Clinical trial NCT02650895
Conditions: Healthy Volunteers
Sponsor: Oncoimmune, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2014-06-02; Completion date: 2015-01-15
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of single ascending intravenous (IV) doses of efprezimod alfa in healthy adult participants.

Detailed description:
This was a Phase I, randomized, double-blind, placebo-controlled, single ascending dose study to assess the safety, tolerability, and pharmacokinetics (PK) of efprezimod alfa in healthy male and female adult participants.

The population for this study was healthy males and females between the ages of 18 and 55 years, inclusive, with a body mass index between 18 kg/m\^2 and 30 kg/m\^2, inclusive.

A total of 40 participants were enrolled in this study, in 5 cohorts of 8 participants each. Six of the 8 participants in each cohort received study drug and 2 participants received placebo (0.9% sodium chloride, saline). The first cohort was dosed with 10 mg. Succeeding cohorts received 30 mg, 60 mg, 120 mg, and 240 mg of efprezimod alfa or matching placebo and were dosed at least 3 weeks apart to allow for review of safety and tolerability data for each prior cohort. Administration of the next higher dose to a new cohort of participants was permitted only if adequate safety and tolerability had been demonstrated.

In each cohort, the initial 2 participants were 1 study drug recipient and 1 placebo recipient on Day 1 (sentinel participants). Participants 3 to 5 and 6 to 8 were dosed after Day 7 (a minimum of 24 hours apart between the subgroups). Each participant was dosed at least 1 hour apart in the same subgroup. If necessary, dosing of the rest of the participants was delayed pending review of any significant safety issues that may have arisen during the post-dose period involving the first or second subgroups in that cohort. The subsequent cohort was dosed at least 3 weeks after the prior cohort.

The total study duration for each participant, including the screening period, was up to 63 days. Single dose administration occurred on Day 1.

The Screening Visit (Visit 1) occurred up to 21 days prior to the beginning of the active treatment period. After providing informed consent, participants underwent screening procedures for eligibility.

Participants were admitted to the Clinical Pharmacology Unit (CPU) on Day -1 (Visit 2), and the randomized treatment period began on Day 1 following a 10-hour minimum overnight fast. Participants were randomly assigned to treatment with efprezimod alfa or placebo as a single dose. Participants remained confined until the morning of Day 4.

All participants returned to the CPU on Day 7, Day 14, Day 21, Day 28, and Day 42 (±1 day) for follow-up visits (Visit 3, Visit 4, Visit 5, Visit 6, and Visit 7). Visit 7 was the final visit for all participants.

The assessment of safety was based primarily on the frequency of adverse events, clinical laboratory assessments (chemistry, hematology, and urinalysis), physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and continuous telemetry monitoring. The Intent--to--treat (ITT) population was used for all summaries.

PK parameters were calculated using actual collection times. The PK parameters for efprezimod alfa were calculated from the individual serum concentrations profile by noncompartmental approaches.

The PK Evaluable Population was defined as all participants in the ITT Population who had evaluable concentration-time profiles for efprezimod alfa. The PK Evaluable Population was the population used for all PK analyses.

The PK listing, summary, and analysis were performed based on the serum concentration of efprezimod alfa by treatment. Pharmacokinetic parameters were calculated using actual collection times. The PK parameters for efprezimod alfa were calculated from the individual serum concentrations profile by non-compartmental approaches.

The concentration of efprezimod alfa was summarized descriptively at each nominal time point by treatment (e.g., n, mean, standard deviation \[SD\], coefficient of variation \[CV%\], standard error, median, minimum, and maximum). Mean concentration (±SD) was plotted on a linear scale against nominal time points by treatment. Geometric mean concentration was plotted on a semi-logarithmic scale against nominal time points. The PK Evaluable Population was used for the summary and individual concentrations.

Individual concentration-time curves for efprezimod alfa were plotted on both a linear and semi-logarithmic scale against actual sampling times by participant.

Pharmacokinetic parameters were summarized for the PK Evaluable Population. All parameters were summarized by treatment with the number of observations, mean, SD, CV%, standard error, median, maximum, and minimum. Geometric mean and geometric CV% were also provided for the summary of area of serum concentration versus time curve (AUC) and maximum serum concentration (Cmax).

Dose proportionality of efprezimod alfa serum PK parameters (AUC and Cmax) was assessed using the power model: y = a Dose β, where y denotes the PK parameter being analyzed and depends on participant. Dose proportionality implies that β = 1 and was assessed by estimated β along with its 90% confidence interval (CI). The exponent, β, in the power model was estimated by regressing the log-transformed PK parameter on log-transformed dose.

The power model was fitted by restricted maximum likelihood using Statistical Analysis System Mixed Model Procedures (SAS Proc Mixed). Both the intercept and slope were fitted as fixed effects. The mean slope was estimated from the power model and the corresponding 90% CI calculated.

The ITT Population consisted of all participants who received at least 1 dose of the study drug. The ITT Population was the primary analysis population for participant information and safety evaluation.

The assessment of safety was based primarily on the frequency and nature of adverse events, clinical laboratory assessments (chemistry, hematology, and urinalysis), physical examinations, vital signs, 12-lead ECGs, and telemetry monitoring. The ITT Population was used for all summaries.

All adverse events were summarized by system organ class, preferred term, and treatment. A list of participants who had serious adverse events (SAEs) and who discontinued from the study due to an adverse event was provided. The number and percentage of participants who experienced at least 1 treatment-emergent adverse event (TEAE) were presented for each system organ class and for each preferred term by treatment. Treatment-emergent adverse events that were considered by the Investigator to be related to study drug were summarized in the same manner. Serious adverse events and adverse events leading to discontinuation from the study were listed separately.

Clinical laboratory evaluations (chemistry, hematology, and urinalysis) were summarized by treatment and visit. Change from baseline was also summarized. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) were summarized by treatment and time point. Change from baseline was also summarized. All physical examination data were listed. Electrocardiogram parameters and the change from baseline were summarized. Overall interpretations were listed.

Arms: arm 1: Single dose of efprezimod alfa is administrated as intravenous infusion in one hour. There are 5 dose cohorts, 10mg, 30mg, 60mg, 120mg, 240mg. Each cohort has 6 subjects in efprezimod alfa and 2 subject in placebo. arm 2: Single dose of 100 ml normal saline is administrated as intravenous infusion in one hour.
Interventions: intervention 1: Efprezimod alfa intervention 2: Saline
Intervention descriptions: intervention 1: Recombinant fusion protein consisting of the extracellular domain of mature human CD24 linked to the human immunoglobulin G1 (IgG1) Fc domain intervention 2: 0.9% sodium chloride

Protocol documents: