Anaphylaxis, Hypersensitivity
Conditions
Keywords
reversal of neuromuscular blockade
Brief summary
The purpose of this study is to assess the potential for hypersensitivity symptoms upon repeat exposure to sugammadex. Healthy participants will be randomized to one of three treatment arms: sugammadex 4 mg/kg, sugammadex 16 mg/kg or placebo. Participants will receive 3 single intravenous (IV) doses of their randomized treatment, with an approximately 5-week washout between Dose 1 and Dose 2 and between Dose 2 and Dose 3. Participants will be confined at the study center from the day before each dose until completion of the 24-hour post dose assessments.
Interventions
DRUGSugammadex
Sugammadex 4 mg/kg or 16 mg/kg administered as a single IV bolus over 10 seconds
DRUGPlacebo
Placebo administered as a single IV bolus over 10 seconds
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or non-pregnant and non-breast feeding female * Females of childbearing potential must have a serum β-human chorionic gonadotropin (β-hCG) level consistent with non-pregnant state and agree to use (and/or have their partner use) two acceptable methods of birth control beginning at screening, throughout the trial (including washout intervals between treatment periods) and until after the post-study follow-up visit * Females not of childbearing potential must be either a) postmenopausal (have not had a menstrual period for at least 1 year and have a follicle stimulating hormone \[FSH\] value in the postmenopausal range) or b) surgically sterile (i.e., have had hysterectomy, oophorectomy or tubal ligation) * In good health based on medical history, laboratory tests and other assessments * Body Mass Index (BMI) ≥19 and ≤32 kg/m\^2 * Non-smoker or smokes ≤10 cigarettes/day or equivalent (2 pipes/day, 1 cigar/day) and agrees not to smoke while confined at the study center
Exclusion criteria
* Mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder of the last 5 years * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases * History of cancer (malignancy) * History of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) * Has had major surgery and/or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to screening * Has participated in another investigational trial within 4 weeks prior to screening * Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks prior to administration of the initial dose of trial drug, throughout the trial (including washout intervals between treatment periods), until the post-study follow-up visit * Has received subcutaneous or sublingual immunotherapy within the past 1 year * Consumes \>3 glasses of alcoholic beverages per day * Consumes excessive amounts, defined as \>6 servings of coffee, tea, cola, energy drinks, or other caffeinated beverages per day * Currently a regular user (including recreational use) of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 12 months * Has a recollection of previously receiving sugammadex, Bridion™, SCH 900616, ORG 25969, or MK-8616 * History of chronic urticaria or angioedema * Is or has an immediate family member (spouse or children) who is a member of investigational site or sponsor staff directly involved with this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adjudicated Symptoms of Hypersensitivity | Up to approximately 28 days after last dose (approximately 14 weeks) | The investigator or designated clinician performed a targeted hypersensitivity assessment (THA) in each participant at 0.5, 4 and 24 hours after each dose for each dosing period. The THA could also be performed at other times if possible hypersensitivity signs were observed. The THA included elicitation of symptoms as well as examination of the participant, covering neurologic, pulmonary, cardiovascular, gastrointestinal and dermatologic domains. Each potential hypersensitivity case identified by the presence of any sign or symptom in a pre-defined list of hypersensitivity signs and symptoms that were found through the THA was reviewed by an independent, blinded adjudication committee, which determined whether the referred case was a case of hypersensitivity (yes/no). In addition, all adverse events (AEs) occurring in study were reviewed for terms associated with hypersensitivity or anaphylaxis, and could also result in referral to the adjudication committee for evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adjudicated Anaphylaxis | Up to approximately 28 days after last dose (approximately 14 weeks) | The investigator or designated clinician performed a THA in each participant at 0.5, 4 and 24 hours after each dose. The THA could also be performed at other times if possible hypersensitivity signs were observed. Each potential hypersensitivity case identified by presence of any sign or symptom in a pre-defined list of hypersensitivity signs and symptoms that were found through the THA was reviewed by an independent, blinded adjudication committee, which determined whether the referred case was a case of anaphylaxis (yes/no) using Sampson Criterion 1 - Acute onset of an illness with involvement of the skin, mucosal tissue or both, and at least one of the following: a) respiratory compromise, b) reduced blood pressure or associated symptoms of end-organ dysfunction (J Allergy Clin Immunol 2006;117:391-397). All AEs occurring in study were reviewed for terms associated with hypersensitivity or anaphylaxis, and could also result in referral to the adjudication committee for evaluation. |
Participant flow
Pre-assignment details
One participant who was randomized to sugammadex 16 mg/kg instead received 3 doses of placebo and completed study. This participant appears in sugammadex 16 mg/kg column in Participant Flow period Randomization through Start Treatment and in placebo column in period Treatment through Study Completion.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administration of 3 single IV doses of placebo, with an approximately 5-week washout between Dose 1 and Dose 2 and between Dose 2 and Dose 3 | 76 |
| Sugammadex 4 mg/kg Administration of 3 single IV doses of sugammadex 4 mg/kg, with an approximately 5-week washout between Dose 1 and Dose 2 and between Dose 2 and Dose 3 | 151 |
| Sugammadex 16 mg/kg Administration of 3 single IV doses of sugammadex 16 mg/kg, with an approximately 5-week washout between Dose 1 and Dose 2 and between Dose 2 and Dose 3 | 148 |
| Total | 375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomization Through Start Treatment | Not treated | 1 | 3 | 3 |
| Treatment Through Study Completion | Adverse Event | 3 | 3 | 5 |
| Treatment Through Study Completion | Lost to Follow-up | 2 | 4 | 6 |
| Treatment Through Study Completion | Physician Decision | 1 | 0 | 0 |
| Treatment Through Study Completion | Protocol Violation | 1 | 4 | 0 |
| Treatment Through Study Completion | Withdrawal by Subject | 5 | 4 | 3 |
Baseline characteristics
| Characteristic | Placebo | Sugammadex 4 mg/kg | Sugammadex 16 mg/kg | Total |
|---|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 10 | 39 years STANDARD_DEVIATION 11 | 38 years STANDARD_DEVIATION 11 | 38 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 35 Participants | 83 Participants | 80 Participants | 198 Participants |
| Sex: Female, Male Male | 41 Participants | 68 Participants | 68 Participants | 177 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 | 18 / 76 | 50 / 151 | 75 / 148 |
| serious Total, serious adverse events | 2 / 76 | 2 / 151 | 1 / 148 |
Outcome results
Primary
Percentage of Participants With Adjudicated Symptoms of Hypersensitivity
The investigator or designated clinician performed a targeted hypersensitivity assessment (THA) in each participant at 0.5, 4 and 24 hours after each dose for each dosing period. The THA could also be performed at other times if possible hypersensitivity signs were observed. The THA included elicitation of symptoms as well as examination of the participant, covering neurologic, pulmonary, cardiovascular, gastrointestinal and dermatologic domains. Each potential hypersensitivity case identified by the presence of any sign or symptom in a pre-defined list of hypersensitivity signs and symptoms that were found through the THA was reviewed by an independent, blinded adjudication committee, which determined whether the referred case was a case of hypersensitivity (yes/no). In addition, all adverse events (AEs) occurring in study were reviewed for terms associated with hypersensitivity or anaphylaxis, and could also result in referral to the adjudication committee for evaluation.
Time frame: Up to approximately 28 days after last dose (approximately 14 weeks)
Population: APaT - All randomized participants who received at least one dose of study treatment, with each participant included in arm corresponding to treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adjudicated Symptoms of Hypersensitivity | 1.3 percentage of participants |
| Sugammadex 4 mg/kg | Percentage of Participants With Adjudicated Symptoms of Hypersensitivity | 6.6 percentage of participants |
| Sugammadex 16 mg/kg | Percentage of Participants With Adjudicated Symptoms of Hypersensitivity | 9.5 percentage of participants |
Comparison: Planned sample size of 150 participants in each sugammadex group (4 mg/kg and 16 mg/kg) allowed estimation of adjudicated hypersensitivity in each sugammadex group with a 95% confidence interval with a half-width between 1.2 and 4.2 percentage points. Calculation, based on method of Clopper and Pearson (Biometrika 1934;26\[4\]:404-413), used underlying event rate of up to 6% in the sugammadex high dose group, based on study results from protocol P06042 (NCT00988065).95% CI: [-0.9, 10.7]
Comparison: Planned sample size of 150 participants in each sugammadex group (4 mg/kg and 16 mg/kg) allowed estimation of adjudicated hypersensitivity in each sugammadex group with a 95% confidence interval with a half-width between 1.2 and 4.2 percentage points. Calculation, based on method of Clopper and Pearson (Biometrika 1934;26\[4\]:404-413), used underlying event rate of up to 6% in the sugammadex high dose group, based on study results from protocol P06042 (NCT00988065).95% CI: [1.7, 14.2]
Secondary
Percentage of Participants With Adjudicated Anaphylaxis
The investigator or designated clinician performed a THA in each participant at 0.5, 4 and 24 hours after each dose. The THA could also be performed at other times if possible hypersensitivity signs were observed. Each potential hypersensitivity case identified by presence of any sign or symptom in a pre-defined list of hypersensitivity signs and symptoms that were found through the THA was reviewed by an independent, blinded adjudication committee, which determined whether the referred case was a case of anaphylaxis (yes/no) using Sampson Criterion 1 - Acute onset of an illness with involvement of the skin, mucosal tissue or both, and at least one of the following: a) respiratory compromise, b) reduced blood pressure or associated symptoms of end-organ dysfunction (J Allergy Clin Immunol 2006;117:391-397). All AEs occurring in study were reviewed for terms associated with hypersensitivity or anaphylaxis, and could also result in referral to the adjudication committee for evaluation.
Time frame: Up to approximately 28 days after last dose (approximately 14 weeks)
Population: APaT - All randomized participants who received at least one dose of study treatment, with each participant included in arm corresponding to treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adjudicated Anaphylaxis | 0.0 percentage of participants |
| Sugammadex 4 mg/kg | Percentage of Participants With Adjudicated Anaphylaxis | 0.0 percentage of participants |
| Sugammadex 16 mg/kg | Percentage of Participants With Adjudicated Anaphylaxis | 0.7 percentage of participants |
95% CI: [-4.8, 2.5]
95% CI: [-4.2, 3.7]