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Double-blind, randomised, parallel-group, placebo-controlled, adaptive, seamless, dose-selecting study to compare the efficacy of APD421 to placebo as treatment of established PONV, in patients who have had prior PONV prophylaxis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| APD421 standard | Experimental | Single (standard) dose IV APD421 |
|
| APD421 high | Experimental | Single (high) dose IV APD421 |
|
| Placebo | Placebo Comparator | Single IV placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| APD421 | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Complete Response (Success of Initial PONV Treatment) | The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication. | 0-24 hours after administration of study medication |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Complete Response 0-2 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication. | 0-2 hours after administration of study medication |
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Inclusion criteria:
Male or female patients ≥ 18 years of age
Provision of written informed consent
Patients scheduled to undergo elective surgery (open or laparoscopic technique) under general anaesthesia (other than total intravenous anaesthesia with propofol) expected to last at least one hour from induction of anaesthesia to extubation
Patients judged by the investigator to have a moderate or high risk of experiencing PONV. In forming this judgment, investigators should pay particular attention to risk factors such as a past history of PONV and/or motion sickness; habitual non-smoking status; female sex; and likely use of opioid analgesia post-operatively.
For females of child-bearing potential: ability and willingness to use a highly effective form of contraception (as defined in ICH M3 guidance, e.g., abstinence from sexual intercourse, surgical sterilisation (of subject or partner), combined oral contraceptive pill, a double-barrier method of contraception such as either an intra-uterine device (IUD) or an occlusive cap with spermicide, in conjunction with partner's use of a condom, or any other method or combination of methods with a failure rate generally considered to be <1% per year) between the date of screening and at least 48 hours after administration of study drug
In order to be eligible for randomisation, subjects must also:
(i) have experienced a first episode of PONV not more than 24 hours after the end of their operation (wound closure) and prior to discharge from hospital ("qualifying PONV episode"), for which they have not already received any anti-emetic treatment; and (ii) not have received any dopamine-antagonist agent likely to prevent or treat nausea or vomiting (given as prophylaxis or otherwise) in the period from 24 hours prior to the start of their operation up to the time of the qualifying PONV episode.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gabriel Fox, MB BChir | Acacia Pharma Ltd | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Jackson Memorial Hospital | Miami | Florida | 33136 | United States | ||
| Duke University Medical Center |
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Three patients were randomised but not dosed: 2 due to withdrawal of consent, 1 for other reasons.
Estimated recruitment was 700, to deliver 690 evaluable, randomised patients, providing an average of 230 evaluable patients in each of the three groups. The number of randomised patients planned per country was as follows: Germany, 190; France, 15; Canada, 100; and USA, 395
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| ID | Title | Description |
|---|---|---|
| FG000 | APD421 5mg | APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes |
| FG001 | APD421 10mg | APD421 10mg administered as a single,slow intravenous (IV) push over about two minutes |
| FG002 | Placebo | Matching Placebo administered as a single, slow intravenous (IV) push over about two minutes |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | APD421 5mg | APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes |
| BG001 | APD421 10mg | APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Number of Participants With Complete Response (Success of Initial PONV Treatment) | The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 0-24 hours after administration of study medication |
|
7 days
Any AE that is serious, occurring during the relevant study period (from study drug administration to 7-day follow-up), irrespective of the treatment received by the subject, must be reported to the Pharmacovigilance provider within 24 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | APD421 IV 5mg | IV dose of APD421 5mg (IV dose)- was administered to each patient in a double-blind fashion, by slow IV push over about two minutes into a peripheral or central venous cannula. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anastomosis Insufficiency | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
There were no limitations or caveats with this study
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Gabriel Fox | Acacia Pharma | 01223875919764 | GabrielFox@acaciapharma.com |
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| ID | Term |
|---|---|
| D020250 | Postoperative Nausea and Vomiting |
| ID | Term |
|---|---|
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009325 | Nausea |
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|
| Number of Participants With Complete Response 0-4 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication. | 0-4 hours after administration of study medication |
| Number of Participants With Complete Response 0-6 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication. | 0-6 hours after administration of study medication |
| Time to Treatment Failure | Time to first violation of the criteria for complete response | 0-24 hours after study drug administration |
| Number of Patients With Incidence of Emesis | Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication | 30 mins to 24 hours after study drug administration |
| Number of Patients Receiving Rescue Medication | Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period | 0-24 hours after study drug administration |
| Number of Patients With an Incidence of Significant Nausea | Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | 30 mins to 24 hours after study drug administration |
| Number of Patients With an Incidence of Nausea | Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | 30 mins to 24 hours after drug administration |
| Maximum Severity of Nausea | Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | 30 mins to 24 hours after study drug administration |
| Evolution Score of Nausea (0-180 Mins) | The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome. | 0-180 minutes after study drug administration |
| Durham |
| North Carolina |
| 27710 |
| United States |
| Wake Forest University School of Medicine | Winston-Salem | North Carolina | 27157 | United States |
| Ohio State University | Columbus | Ohio | 43210 | United States |
| CHU de Hautepierre | Strasbourg | France |
| HELIOS Klinikum Aue | Aue | 08280 | Germany |
| Universität Heidelberg | Heidelberg | Germany |
| Philipps University | Marburg | Germany |
| BG002 | Placebo | Matching placebo administered as a single, slow, IV push over about two minutes |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes |
| OG002 | Placebo | Matching placebo administered as a single, slow, IV push over about two minutes |
|
|
|
| Secondary | Number of Participants With Complete Response 0-2 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 0-2 hours after administration of study medication |
|
|
|
|
| Secondary | Number of Participants With Complete Response 0-4 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 0-4 hours after administration of study medication |
|
|
|
|
| Secondary | Number of Participants With Complete Response 0-6 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 0-6 hours after administration of study medication |
|
|
|
|
| Secondary | Time to Treatment Failure | Time to first violation of the criteria for complete response | Modified ITT population | Posted | Median | Inter-Quartile Range | minutes | 0-24 hours after study drug administration |
|
|
|
|
| Secondary | Number of Patients With Incidence of Emesis | Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication | Posted | Count of Participants | Participants | 30 mins to 24 hours after study drug administration |
|
|
|
|
| Secondary | Number of Patients Receiving Rescue Medication | Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period | Modified ITT population | Posted | Count of Participants | Participants | 0-24 hours after study drug administration |
|
|
|
|
| Secondary | Number of Patients With an Incidence of Significant Nausea | Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 30 mins to 24 hours after study drug administration |
|
|
|
|
| Secondary | Number of Patients With an Incidence of Nausea | Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | Modified ITT population | Posted | Count of Participants | Participants | 30 mins to 24 hours after drug administration |
|
|
|
|
| Secondary | Maximum Severity of Nausea | Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. | Modified ITT population | Posted | Mean | Standard Deviation | Score on a scale | 30 mins to 24 hours after study drug administration |
|
|
|
|
| Secondary | Evolution Score of Nausea (0-180 Mins) | The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome. | Modified ITT population | Posted | Mean | Standard Deviation | Score on a scale*min | 0-180 minutes after study drug administration |
|
|
|
|
| 0 |
| 237 |
| 6 |
| 237 |
| 64 |
| 237 |
| EG001 | APD421 IV 10mg | IV dose of APD421 10mg (IV dose)- was administered to each patient in a double-blind fashion by slow IV push over about two minutes into a peripheral or central venous cannula. | 0 | 230 | 3 | 230 | 66 | 230 |
| EG002 | Placebo | IV dose of Placebo (IV dose)- was administered to each patient in a double-blind fashion by slow IV push over about two minutes into a peripheral or central venous cannula. | 0 | 235 | 5 | 235 | 78 | 235 |
| Leukocytosis | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Non-infectious gastroenteritis | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Unspecified Colitis | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Intra-abdominal Hematoma | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Intractable vomiting | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Post procedural hemorrhage | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Abscess Presacral | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Fatty tissue prolapse at the tempral lobe | Eye disorders | MedDRA 18.1 | Systematic Assessment |
|
| Numbness in the leg | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Postoperative rise in creatinine | Investigations | MedDRA 18.1 | Systematic Assessment |
|
| Post cholecystectomy bile leak | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
| Acute Myocardial Infarction | Cardiac disorders | MedDRA 18.1 | Systematic Assessment |
|
| Postoperative Ileus | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
|
| Gastrointestinal bleed | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA 18.1 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
|
| Infusion site pain | General disorders | MedDRA 18.1 | Systematic Assessment |
|
| Pruritus | General disorders | MedDRA 18.1 | Systematic Assessment |
|
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| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D014839 | Vomiting |
| 0.059 |
One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025. |
| Superiority |
| 0.053 |
One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025. |
| Superiority |
| 0.021 |
One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025. |
| Superiority |
| Superiority |
| Superiority |
| Superiority |
| Superiority |
| Superiority |
| Superiority |
| Superiority |