Hypersensitivity
Conditions
Brief summary
This trial was conducted to study the potential for hypersensitivity symptoms at the time of initial exposure to sugammadex and upon repeat exposure, since it was unknown whether the frequency or severity of hypersensitivity symptoms may worsen at repeat exposure over a prolonged period. In total 450 participants (all healthy subjects) were to be randomized to receive one of three study treatments: three repeated doses of either sugammadex 4 mg/kg, sugammadex 16 mg/kg, or placebo. Participants were to receive one dose of study treatment on Day 8, Day 36, and Day 78 of the study in order to determine the safety of each treatment dose.
Detailed description
All subjects were to be admitted to the study center the day before each scheduled dose and were to leave the unit the morning of the day after each dose. In cases of suspected hypersensitivity symptoms, healthy subjects were to remain confined to the study center until all signs and symptoms regressed, the subject was stable, and the investigator considered it safe for the subject to leave the study center. Four sites participated in this trial.
Interventions
DRUGPlacebo run-in dose
Single-blind placebo intravenous bolus injection on Day 1 of the study, 7 days prior to randomization
Sugammadex 4 mg/kg intravenous bolus injection on Day 8, Day 36, and Day 78 of the study
Sugammadex 16 mg/kg intravenous bolus injection on Day 8, Day 36, and Day 78 of the study
DRUGPlacebo
Placebo intravenous bolus injection on Day 8, Day 36, and Day 78 of the study
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* 18-55 years of age * Serum tryptase \<=11.4 mcg/L and fasting triglyceride levels within normal limits * Safety laboratory tests and vital signs must have been within normal limits * Screening electrocardiogram must have been clinically acceptable and parameters within normal limits * Body Mass Index between 19 and 32 kg/m\^2 * Females must have agreed to use contraceptives * Other certain administrative criteria as described in the protocol
Exclusion criteria
* Females who were pregnant or intending to become pregnant * Subjects who would not be able to participate optimally in the study, in the opinion of the investigator * Certain surgical or medical conditions, recent infections, or mental instability * Positive test for certain drugs or history of alcohol or drug abuse * Positive test for hepatitis B, hepatitis C, or Human Immunodeficiency Virus (HIV) * Blood donation in the past 60 days * A history of unexplained reaction or hypersensitivity reaction during previous surgery and/or anesthesia * History of anaphylaxis from any cause, suspected history of hypersensitivity to cyclodextrins, or multiple drug hypersensitivities * Heavy smoker * Received certain medications in the past * History of allergy, hypersensitivity, or intolerance to epinephrine at greater risk of developing adverse reactions after epinephrine administration * Other certain administrative criteria as described in the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms, for Each Sugammadex Dose Group and Placebo. | Day 8, Day 36, and Day 78 of the study | Hypersensitivity signs/symptoms were systematically collected for each subject by the investigator. Suspected cases of hypersensitivity signs/symptoms were sent to the independent Adjudication Committee (comprised of anesthesiologists & allergists/immunologists) for blinded review and determination of adjudicated hypersensitivity &/or anaphylaxis based on expert evaluation of all clinical data from the healthy subject. The percentages of subjects who had adjudicated hypersensitivity at any dose (dose 1/Day 8, dose 2/Day 36, or dose 3/Day 78) were compared between the 3 treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants With Adjudicated Anaphylaxis According to the Definition by Sampson et al., for Each Sugammadex Dose Group and Placebo. | Day 8, Day 36, and Day 78 of the study | The Adjudication Committee evaluated each case to determine whether the subject's hypersensitivity sign/symptoms fulfilled the definition of anaphylaxis according to the criteria defined by the Symposium on the Definition and Management of Anaphylaxis as described by Sampson et al. (J Allergy Clin Immunol 2006; 117:391-7). The percentages of subjects who had adjudicated anaphylaxis according to the Sampson Criteria at any dose (dose 1 \[\ Day 8\], dose 2 \[\ Day 36\], or dose 3 \[Day \ 78\]) were compared between the 3 treatment groups. |
| The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Day 8, Day 36, and Day 78 of the study | The Adjudication Committee evaluated each case to determine anaphylaxis according to the criteria put forth by the guidelines of the Brighton Collaboration Anaphylaxis Working Group as described by Rüggeberg et al. (Vaccine 2007; 25:5675-5684). Level 1 represents the highest level of certainty of anaphylaxis and level 3 the lowest level of certainty. The percentages of subjects who had adjudicated anaphylaxis according to the Rüggeberg Criteria at any dose (dose 1 \[\ Day 8\], dose 2 \[\ Day 36\], or dose 3 \[Day \ 78\]) were compared between the 3 treatment groups. |
| The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | Day 8, Day 36, and Day 78 of the study | Hypersensitivity signs/symptoms were systematically collected for each subject by the investigator. Suspected cases of hypersensitivity signs/symptoms were sent to the independent Adjudication Committee (comprised of anesthesiologists & allergists/immunologists) for blinded review & determination of adjudicated hypersensitivity &/or anaphylaxis based on expert evaluation of all clinical data from the healthy subject. The percentages of subjects who had adjudicated hypersensitivity (dose 1/Day 8, dose 2/Day 36, or dose 3/Day 78) are presented for each of the 3 treatment arms for each dose. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | From first randomized dose (Day 8) up to 30 days after day of last randomized dose of study medication. | All adverse events from the study were reviewed for potential safety signals. The reported incidences suggestive of a dose-dependent trend and with a frequency threshold above 5% (including both serious and non-serious adverse events) are presented. |
Participant flow
Pre-assignment details
A total of 480 participants received a single-blind placebo dose 7 days prior to randomization. Of these 480 participants, 448 were randomized to double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| Sugammadex 4 mg/kg Participants were to receive one dose of sugammadex 4 mg/kg intravenous bolus injection on Day 8, Day 36, and Day 78 of the study. | 148 |
| Sugammadex 16 mg/kg Participants were to receive one dose of sugammadex 16 mg/kg intravenous bolus injection on Day 8, Day 36, and Day 78 of the study. | 150 |
| Placebo Participants were to receive one dose of placebo intravenous bolus injection on Day 8, Day 36, and Day 78 of the study. | 150 |
| Total | 448 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 10 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 2 |
| Overall Study | Noncompliance with protocol | 5 | 6 | 9 |
| Overall Study | Subject withdrew consent | 3 | 5 | 2 |
Baseline characteristics
| Characteristic | Sugammadex 4 mg/kg | Sugammadex 16 mg/kg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 34.4 years STANDARD_DEVIATION 10.6 | 33.2 years STANDARD_DEVIATION 10.2 | 33.8 years STANDARD_DEVIATION 10.8 | 33.8 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 70 Participants | 73 Participants | 75 Participants | 218 Participants |
| Sex: Female, Male Male | 78 Participants | 77 Participants | 75 Participants | 230 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 148 | 64 / 150 | 33 / 150 |
| serious Total, serious adverse events | 0 / 148 | 2 / 150 | 1 / 150 |
Outcome results
Primary
The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms, for Each Sugammadex Dose Group and Placebo.
Hypersensitivity signs/symptoms were systematically collected for each subject by the investigator. Suspected cases of hypersensitivity signs/symptoms were sent to the independent Adjudication Committee (comprised of anesthesiologists & allergists/immunologists) for blinded review and determination of adjudicated hypersensitivity &/or anaphylaxis based on expert evaluation of all clinical data from the healthy subject. The percentages of subjects who had adjudicated hypersensitivity at any dose (dose 1/Day 8, dose 2/Day 36, or dose 3/Day 78) were compared between the 3 treatment groups.
Time frame: Day 8, Day 36, and Day 78 of the study
Population: All-Subjects as treated (i.e., who received at least one dose of randomized study medication).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms, for Each Sugammadex Dose Group and Placebo. | 0.7 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms, for Each Sugammadex Dose Group and Placebo. | 4.7 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms, for Each Sugammadex Dose Group and Placebo. | 0 percentage of participants |
95% CI: [-1.8, 3.7]
95% CI: [2.1, 9.3]
Secondary
The Percentage of Participants With Adjudicated Anaphylaxis According to the Definition by Sampson et al., for Each Sugammadex Dose Group and Placebo.
The Adjudication Committee evaluated each case to determine whether the subject's hypersensitivity sign/symptoms fulfilled the definition of anaphylaxis according to the criteria defined by the Symposium on the Definition and Management of Anaphylaxis as described by Sampson et al. (J Allergy Clin Immunol 2006; 117:391-7). The percentages of subjects who had adjudicated anaphylaxis according to the Sampson Criteria at any dose (dose 1 \[\ Day 8\], dose 2 \[\ Day 36\], or dose 3 \[Day \ 78\]) were compared between the 3 treatment groups.
Time frame: Day 8, Day 36, and Day 78 of the study
Population: All-Subjects as treated (i.e., who received at least one dose of randomized study medication).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Anaphylaxis According to the Definition by Sampson et al., for Each Sugammadex Dose Group and Placebo. | 0 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Anaphylaxis According to the Definition by Sampson et al., for Each Sugammadex Dose Group and Placebo. | 0.7 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Anaphylaxis According to the Definition by Sampson et al., for Each Sugammadex Dose Group and Placebo. | 0 percentage of participants |
95% CI: [-1.8, 3.7]
95% CI: [-2.5, 2.5]
Secondary
The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo.
Hypersensitivity signs/symptoms were systematically collected for each subject by the investigator. Suspected cases of hypersensitivity signs/symptoms were sent to the independent Adjudication Committee (comprised of anesthesiologists & allergists/immunologists) for blinded review & determination of adjudicated hypersensitivity &/or anaphylaxis based on expert evaluation of all clinical data from the healthy subject. The percentages of subjects who had adjudicated hypersensitivity (dose 1/Day 8, dose 2/Day 36, or dose 3/Day 78) are presented for each of the 3 treatment arms for each dose.
Time frame: Day 8, Day 36, and Day 78 of the study
Population: All-Subjects as treated, per dose (i.e. who received the corresponding dose of randomized study medication).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 1st randomized dose | 0.7 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 2nd randomized dose (n=139; n=135; n=145) | 0.7 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 3rd randomized dose (n=135; n=127; n=135) | 0 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | after any randomized dose | 0.7 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | after any randomized dose | 4.7 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 1st randomized dose | 4.0 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 3rd randomized dose (n=135; n=127; n=135) | 0.8 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 2nd randomized dose (n=139; n=135; n=145) | 1.5 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | after any randomized dose | 0 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 2nd randomized dose (n=139; n=135; n=145) | 0 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 3rd randomized dose (n=135; n=127; n=135) | 0 percentage of participants |
| Placebo | The Percentage of Participants With Adjudicated Hypersensitivity Signs/Symptoms After Each Randomized Dose of Study Treatment, for Each Sugammadex Dose Group and Placebo. | 1st randomized dose | 0 percentage of participants |
Secondary
The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo.
The Adjudication Committee evaluated each case to determine anaphylaxis according to the criteria put forth by the guidelines of the Brighton Collaboration Anaphylaxis Working Group as described by Rüggeberg et al. (Vaccine 2007; 25:5675-5684). Level 1 represents the highest level of certainty of anaphylaxis and level 3 the lowest level of certainty. The percentages of subjects who had adjudicated anaphylaxis according to the Rüggeberg Criteria at any dose (dose 1 \[\ Day 8\], dose 2 \[\ Day 36\], or dose 3 \[Day \ 78\]) were compared between the 3 treatment groups.
Time frame: Day 8, Day 36, and Day 78 of the study
Population: All-Subjects as treated (i.e., who received at least one dose of randomized study medication).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sugammadex 4 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 | 0 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 2 | 0 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 3 | 0 percentage of participants |
| Sugammadex 4 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 or Level 2 | 0 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 or Level 2 | 2.0 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 | 0.7 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 3 | 0 percentage of participants |
| Sugammadex 16 mg/kg | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 2 | 1.3 percentage of participants |
| Placebo | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 or Level 2 | 0 percentage of participants |
| Placebo | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 2 | 0 percentage of participants |
| Placebo | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 3 | 0 percentage of participants |
| Placebo | The Percentage of Participants With Each of the 3 Levels of Diagnostic Certainty of Adjudicated Anaphylaxis According to the Definition by Rüggeberg et al., for Each Sugammadex Dose Group and Placebo. | Level 1 | 0 percentage of participants |
Comparison: Comparison of participants who had Level 1 or Level 2 diagnostic certainty.95% CI: [-0.5, 5.7]
Comparison: Comparison of participants who had Level 1 or Level 2 diagnostic certainty.95% CI: [-2.5, 2.5]
Other Pre-specified
Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events).
All adverse events from the study were reviewed for potential safety signals. The reported incidences suggestive of a dose-dependent trend and with a frequency threshold above 5% (including both serious and non-serious adverse events) are presented.
Time frame: From first randomized dose (Day 8) up to 30 days after day of last randomized dose of study medication.
Population: All-Subjects as treated (i.e., who received at least one dose of randomized study medication).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sugammadex 4 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Nausea | 5.4 percentage of participants |
| Sugammadex 4 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Flushing | 1.4 percentage of participants |
| Sugammadex 4 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Dysgeusia | 3.4 percentage of participants |
| Sugammadex 16 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Nausea | 16.0 percentage of participants |
| Sugammadex 16 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Flushing | 5.3 percentage of participants |
| Sugammadex 16 mg/kg | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Dysgeusia | 21.3 percentage of participants |
| Placebo | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Flushing | 0.7 percentage of participants |
| Placebo | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Dysgeusia | 0 percentage of participants |
| Placebo | Percentage of Participants With an Adverse Event Suggestive of a Dose-dependent Trend That Also Exceeds a Frequency Threshold Above 5% in Any Treatment Arm (Including Both Serious and Non-serious Adverse Events). | Nausea | 1.3 percentage of participants |