Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Minocin (Minocycline) for Injection in Healthy Adults

Study Overview
=================
Brief Summary
-----------------
This was a Phase 1, randomized, double-blind, placebo-controlled, single and multiple ascending dose study of the safety, tolerability, and pharmacokinetics of Minocin (minocycline) for injection in healthy adult participants.

Detailed Description
-----------------
The purpose of this study was to collect safety, tolerability, and pharmacokinetic (PK) data on ascending dose regimens of Minocin (minocycline) for Injection. The safety, tolerability, and PK data was to support the compound as a potential clinical candidate in Europe and allow recommendations of dose levels to be used in future Phase 2/3 studies.

Official Title
-----------------
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics of Minocin® (Minocycline) for Injection in Healthy Adult Subjects

Conditions
-----------------
Normal Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Minocin (minocycline) for Injection
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A signed informed consent form, the ability to understand the study conduct and tasks that were required for study participation, and a willingness to cooperate with all tasks, tests, and examinations as required by the protocol, whether in the research unit or after discharge, for the duration of the study Male or female between 18 and 50 years of age inclusive Participant had a body mass index ≥18 kilograms/square meter (kg/m^2) and ≤30 kg/m^2. Participant was non-smoker or smokes up to 5 cigarettes per day (or equivalent). Participant was in good health based on medical history and physical examination findings and had no clinically meaningful safety laboratory abnormalities (hematology, blood chemistry, and urinalysis) or 12-lead electrocardiogram results, as assessed by the Principal Investigator. Vital signs (blood pressure, pulse, respiratory rate and temperature) measured at screening/baseline must have been within the following ranges: systolic blood pressure ≥90 to ≤150 millimeters of mercury (mm Hg), diastolic blood pressure ≥45 to ≤90 mm Hg; heart rate ≥45 to ≤90 beats per minute (taken after resting in a supine position for at least 5 minutes). Expectation that intravenous access would be sufficient to allow for ease of study drug infusion, and for all protocol-required blood sampling to take place Participant committed to remaining admitted in the research unit for the course of the study. Female participant was surgically sterile, postmenopausal: period of amenorrhea for at least 2 years, or if of childbearing potential, agreed to abstinence or to use at least 2 acceptable methods of birth control (for example prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, barrier methods) or male partner sterilization alone, between the first dose (Day 1) and for 90 days after the completion of the study. Exclusion Criteria: Had any condition, including findings in the medical history or in pre-study assessments that constituted a risk or a contraindication for the participation in the study or completing the study Positive breath test for alcohol and/or positive urine test for drugs of abuse at Screening and Day -1 Visits Had a history or presence of alcohol/drug abuse within 2 years. Alcohol abuse was defined as regularly consuming >3 units/day (21 units per week for men), >2 units/day (14 units/week) for women. A unit was defined as a can of 4% beer (330 mL), approximately 190 mL of 6-7% beer (malt liquor), a glass of 40% spirits (30 mL), a glass of wine (100 mL). Participant showed positive hepatitis B surface antigen, hepatitis C virus antibodies, or human immunodeficiency virus I/II antibodies and antigen tests. Participant had active or ongoing candida infection. Blood or plasma donation within past 2 months Females who were pregnant or nursing or who had a positive pregnancy test result at the Screening Visit or Day -1 prior to dosing Males who were unwilling to practice abstinence or use an acceptable method of birth control during the entire study period and for 90 days after the completion of the study (that is condom with spermicide, where locally available) Presence of known raised intracranial pressure Use of retinoids (for example, isotretinoin) History of significant hypersensitivity or allergic reaction to any of the tetracycline class of antibiotics or the components of those antibiotics Receipt of any investigational medication or investigational device during the last 30 days prior to randomization Treatment with any prescription, vitamins or over-the-counter drugs, within 2 weeks or five half-lives, whichever was longer, or herbal nutritional supplements within 2 weeks of screening, with the exception of acetaminophen/paracetamol for minor headache. Participants were not allowed to receive medications for the duration of the study (except the abovementioned acetaminophen/paracetamol). Birth control or other hormone replacement were also permitted as long as it had been taken at a stable dose for at least 3 months before the Screening Visit and remained stable for the duration of the study. A corrected QT interval by Fridericia >480 milliseconds Calculated creatinine clearance less than 50 mL/minute (Cockcroft-Gault method) at screening or check-in (Day -1) Unable or unwilling, in the judgment of the Investigator, to comply with the protocol An employee of the Investigator, the study center, the sponsor or The Medicines Company with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, or a family member of the employee or the Investigator Prior enrollment in any minocycline study including prior cohorts in this trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Model Description: Cohorts 1 and 2 were run concurrently as they were using the approved doses of intravenous minocycline in the United States. Cohorts 3, 4, 5 and 6 were run sequentially and only after review of data from the preceding cohorts by the data monitoring committee.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Minocin (minocycline) for Injection<br>Minocin (minocycline) for Injection was supplied as a sterile lyophilized powder in single-use 10-milliliter (mL) glass vials. Each vial contained 108 milligrams (mg) of minocycline hydrochloride equivalent to 100 mg of minocycline. Each cohort received one of the following dosages of Minocin (minocycline) for Injection: 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg. Within each cohort, participants received a single dose on Day 1, followed by 7 days of multiple doses (Days 4 to 10, given every 12 hours), followed by a single dose on Day 11. | Drug: Minocin (minocycline) for Injection<br>* Intravenous formulation of minocycline, a derivative of tetracycline<br>* Other names: Minocycline;|
| Placebo Comparator: 0.9% Sodium Chloride Injection USP<br>Placebo was in the form of the same 100-mL bags of normal saline (0.9% Sodium Chloride Injection United States Pharmacopeia [USP]). Dosing was on the same schedule as participants randomized to Minocin (minocycline) for Injection. | Other: Placebo<br>* Placebo - Normal Saline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Participants Experiencing Treatment-emergent Adverse Events | Safety and tolerability of single and multiple intravenous doses of Minocin (minocycline) for Injection assessed by number of participants with adverse events. | Day 1 through Day 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Area Under The Concentration-time Curve From Zero Hours To The Last Measured Concentration (AUC0-t) After A Single Dose Of Minocin On Day 1 | Assessment of AUC0-t by cohort after a single intravenous dose of Minocin (minocycline) for Injection on Day 1 is reported as mg times hour/liter (mg*h/L). | Day 1 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment Of AUC0-t By Cohort After A Single Dose Of Minocin On Day 4 | Assessment of AUC0-t by cohort after a single dose of Minocin (minocycline) for Injection using plasma from serial blood samples on Day 4 is reported. | Day 4 (Measurements taken at 1 [end of infusion], 2, 4, 8, and 12 hours after the start of dosing) | 
| Assessment Of AUC0-t By Cohort After Multiple Doses Of Minocin On Day 11 | Assessment of AUC0-t by cohort after 7 days of multiple doses of Minocin (minocycline) for Injection using plasma from serial blood samples on Day 11 is reported. | Day 11 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment Of Maximum Plasma Concentration (Cmax) By Cohort For A Single Dose Of Minocin On Day 1 | Assessment of Cmax by cohort for a single intravenous dose of Minocin (minocycline) for Injection using serial blood samples on Day 1 is reported. | Day 1 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment of Cmax by Cohort for a Single Dose of Minocin on Day 4 | Assessment of Cmax by cohort for a single intravenous dose of Minocin (minocycline) for Injection using serial blood samples on Day 4 is reported. | Day 4 (Measurements taken at 1 [end of infusion], 2, 4, 8, and 12 hours after the start of dosing) | 
| Assessment Of Cmax By Cohort For Multiple Doses Of Minocin On Day 11 | Assessment of Cmax by cohort after 7 days of twice daily dosing of Minocin (minocycline) for Injection using serial blood samples on Day 11 is reported. | Day 11 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment Of Apparent Terminal Elimination Half-life (T1/2) By Cohort For A Single Dose Of Minocin Using Plasma From Serial Blood Samples On Day 1 | Assessment of T1/2, defined by T1/2 = natural log of 2 divided by elimination constant (Kel) (T1/2), by cohort after a single intravenous dose of Minocin (minocycline) for Injection on Day 1 is reported. | Day 1 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment Of T1/2 By Cohort After Multiple Doses Of Minocin Using Plasma From Serial Blood Samples On Day 11 | Assessment of T1/2, defined by T1/2 = natural log of 2 divided by Kel (T1/2), by cohort after 7 days of twice daily dosing of intravenous doses of Minocin (minocycline) for Injection on Day 11 is reported. | Day 11 (Measurements taken at 1 [end of infusion], 2, 4, 8, 12, 18, 24, 36, 48, and 72 hours after the start of dosing) | 
| Assessment Of Amount Of Drug Excreted In Urine After A Single Dose Of Minocin Using Serial Urine Samples On Day 1 | Assessment of amount of drug excreted in urine after a single intravenous dose of Minocin (minocycline) for Injection using serial urine samples on Day 1 is reported. | Day 1 (Measurements collected from 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the start of dosing | 
| Assessment Of Amount Of Drug Excreted In Urine After Multiple Intravenous Doses Of Minocin Using Serial Urine Samples On Day 11 | Assessment of amount of drug excreted in urine after 7 days of twice daily intravenous doses of Minocin (minocycline) for Injection using serial urine samples on Day 11 is reported. | Day 11 (Measurements collected from 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the start of dosing | 
| Assessment Of Percent of Dose Excreted In Urine After A Single Dose Of Minocin Using Serial Urine Samples On Day 1 | Assessment of percent of dose excreted in urine after a single intravenous dose of Minocin (minocycline) for Injection using serial urine samples on Day 1 is reported. | Day 1 (Measurements collected from 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the start of dosing) | 
| Assessment Of Percentage Of Drug Excreted In Urine After Multiple Intravenous Doses Of Minocin Using Serial Urine Samples On Day 11 | Assessment of percentage of drug excreted in urine after 7 days of twice daily intravenous doses of Minocin (minocycline) for Injection using serial urine samples on Day 11 is reported. | Day 11 (Measurements collected from 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 hours after the start of dosing | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bacterial infections