Healthy
Conditions
Brief summary
A Phase I studyto evaluate the safety and tolerability of escalating subcutaneous (SC) doses of MEDI-528 in to healthy adult volunteers.
Detailed description
The primary objective of this Phase I study is to evaluate the safety and tolerability of escalating single SC doses of MEDI-528 administered to healthy adult volunteers in four dose groups.
Interventions
BIOLOGICALMEDI-528 0.3 mg/kg
MEDI-528 (0.3 mg/kg) administered as a single, subcutaneous (SC) dose
BIOLOGICALMEDI-528 1 mg/kg
MEDI-528 (1 mg/kg) administered as a single, SC dose
BIOLOGICALMEDI-528 3 mg/kg
MEDI-528 (3 mg/kg) administered as a single, SC dose
BIOLOGICALMEDI-528 9 mg/kg
MEDI-528 (9 mg/kg) administered as a single, SC dose
Sponsors
MedImmune LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and females age 19 up to, and including, 49 years of age at the time of the first dose of study drug * Weight less than 89 kg * Written informed consent obtained from the volunteer * Healthy by medical history and physical examination * Sexually active females, unless surgically sterile or at least two years post-menopausal or an FSH≥40 mIu/mL, must use an effective method of avoiding pregnancy (including oral, injectable, transdermal, abstinence, use of a condom by the sexual partner or sterile sexual partner) for 3 months before the first dose of study drug, and must agree to continue using such precautions through the study period of 84 days. Cessation of birth control after this point should be discussed with a responsible physician. Sexually active males, unless surgically sterile, must likewise use an effective method of birth control (condom or abstinence) and must agree to continue using such precautions through Study Day 84 after their dose of study drug. * Use of common over-the-counter medications such as topical corticosteroids, decongestants, antihistamines, analgesics, and antacids is permitted unless, in the opinion of the investigator, it would interfere with either the volunteer's ability to complete the study or interpretation of the study results. * Ability to complete the follow-up period of 84 days * Willing to forego other forms of experimental treatment during the study period of 84 days * Willing to forego vigorous activity 1 - 2 days before dosing, and before each study visit.
Exclusion criteria
* Acute illnesses or evidence of significant active infection, such as fever greater than or equal to 38.0 C (100.5°F) at the start of the study * Use of prescription medications, other than oral contraceptives, in the 28-day period before Study Day 0 * Any blood donation or significant loss of blood within 6 months of time of entry into the study * History of immunodeficiency or receipt of immunosuppressive drugs * History of allergy or reaction to any component of the MEDI-528 formulation * History of substance abuse that, in the opinion of the investigator, may compromise the ability of the study subject to complete the study and follow-up period * Evidence of any systemic disease, neurologic abnormality, lymphadenopathy, or splenomegaly upon physical examination * Evidence of infection with hepatitis A, B, or C virus or HIV-1 * Receipt of immunoglobulins or blood products within 60 days of entering the study * Receipt of any investigational drug therapy or standard vaccine therapy, other than vaccination for influenza, within 60 days of the first dose of study drug through Study Day 84 (use of licensed agents for indications not listed in the package insert is permitted) * Receipt of MEDI-528 in any previous clinical study * At Screening (must be within 21 days before study dose administration) any of the following: Hgb, total WBC, platelet count, Na, K, C1, CO2, AST, ALT, BUN, glucose, amylase, lipase, creatinine, or troponin out of the normal range; other abnormal laboratory values in the screening panel that, in the opinion of the principal investigator, are judged to be clinically significant * Clinically significant abnormality, as determined by the investigator, on 12-lead electrocardiogram at the time of initial screening * Clinically significant abnormalities noted on baseline brain MRI * Elective surgery planned during the study period through Study Day 84 * Pregnancy (sexually active females must have a negative serum pregnancy test on the day of the first dose of study drug, before dosing) * Nursing mother * The presence of any condition or concern which, in the opinion of the investigator, may interfere with the conduct or interpretation of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | Days 0 - 84 | Number of participants experiencing adverse events (includes both adverse events and serious adverse events) |
| Incidence of Abnormal Troponin Levels | Days 0, 1, 7, 14, and 28 | Number of participants with troponin levels greater than upper limit of normal |
| Incidence of Clinically Significant Changes From Baseline in Neurologic Exam | Days 0, 7, 14, 21, 28, 42, and 84 | Number of participants with clinically significant changes from baseline in neurologic exam |
| Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain | Days 0 and 28 | Number of participants with changes from baseline in the Day 28 MRI of the brain |
| Incidence of Serious Adverse Events | Days 0 - 84 | Number of participants experiencing serious adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | AUC(ext) of MEDI-528 |
| Total Body Clearance (CL) | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | CL of MEDI-528 |
| Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | Days 0, 14, 28, 42, and 84 | Number of participants with ADA to MEDI-528 |
| Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F) | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | Vz/F of MEDI-528 |
| Half-life (T1/2) | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | T1/2 of MEDI-528 |
| Time to Observed Maximum Serum Concentration (Tmax) | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | Tmax of MEDI-528 |
| Observed Maximum Serum Concentration (Cmax) | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | Cmax of MEDI-528 |
| Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | AUC(0-t) of MEDI-528 |
| Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528 | Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84 | AUC(0-infinity) of MEDI-528 |
Countries
United States
Participant flow
Recruitment details
A total of 29 participants provided written informed consent and participated in the study at 2 sites in the United States of America between 10Jun2005 and 18Apr2006.
Pre-assignment details
Eligible participants received MEDI-528 in an open-label manner.
Participants by arm
| Arm | Count |
|---|---|
| MEDI-528 0.3 mg | 6 |
| MEDI-528 1 mg | 11 |
| MEDI-528 3 mg | 6 |
| MEDI-528 9 mg | 6 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 5 | 0 | 0 |
Baseline characteristics
| Characteristic | MEDI-528 0.3 mg | MEDI-528 1 mg | MEDI-528 3 mg | MEDI-528 9 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 27.2 Years STANDARD_DEVIATION 8.7 | 25.2 Years STANDARD_DEVIATION 9.7 | 34.7 Years STANDARD_DEVIATION 7.8 | 33.2 Years STANDARD_DEVIATION 13.9 | 29.2 Years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 3 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 3 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 4 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Incidence of Abnormal Troponin Levels
Number of participants with troponin levels greater than upper limit of normal
Time frame: Days 0, 1, 7, 14, and 28
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Abnormal Troponin Levels | 0 Participants |
| MEDI-528 1 mg/kg | Incidence of Abnormal Troponin Levels | 0 Participants |
| MEDI-528 3 mg/kg | Incidence of Abnormal Troponin Levels | 0 Participants |
| MEDI-528 9 mg/kg | Incidence of Abnormal Troponin Levels | 0 Participants |
Primary
Incidence of Adverse Events
Number of participants experiencing adverse events (includes both adverse events and serious adverse events)
Time frame: Days 0 - 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Adverse Events | 5 Participants |
| MEDI-528 1 mg/kg | Incidence of Adverse Events | 4 Participants |
| MEDI-528 3 mg/kg | Incidence of Adverse Events | 6 Participants |
| MEDI-528 9 mg/kg | Incidence of Adverse Events | 6 Participants |
Primary
Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain
Number of participants with changes from baseline in the Day 28 MRI of the brain
Time frame: Days 0 and 28
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain | 0 Participants |
| MEDI-528 1 mg/kg | Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain | 1 Participants |
| MEDI-528 3 mg/kg | Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain | 1 Participants |
| MEDI-528 9 mg/kg | Incidence of Changes From Baseline in the Day 28 Magnetic Resonance Imaging (MRI) of the Brain | 1 Participants |
Primary
Incidence of Clinically Significant Changes From Baseline in Neurologic Exam
Number of participants with clinically significant changes from baseline in neurologic exam
Time frame: Days 0, 7, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Clinically Significant Changes From Baseline in Neurologic Exam | 0 Participants |
| MEDI-528 1 mg/kg | Incidence of Clinically Significant Changes From Baseline in Neurologic Exam | 0 Participants |
| MEDI-528 3 mg/kg | Incidence of Clinically Significant Changes From Baseline in Neurologic Exam | 0 Participants |
| MEDI-528 9 mg/kg | Incidence of Clinically Significant Changes From Baseline in Neurologic Exam | 0 Participants |
Primary
Incidence of Serious Adverse Events
Number of participants experiencing serious adverse events
Time frame: Days 0 - 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Serious Adverse Events | 0 Participants |
| MEDI-528 1 mg/kg | Incidence of Serious Adverse Events | 0 Participants |
| MEDI-528 3 mg/kg | Incidence of Serious Adverse Events | 0 Participants |
| MEDI-528 9 mg/kg | Incidence of Serious Adverse Events | 0 Participants |
Secondary
Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F)
Vz/F of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F) | 4.58 Liters | Standard Deviation 0.64 |
| MEDI-528 1 mg/kg | Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F) | 14.57 Liters | Standard Deviation 8.61 |
| MEDI-528 3 mg/kg | Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F) | 10.91 Liters | Standard Deviation 1.21 |
| MEDI-528 9 mg/kg | Apparent Extravascular Terminal Phase Volume of Distribution (Vz/F) | 8.65 Liters | Standard Deviation 1.4 |
Secondary
Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528
AUC(0-infinity) of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528 | 40.78 Microgram times day per milliliter | Standard Deviation 0.34 |
| MEDI-528 1 mg/kg | Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528 | 667.68 Microgram times day per milliliter | Standard Deviation 201.99 |
| MEDI-528 3 mg/kg | Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528 | 1287.31 Microgram times day per milliliter | Standard Deviation 413.92 |
| MEDI-528 9 mg/kg | Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] of MEDI-528 | 3770.06 Microgram times day per milliliter | Standard Deviation 1396.66 |
Secondary
Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)]
AUC(0-t) of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | 18.47 Micrograms times day per milliliter | Standard Deviation 10.26 |
| MEDI-528 1 mg/kg | Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | 329.7 Micrograms times day per milliliter | Standard Deviation 113.72 |
| MEDI-528 3 mg/kg | Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | 923.27 Micrograms times day per milliliter | Standard Deviation 226.71 |
| MEDI-528 9 mg/kg | Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | 3053.34 Micrograms times day per milliliter | Standard Deviation 908.3 |
Secondary
Half-life (T1/2)
T1/2 of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Half-life (T1/2) | 6.47 Days | Standard Deviation 0.85 |
| MEDI-528 1 mg/kg | Half-life (T1/2) | 86.85 Days | Standard Deviation 19.86 |
| MEDI-528 3 mg/kg | Half-life (T1/2) | 44.43 Days | Standard Deviation 11.48 |
| MEDI-528 9 mg/kg | Half-life (T1/2) | 33.44 Days | Standard Deviation 11.32 |
Secondary
Incidence of Anti-drug Antibodies (ADA) to MEDI-528
Number of participants with ADA to MEDI-528
Time frame: Days 0, 14, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety or ADA information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Partial ADA information was available in the 0.3 mg/kg group (Day 0 and 14, n=5; Day 28, n=2; Day 42 and 84, n = 0)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI-528 0.3 mg/kg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
| MEDI-528 1 mg/kg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
| MEDI-528 3 mg/kg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
| MEDI-528 9 mg/kg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
Secondary
Observed Maximum Serum Concentration (Cmax)
Cmax of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Observed Maximum Serum Concentration (Cmax) | 2.83 Micrograms per milliliter | Standard Deviation 0.73 |
| MEDI-528 1 mg/kg | Observed Maximum Serum Concentration (Cmax) | 14.48 Micrograms per milliliter | Standard Deviation 6.68 |
| MEDI-528 3 mg/kg | Observed Maximum Serum Concentration (Cmax) | 23.00 Micrograms per milliliter | Standard Deviation 5.62 |
| MEDI-528 9 mg/kg | Observed Maximum Serum Concentration (Cmax) | 82.50 Micrograms per milliliter | Standard Deviation 19.64 |
Secondary
Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)]
AUC(ext) of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | 33.32 Percent | Standard Deviation 6.26 |
| MEDI-528 1 mg/kg | Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | 50.90 Percent | Standard Deviation 13.82 |
| MEDI-528 3 mg/kg | Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | 26.05 Percent | Standard Deviation 9.16 |
| MEDI-528 9 mg/kg | Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | 16.61 Percent | Standard Deviation 8.97 |
Secondary
Time to Observed Maximum Serum Concentration (Tmax)
Tmax of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Time to Observed Maximum Serum Concentration (Tmax) | 5.51 Days | Standard Deviation 1.9 |
| MEDI-528 1 mg/kg | Time to Observed Maximum Serum Concentration (Tmax) | 4.17 Days | Standard Deviation 1.6 |
| MEDI-528 3 mg/kg | Time to Observed Maximum Serum Concentration (Tmax) | 4.50 Days | Standard Deviation 1.52 |
| MEDI-528 9 mg/kg | Time to Observed Maximum Serum Concentration (Tmax) | 5.00 Days | Standard Deviation 1.9 |
Secondary
Total Body Clearance (CL)
CL of MEDI-528
Time frame: Days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, and 84
Population: All subjects who received MEDI-528 (no safety information was available for 5 subjects in the 1.0 mg/kg group due to Hurricane Katrina). Two subjects in the 0.3 mg/kg group had no blood samples for pharmacokinetic analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI-528 0.3 mg/kg | Total Body Clearance (CL) | 0.49 Liter per day | Standard Deviation 0 |
| MEDI-528 1 mg/kg | Total Body Clearance (CL) | 0.12 Liter per day | Standard Deviation 0.05 |
| MEDI-528 3 mg/kg | Total Body Clearance (CL) | 0.19 Liter per day | Standard Deviation 0.1 |
| MEDI-528 9 mg/kg | Total Body Clearance (CL) | 0.20 Liter per day | Standard Deviation 0.09 |