Time 0 VAS Pain intensity score at each scheduled assessment time point VAS SPID over 0 to 6 hours (SPID-6), over 0 to 12 hours (SPID-12), and over 0 to 24 hours (SPID-24) after Time 0

Summed pain relief (TOTPAR) (calculated as a time-weighted average) over 0 to 6 hours (TOTPAR-6), over 0 to 12 hours (TOTPAR-12), over 0 to 24 hours (TOTPAR-24) after Time 0, and over 0 to 48 hours (TOTPAR-48) after Time 0

Time to onset of analgesia (measured as time to perceptible pain relief confirmed by meaningful pain relief) using the two-stopwatch method Pain relief score on a 5-point categorical scale at each scheduled time point after Time 0

Peak pain relief

Time to peak pain relief

Time to first perceptible pain relief

Time to meaningful pain relief

Proportion of subjects using rescue medication

Time to first use of rescue medication (duration of analgesia)

Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours Patient's global evaluation of study drug

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Maxigesic IV	Experimental	intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours	Drug: Maxigesic IV
IV Acetaminophen	Active Comparator	IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL. every 6 hours for 48 hours	Drug: IV Acetaminophen
IV Ibuprofen	Active Comparator	IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL every 6 hours for 48 hours	Drug: IV Ibuprofen
Placebo IV	Placebo Comparator	Placebo IV- 100 mL saline for infusion, 100mL every 6 hours for 48 hours	Drug: Placebo IV

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Maxigesic IV	Drug	IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours	Maxigesic IV

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Summed Pain Intensity Difference (SPID)-Calculated From the Pain Intensity Scores Recorded on a 100mm Long Scale With Anchors for "no Pain" (0 mm) and "Worst Pain Imaginable" (100 mm).	A Pain Intensity Difference (PID) is the difference between the Visual Analogue Scale (VAS) pain intensity score recorded at baseline and a score recorded at any time after the first dose of study medication. Taken together, a patient's PID scores capture the pain relief profile attributable to the assigned study medication. A high PID score indicates a better pain relief experienced. The extent of pain relief can then be calculated by the Area Under the Curve the PID scores (also referred to as the Sum of Pain Intensity Differences [SPID]). SPID48 scores were adjusted by the time interval from baseline to the final VAS score used in the SPID, using the following formula: Time-adjusted SPID48 (mm) = SPID (mm*hr) / Time (hr) In the event that a patient required rescue medication, the SPID was calculated up until the first Pre-Rescue VAS pain assessment (inclusive).	48 hours after the first dose

Secondary Outcomes

Measure	Description	Time Frame
VAS Pain Intensity Difference (PID)-Calculated From the Pain Intensity Scores Recorded on a 100mm Long VAS Scale With Anchors for "no Pain" (0 mm) and "Worst Pain Imaginable" (100 mm).	VAS Pain intensity difference (PID) at each scheduled assessment time point after Time 0. A Pain Intensity Difference (PID) is the difference between the Visual Analogue Scale (VAS) pain intensity score recorded at baseline and a score recorded at any time after the first dose of study medication. Taken together, a patient's PID scores capture the pain relief profile attributable to the assigned study medication. A high PID score indicates a better pain relief experienced.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Is male or female ≥ 18 and ≤ 65 years of age.
Is classified by the anesthesiologist as P1 to P2 in the American Society of Anesthesiologists (ASA) Physical Status Classification System.
Has undergone primary, unilateral, distal, first metatarsal bunionectomy (osteotomy and internal fixation) with no additional collateral procedures.
Experiences a pain intensity rating of ≥ 40 mm on a 100-mm Visual Analogue Scale (VAS) during the 9-hour period after discontinuation of the anesthetic block.
Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2.
If female and of childbearing potential, is nonlactating and nonpregnant (has negative pregnancy test results at Screening [urine] and on the day of surgery prior to surgery [urine]).
If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 1 of the following medically acceptable methods of birth control:

Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle period) before study drug administration.

Total abstinence from sexual intercourse since the last menses before study drug administration through completion of final study visit.

Intrauterine device (IUD). Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream).
Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements.
Must voluntarily sign and date an informed consent form (ICF) that is approved by an Institutional Review Board (IRB) before the conduct of any study procedure.
Is willing and able to comply with study requirements (including diet, alcohol, and smoking restrictions), complete the pain evaluations, remain at the study site for approximately 72 hours, and return for follow-up 7 ± 2 days after surgery.

Exclusion Criteria:

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.
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 continues into randomized treatment period or could confound the results of the study.
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.
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.
Has any ongoing condition, other than a condition associated with the current primary, unilateral, first metatarsal bunionectomy that could generate levels of pain sufficient to confound the results of the study (eg, gout, severe osteoarthritis of the target joint or extremity).
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.
Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. Subjects who test positive at Screening only and can produce a prescription for the medication from their physician may be considered for study enrolment at the discretion of the investigator.
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.
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.
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 for IV Maxigesic®), to be an unsuitable candidate to receive the study drug.
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).
Is currently receiving anticoagulants (eg, heparin or warfarin).
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).
Has received or will require any analgesic medication within 5 half-lives (or, if half-life is unknown, within 48 hours) before surgery.
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 ≤ 325 mg is allowed for cardiovascular prophylaxis if the subject has been on a stable dose regimen for ≥ 30 days before Screening and has not experienced any relevant medical problem.
Has been treated with agents that could affect the analgesic response (such as central alpha agents [clonidine and tizanidine], neuroleptic agents, and other antipsychotic agents) within 2 weeks before dosing with study drug.
Has a significant renal or hepatic disease, as indicated by clinical laboratory assessment (results ≥ 3 times the upper limit of normal [ULN] for any liver function test, including aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase, or creatinine ≥ 1.5 times the ULN).
Has any clinically significant laboratory finding at Screening that, in the opinion of the investigator, contraindicates study participation.
Has significant difficulties swallowing capsules or is unable to tolerate oral medication.
Previously participated in another clinical study of Maxigesic® IV or received any investigational drug or device or investigational therapy within 30 days before Screening.

Contacts/Locations Module

Name	Affiliation	Role
Stephen E Daniels, DO	Optimal Research LLC	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Chesapeake Reserach Group		Pasadena	Maryland	21122	United States
Optimal Research

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
34499349	Derived	Ferguson MC, Schumann R, Gallagher S, McNicol ED. Single-dose intravenous ibuprofen for acute postoperative pain in adults. Cochrane Database Syst Rev. 2021 Sep 9;9(9):CD013264. doi: 10.1002/14651858.CD013264.pub2.
31447129	Derived	Daniels SE, Playne R, Stanescu I, Zhang J, Gottlieb IJ, Atkinson HC. Efficacy and Safety of an Intravenous Acetaminophen/Ibuprofen Fixed-dose Combination After Bunionectomy: a Randomized, Double-blind, Factorial, Placebo-controlled Trial. Clin Ther. 2019 Oct;41(10):1982-1995.e8. doi: 10.1016/j.clinthera.2019.07.008. Epub 2019 Aug 22.

IPD Sharing Statement Module

Arm/Group Information

ID	Title	Description
FG000	Maxigesic IV	intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours Maxigesic IV: IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours
FG001	IV Acetaminophen	IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL. every 6 hours for 48 hours IV Acetaminophen: IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours
FG002	IV Ibuprofen	IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL every 6 hours for 48 hours IV Ibuprofen: IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours
FG003	Placebo IV	Placebo IV- 100 mL saline for infusion, 100mL every 6 hours for 48 hours Placebo IV: Placebo IV- 100 mL intravenous saline for infusion, 100mL, every 6 hours for 48 hours

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00075 subjects FG00175 subjects FG00276 subjects FG00350 subjects
COMPLETED		FG00075 subjects FG00173 subjects FG00273 subjects FG00350 subjects
NOT COMPLETED		FG0000 subjects FG0012 subjects FG0023 subjects FG0030 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Maxigesic IV	intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours Maxigesic IV: IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours
BG001	IV Acetaminophen

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Summed Pain Intensity Difference (SPID)-Calculated From the Pain Intensity Scores Recorded on a 100mm Long Scale With Anchors for "no Pain" (0 mm) and "Worst Pain Imaginable" (100 mm).	A Pain Intensity Difference (PID) is the difference between the Visual Analogue Scale (VAS) pain intensity score recorded at baseline and a score recorded at any time after the first dose of study medication. Taken together, a patient's PID scores capture the pain relief profile attributable to the assigned study medication. A high PID score indicates a better pain relief experienced. The extent of pain relief can then be calculated by the Area Under the Curve the PID scores (also referred to as the Sum of Pain Intensity Differences [SPID]). SPID48 scores were adjusted by the time interval from baseline to the final VAS score used in the SPID, using the following formula: Time-adjusted SPID48 (mm) = SPID (mm*hr) / Time (hr) In the event that a patient required rescue medication, the SPID was calculated up until the first Pre-Rescue VAS pain assessment (inclusive).	All participants randomized (276 in total) received the first dose of study medication under study staff supervision were included in the primary efficacy endpoint analysis.	Posted		Mean	Full Range	score on a scale		48 hours after the first dose

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Maxigesic IV	intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours Maxigesic IV: IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Jennifer Zhang -Project Manager	AFT Pharmaceuticals	+ 64 9 488 0232	710	jenniferz@aftpharm.com

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 4, 2017	Jan 11, 2021	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Nov 22, 2017	Jan 11, 2021	SAP_001.pdf

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D010149	Pain, Postoperative

ID	Term
D011183	Postoperative Complications
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D010146	Pain

Intervention Browse Module

ID	Term
D000082	Acetaminophen
D007052	Ibuprofen

ID	Term
D000083	Acetanilides
D000813	Anilides
D000577	Amides
D009930	Organic Chemicals
D000814

Masking Info

ID	Title	Description
OG000	Maxigesic IV	intravenous acetaminophen1000 mg + intravenous ibuprofen 300 mg/100 ml solution for infusion, 100 mL, every 6 hours for 48 hours Maxigesic IV: IV acetaminophen 1000 mg and IV ibuprofen 300 mg /100 mL solution for infusion, 100mL, every 6 hours for 48 hours
OG001	IV Acetaminophen	IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL. every 6 hours for 48 hours IV Acetaminophen: IV Acetaminophen 1000 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours
OG002	IV Ibuprofen	IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL every 6 hours for 48 hours IV Ibuprofen: IV Ibuprofen 300 mg/100 mL solution for infusion, 100mL, every 6 hours for 48 hours
OG003	Placebo IV	Placebo IV- 100 mL saline for infusion, 100mL every 6 hours for 48 hours Placebo IV: Placebo IV- 100 mL intravenous saline for infusion, 100mL, every 6 hours for 48 hours

EG00037 events22 affected75 at risk

EG00128 events25 affected75 at risk

EG00233 events26 affected76 at risk

EG00322 events16 affected50 at risk