Clinical trial NCT02802631
Conditions: Normal Healthy Volunteers
Keywords: Bacterial infections
Sponsor: Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.)
Start date: 2017-04-20; Completion date: 2018-02-08
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Minocin (minocycline) for Injection intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous formulation of minocycline, a derivative of tetracycline intervention 2: Placebo - Normal Saline

Protocol documents:
Prot_000.pdf: 
Confidential 
1 
Investigational New Drug 
Minocin® (minocycline) for Injection 
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 
Protocol No.: MDCO-MIN-16-02 
U.S.  NDA No.: 50-444 
EudraCT No.: 2016-002246-24 
PROTOCOL VERSION: 5.0, Amendment 3.0 
Development Phase: 
Phase 1 
Sponsor: 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Sponsor Representative in the 
European Union: 
The Medicines Company – UK 
Medical.Information@THEMEDCO.com 
+44 1235 448 500 
Principal Investigator: 
Christine Voors-Pette, MD 
QPS Netherlands BV 
Petrus Campersingel 123  
Groningen, 9713 AG 
The Netherlands 
 
Sponsor Representatives: 
 
Medical Director: 
Name: 
Jeffery Loutit, MBChB 
Project Lead: 
Name: 
Brooke Lohse 
Global Safety Officer: 
Name: 
Isabelle Degeyter, MD 
IMI/Combacte NET 
 
 
Medical Lead: 
Name: 
Oliver Cornely, MD 
Project Lead: 
Name:  
Dorothee Arenz 
 
 
Issue Date: 
Date:  09 Nov 2017 
Property of The Medicines Company 
May not be used, divulged, published or otherwise disclosed without the consent of The Medicines 
Company 
This study will be conducted in compliance with Good Clinical Practice (GCP) and protection of the 
subject as required by the regulations and directives in operation at this time. 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
2 
IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
Medical Director 
Jeffery Loutit, MBChB 
+1-650-888-5007 
Academic Medical Lead 
Oliver Cornely, MD 
+49 172 2442726 
Global Safety Officer 
Isabelle Degeyter, MD 
+1 973-290-6393 
 
 
 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
3 
KEY CONTACTS 
Role in Study 
Name 
Contact Information 
Medical Monitor 
Jeffery Loutit, MBChB 
The Medicines Company 
Health Science Infectious Disease Care 
3013 Science Park Road 
San Diego, CA 92121, USA 
tel 
+1 650 888-5007 
 
+1 858 875-6665 
jeff.loutit@themedco.com 
Academic Medical Lead  
Oliver Cornely, MD 
University Hospital of Cologne (UKK) 
Clinical Trials Center Cologne (CTCC) 
Department I for Internal Medicine 
Kerpener Str. 62 
50937 Koeln, Germany 
tel 
+49 172 2442726 
 
+49 221 478-88120 
oliver.cornely@uk-koeln.de 
Trial Statistician 
Stefanie Hamacher 
University Hospital of Cologne (UKK) 
IMSIE (IMSIE) 
Kerpener Str. 62 
50937 Koeln, Germany 
tel +49 221 478-6517 
stefanie.hamacher@uni-koeln.de 
Sponsor Project Lead 
Brooke Lohse 
The Medicines Company 
3013 Science Park Road 
San Diego, CA 92121, USA 
tel +1-858-875-6672 
brooke.lohse@themedco.com 
UKK Project Lead 
Dorothee Arenz 
University Hospital of Cologne (UKK) 
Department I for Internal Medicine 
Kerpener Str. 62 
50937 Koeln, Germany 
tel 
+49 221 478-32786 
dorothee.arenz@uk-koeln.de 
 
 




Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
5 
 
INSTITUTIONS INVOLVED 
 
Responsibility 
Address 
Bioanalytical Laboratory and Pharmacokinetic 
Analysis/Sample Repository 
North Bristol NHS Trust 
Southmead Hospital Bristol 
Department of Medical Microbiology 
Westbury on Trym 
Bristol, BS10 5NB 
United Kingdom 
Clinical Laboratory - Hematology 
KCL Bioanalysis BV 
Borniastraat 34 
8934 AD Leeuwarden 
The Netherlands 
Clinical Laboratory - Biochemistry 
KCL Bioanalysis BV 
Borniastraat 34 
8934 AD Leeuwarden 
The Netherlands 
Data Management 
University Hospital of Cologne (UKK) 
Clinical Trials Center Cologne (CTCC) 
Kerpener Str. 62 
50937 Koeln 
Germany 
 
 
 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
6 
1. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: The Medicines Company 
Name of Finished Drug: Minocin® (minocycline) for Injection, referred to as Minocin IV in this 
protocol 
Name of Active Ingredient: Minocycline 
Title of Study: 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 
Phase of Development: Phase 1 
Study Center: Single study site is QPS Netherlands BV, Groningen, The Netherlands  
Number of Subjects: Approximately 60 healthy subjects (approximately 30 men and 30 women). 
Each randomized subject can be part of one cohort only, i.e. cannot be randomized twice. 
Principal Investigator: Christine Voors-Pette, MD 
Study Period: 
The estimated study period will be approximately 36 weeks from screening of the first subject to 
completion of the last subject. 
Objectives: 
 
The primary objective is to assess the safety and tolerability of single and multiple intravenous 
doses of Minocin IV when administered to healthy adult subjects. 
 
The secondary objective is to assess the pharmacokinetics of single and multiple intravenous 
doses of Minocin IV when administered to healthy adult subjects. 
Rationale: 
Minocin® (minocycline) for Injection, and referred to as Minocin IV in this protocol, is an 
intravenous (IV) formulation of minocycline, a derivative of tetracycline. Minocin IV is similar to 
other drugs developed in the era prior to the maturation of the field of pharmacodynamics, in that 
human doses were not systematically determined or optimized. Minocycline was first approved in the 
United States (US) as both oral and IV formulations in the 1970s. Only oral dosage formulations of 
minocycline have been approved for use in countries in the EU. An updated development program for 
Minocin IV would enable the availability of a new agent in the European Union (EU) to address 
highly resistant strains of Acinetobacter baumannii. The program will build on recently acquired 
information in preclinical studies and allow for optimization of the dosage regimen prior to use in 
controlled studies.  
The overall development strategy in the EU is summarized below: 
 
Establish safety, tolerability, and PK of escalating doses of Minocin IV in normal subjects 
 
Link PK data in human subjects with PK-PD efficacy targets in animal models of infection to 
select dosage regimen 
 
Conduct a pathogen-directed clinical study of Minocin IV in infections due to Acinetobacter 
baumannii, assisted by the use of a rapid diagnostic test 
Two recent studies using high doses of minocycline (single doses up to 800 mg and multiple doses of 
400 mg twice a day) have been conducted in patients with stroke (Fagan 2010) and spinal cord injury 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
7 
(Casha 2011). These studies were conducted to investigate the potential clinical uses of higher doses 
of minocycline taking advantage of its properties unrelated to its antimicrobial effects (Garrido-Mesa, 
2013), and resulted in pharmacokinetic and safety data of intravenous minocycline at high doses.  The 
results of these studies indicate that doses of minocycline higher than those currently approved for IV 
administration in the US, and oral in the US and EU, appear to be safe and well tolerated in humans.  
Based on these data, the sponsor believes it is rational to investigate higher doses of minocycline to 
optimize PK-PD properties for treatment of serious gram-negative pathogens, particularly non-
fermenting organisms such as Acinetobacter baumannii complex. 
This study is the first in the EU development program described above and will start with doses 
already approved in the US, namely 100 mg and 200 mg, in order to build a population PK model. 
Doses will be increased up to 600 mg if safety is observed at the lower doses. Data from this study 
will determine the dose of Minocin IV to be used in the Phase 3 study in the treatment of subjects with 
pneumonia secondary to Acinetobacter baumannii.  
 
Methodology: 
 
This is a double-blind, randomized, placebo-controlled, single- and multiple ascending dose study of 
up to 5 doses (cohorts) of Minocin IV. An effort should be made to include balanced numbers of male 
and female subjects. At least 2 male and 2 female subjects must be assigned to receive Minocin, 1 
male and 1 female to receive placebo in each cohort. 
Each cohort will consist of 10 subjects (8 active drug and 2 placebo). 
Planned Cohorts: 
Cohort 1: 100 mg* 
Cohort 2: 200 mg* 
Cohort 3: 300 mg 
Cohort 4: 400 mg 
In the ongoing study, dose escalation was stopped after the multiple dose phase of 400 mg cohort due 
to 6/10 subjects in this cohort discontinuing due to AEs of dizziness and nausea. Consequently, 
cohorts 5 and 6 are adapted to 500 mg or 600 mg respectively as a single dose on day 1 and as a 
loading dose on day 4 followed 12 hours later by multiple doses of 300 mg every 12 hours. 
Cohort 5: 500/300 mg 
Cohort 6: 600/300 mg 
* Cohorts 1 and 2 may be run concurrently as they are the approved doses of minocycline IV in the 
US. Cohorts 1/2, 3, 4, 5 and 6 will be run sequentially. 
 
Within each cohort, subjects will receive a single dose on Day 1, followed by 7 days of multiple doses 
(Days 4-10), followed by a single dose on Day 11. Subjects will be discharged from the clinic on Day 
14 upon having an EOS evaluation and a follow-up phone call will occur on Day 17 (See Schedule 
and Events Table for details). 
Subjects are required to remain admitted in the research unit from the time of randomization (Day 1) 
until the discharge on Day 14. Subjects that discontinue the study early are required to complete Early 
Termination procedures. 
 
Safety will be assessed throughout the study and serial blood and urine samples will be collected for 
the safety and PK assessment of Minocin IV. 
 
Adverse events and serious adverse events will be collected and recorded. Safety will be evaluated by 
the assessment of clinical safety laboratory results, vital sign measurements, ECG and physical 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
8 
examination findings. A Day 17 follow up phone call will be performed to evaluate safety by the 
assessment of adverse events and serious adverse events. 
Main Criteria for Selection:  
Inclusion Criteria 
Subjects must meet all of the following criteria in order to be eligible for the study: 
1. 
A signed informed consent form, the ability to understand the study conduct and tasks that 
are 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; 
2. 
Male or female between 18 and 50 years of age inclusive; 
3. 
Subject has a body mass index (BMI) ≥18 kg/m2 and ≤ 30 kg/m2; 
4. 
Subject is non-smoker or smokes up to 5 cigarettes per day (or equivalent); 
5. 
Subject is in good health based on medical history and physical examination findings and 
has no clinically meaningful safety laboratory abnormalities (Haematology, blood 
chemistry, and urinalysis) or 12-lead ECG results, as assessed by the Principal 
Investigator (PI); 
6. 
Vital signs (BP, pulse, respiratory rate and temperature) measured at screening/baseline 
must be within the following ranges: SBP ≥90 to ≤150 mm Hg, DBP ≥45 to ≤90 mm Hg; 
Heart Rate ≥ 45 to ≤90 bpm (taken after resting in a supine position for at least 5 
minutes); 
7. 
Expectation that intravenous access will be sufficient to allow for ease of study drug 
infusion, and for all protocol required blood sampling to take place; 
8. 
Subject commits to remaining admitted in the research unit for the course of the study; 
9. 
Female subject is surgically sterile, postmenopausal: period of amenorrhea for at least 2 
years, or if of childbearing potential, agrees to abstinence or to use at least 2 acceptable 
methods of birth control (e.g. prescription oral contraceptives, contraceptive injections, 
contraceptive patch, intrauterine device, barrier methods, etc.) or male partner sterilization 
alone, between the first dose (Day 1) and for 90 days after the completion of the study. 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria will not be enrolled in the study: 
1. 
Has any condition, including findings in the medical history or in pre-study assessments 
that constitutes a risk or a contraindication for the participation in the study or completing 
the study; 
2. 
Positive breath test for alcohol and/or positive urine test for drugs of abuse at Screening 
and Day -1 Visits; 
3. 
Has a history or presence of alcohol/drug abuse within 2 years. Alcohol abuse is defined 
as regularly consuming >3 units/day (21 units per week for men), >2 units/day (14 
units/week) for women. A unit is 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); 
4. 
Subject shows positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies 
(anti-HCV), or human immunodeficiency virus (HIV) I/II antibodies and antigen tests; 
5. 
Subject has active or ongoing candida infection; 
6. 
Blood or plasma donation within past 2 months; 
7. 
Females who are pregnant or nursing or who have a positive pregnancy test result at the 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
9 
Screening Visit or Day -1 prior to dosing; 
8. 
Males who are 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 (i.e. 
condom with spermicide, where locally available); 
9. 
Presence of known raised intracranial pressure; 
10. 
Use of retinoids (e.g., Isotretinoin); 
11. 
History of significant hypersensitivity or allergic reaction to any of the tetracycline class 
of antibiotics or the components of those antibiotics; 
12. 
Receipt of any investigational medication or investigational device during the last 30 days 
prior to randomization; 
13. 
Treatment with any prescription, vitamins or OTC drugs, within 2 weeks or five half-
lives, whichever is longer, or herbal nutritional supplements within 2 weeks of screening, 
with the exception of acetaminophen/paracetamol for minor headache. Subjects will not 
be allowed to receive medications for the duration of the study (except the 
abovementioned acetaminophen/paracetamol). Birth control or other hormone 
replacement is also permitted as long as it has been taken at a stable dose for at least three 
months before the Screening Visit and remains stable for the duration of the study; 
14. 
A QTcF >480 msec; 
15. 
Calculated creatinine clearance less than 50 mL/min (Cockcroft-Gault method) at 
screening or check-in (Day -1); 
16. 
Unable or unwilling, in the judgment of the Investigator, to comply with the protocol; 
17. 
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; 
18. 
Prior enrollment in any minocycline study including prior cohorts in this trial. 
 
Test Drug Mode of Administration: 
Minocin IV or placebo doses should be prepared by an unblinded pharmacist (or qualified designee). 
Subjects randomized to Minocin IV will receive 100-600 mg depending on cohort. Cohorts 1-4 
received 100-400 mg, respectively. Cohorts 5 and 6 are adapted to 500 mg or 600 mg respectively as a 
single dose on Day 1 and as a loading dose on Day 4 followed 12 hours later by multiple doses of 300 
mg every 12 hours. Doses will be administered over 60 minutes in 0.9% Sodium Chloride Injection 
(referred to as Normal Saline for the remainder of the document). Detailed dosing preparation is 
described in the Pharmacy Manual. 
The placebo will be Normal Saline  and will be administered at a rate and volume matching the rate 
and volume of Minocin IV for each respective Cohort.  
All doses of Minocin IV or placebo will be administered intravenously into a peripheral vein. 
Duration of Treatment: The Screening period for all cohorts is ≤28 days prior to admission on Day -
1, with single dose administration on Days 1 and 11; multiple-dose administration on Days 4-10; 
Serial PK collection on Days 1-4 and 11-14. Subjects are discharged on Day 14 after the final study 
assessments are completed. A Follow-up phone call will occur on Day 17. 
Reference Therapy, Dose and Mode of Administration: Normal Saline (placebo) as administered at 
a rate and volume matching the rate and volume of Minocin IV for each respective Cohort. 
Criteria for Evaluation: 


Minocin® (minocycline) for Injection 
Clinical Study
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Confidential 
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Endpoints: 
 
Assess the safety and tolerability of single and multiple intravenous doses of Minocin IV 
when administered to healthy adult subjects (see below section Safety). 
 
Assess the pharmacokinetics of single and multiple intravenous doses of Minocin IV when 
administered to healthy adult subjects (see below section Pharmacology). 
Efficacy: Efficacy will not be assessed in this study. 
Safety Evaluations: 
Safety will be evaluated by the assessment of AEs/SAEs, clinical safety laboratory results, ECG, vital 
sign measurements, and physical examination findings. 
 
Dose Escalations and Stopping Rules: 
 
Intra-Cohort Data Review:  
For Cohorts 3-6, single dose safety data will be reviewed by the Medical Monitor and Principal 
Investigator on Day 3 prior to the start of the multi- dosing on Day 4.  During the review, blinded 
safety data from the single dose infusions will be assessed and one of the following will be decided 
before the start of the Multiple Dose Phase on Day 4: 
1. 
To continue with the Multi-dose phase as planned, 
2. 
To continue with the Multi-dose phase and add additional safety evaluations, 
3. 
To not continue with the Multi-dose phase. 
 
Between- Cohort Data Monitoring Committee Review: 
Safety data will be reviewed by the Data Monitoring Committee (DMC) following each cohort and 
prior to the start of the next cohort. 
 
After completion of cohorts 1 and 2, which may run concurrently, and prior to dosing of each cohort 
3, 4,5 and 6, the DMC will review all pertinent blinded safety data (e.g., physical examinations, vital 
signs, electrocardiograms (ECGs), clinical laboratory tests, and AEs) from the preceding cohort to 
determine one of the following: 
1. 
To continue with the next cohort as planned, 
2. 
To continue with the next cohort and add additional safety evaluations, 
3. 
To continue with the next cohort by adjusting the planned dose of Minocin IV, or 
4. 
To not continue with the next cohort. 
 
Stopping Rules 
The study will be terminated if ≥ 2 subjects in a cohort meet any of the following criteria and the 
subject was determined to have received active drug after unblinding: 
 
Has a drug related SAE 
 
Experiences a drug related AE grade > 3 toxicity 
Plasma and Urine PK Assessments: 
Plasma and urine samples will be collected during the Single and Multiple Dose Phases to determine 
concentrations of Minocin IV and metabolites in plasma and urine (see Schedule of Events Flowchart 
for specific collection times). 
Pharmacology: 
The plasma concentration-time data for Minocin IV will be analyzed by non-compartmental methods. 


Minocin® (minocycline) for Injection 
Clinical Study
The Medicines Company 
Confidential 
11 
Treatment arms (doses, placebo) are compared regarding plasma AUC0-t, AUC0-inf, Cmax, and Tmax. 
Individual as well as mean time-concentration profiles will be graphed. Statistical analysis of dose 
proportionality of exposure parameters will be performed. 
Urine PK parameters such as amount excreted and % dose excreted will be calculated from urinary 
excretion data. 
Detailed methods used and the results obtained will be included in a separate PK report. 
Statistical Methods: 
Ten subjects per cohort are planned, hence n = 60 subjects in total. This sample size was selected 
based on previous experience attempting to minimize the number of subjects on study drug while 
obtaining sufficient PK data from different subjects to produce a good estimate of exposure. 
Descriptive statistics will be performed for patient characteristics, laboratory evaluations, vital signs 
and ECG results. Additional shift tables will be provided for laboratory evaluations and ECG results. 
TEAEs will be listed and number (percentage) of subjects reporting TEAEs and number (percentage) 
of TEAEs will be tabulated. 


Minocin® (minocycline) for Injection 
Clinical Study Protoc
The Medicines Company 
Confidential 
2. 
SCHEDULE OF EVENTS/ASSESSMENTS COHORT 1-6 
Study Procedures 
Screening 
(≤28 days 
to -1) 
Day -
11 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7  
Day 
8 
Day 
9 
Day 
10 
Day 
11  
D
1
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, weight and BMI 3 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Physical Examination 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Vital Signs:RR/BP/HR/Temperature 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 5 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 6 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Creatinine clearance 7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Test for HIV, Hep B sAg, HCV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen / Alcohol breath test 8 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 9 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
PK Blood Collection 10 
 
 
X 
X 
X 
X2 
 
 
 
 
 
 
X 
PK Urine Collection 11 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Inclusion / Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Dose Administration (1h Infusion) 12 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X  
X 
Concomitant Medications 
<---------------------------------------------------------------------------------------------------------------X------------------------------------
-------- > 
Adverse Events / SAEs 
 
 
< ------------------------------------------------------------------------------------------ X------------------------
-------- > 
Follow-Up Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Day -1 procedures should be completed within approximately 24 hours before dosing on Day 1. 
2 The 72 h post-dose PK collection should occur before the start of the 2nd infusion on Day 4. 
3 BMI will only be calculated at screening. Weight will be collected on Day -1, 10 and 14. 
4 Vital signs (blood pressure, pulse, temperature, respirations) will be measured before and at 1, 3, and 6 h after the start of the morning dose and before and at 1 hour a
On Day 1 vitals will be collected at 1, 3, and 6 h after the start of dosing. Vital signs may be collected once in the morning on days where no dosing occurs. 
5 On Day -1, ECGs should be performed in triplicate. On Days 1 a triplicate ECGs will be performed 1h/end of infusion (+/- 10 minutes). Day4 triplicate ECGs will be 
h/end of infusion (+/-10 minutes) after the start of the morning dosing. On Days 5-11 and 14, single ECGs are performed. Triplicate recording may be required depend
11.1.7. 
6 Includes serum chemistry, hematology, and urinalysis. On Days 4, 6, 8, and 10, collect blood and urine for clinical laboratory tests approx. 4 h after the start of the mo
7 Urine from the PK collection on Day 1 (hours: 0-4, 4-8, 8-12, 12-24) will also be used to determine 24h creatinine clearance. 
8 Required for all subjects. 
9 Serum pregnancy should be performed during Screening, Day -1 and Day 14 EOS. Urine pregnancy test should be performed before dosing on Day 1. 


Minocin® (minocycline) for Injection 
Clinical Study Protoc
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Confidential 
10 Serial plasma PK samples at the following time points (in hours) on Day 1:Before dosing and at 1 (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48, and 72 h (pre-dose on
Post-Day 4 dose: 1 (end-of-infusion), 2, 4, 8, and 12 h after the start of dosing; On Day 11: Before the Final Dose and at 1 (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48
11 Urine for PK analysis will be collected at Day 1 before dosing and during intervals: 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72 h (pre-dose on Day 4) after dosing. Day 
intervals: 0-4, 4-8, 8-12, 12-24, 24-48 and 48-72 hours after dosing. 
12 Subjects will receive a single dose on Day 1. Dosing on Days 4-10 will occur every 12 h. Only the one morning dose on Day 11 will be administered. 


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Minocin® (minocycline) for Injection 
Clinical Study Protoc
The Medicines Company 
Confidential 
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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ........................................................................................................ 6 
2. 
SCHEDULE OF EVENTS/ASSESSMENTS COHORT 1-5  ................................................... 12 
3. 
SCHEMATIC DIAGRAM OF TRIAL DESIGN ................................................................... 14 
4. 
LIST OF ABBREVIATIONS ................................................................................................ 19 
5. 
INTRODUCTION ................................................................................................................. 23 
5.1. 
Background ............................................................................................................. 23 
5.2. 
Minocin IV (minocycline) for Injection ..................................................................... 24 
5.2.1. 
Nonclinical Studies .................................................................................... 24 
5.2.2. 
Clinical Studies ......................................................................................... 24 
5.2.3. 
Known and Potential Risks and Benefits ...................................................... 25 
5.3. 
Study Rationale ........................................................................................................ 27 
5.4. 
Study Population ...................................................................................................... 29 
6. 
TRIAL OBJECTIVES AND PURPOSE ................................................................................ 30 
6.1. 
Primary Objective .................................................................................................... 30 
6.2. 
Secondary Objective................................................................................................. 30 
7. 
TRIAL DESIGN .................................................................................................................... 31 
7.1. 
Type/Design of Trial ................................................................................................. 31 
7.2. 
Study Endpoints ....................................................................................................... 31 
7.3. 
Measures to Minimize/Avoid Bias ............................................................................ 32 
7.3.1. 
Blinded Study Where Pharmacist is Unblinded ............................................ 32 
8. 
SUBJECT POPULATION .................................................................................................... 33 
8.1. 
Number of Subjects .................................................................................................. 33 
8.2. 
Inclusion Criteria ..................................................................................................... 33 
8.3. 
Exclusion Criteria .................................................................................................... 33 
8.4. 
Withdrawal Criteria................................................................................................. 35 
9. 
TREATMENT OF SUBJECTS ............................................................................................. 37 
9.1. 
Study Medications .................................................................................................... 37 
9.1.1. 
Minocin IV ............................................................................................... 37 
9.1.2. 
Placebo ..................................................................................................... 37 
9.1.3. 
Packaging and Labeling ............................................................................. 37 
9.1.4. 
Storage ..................................................................................................... 37 
9.1.5. 
Accountability ........................................................................................... 38 
9.1.6. 
Product Complaints ................................................................................... 38 
9.2. 
Concomitant Medications ......................................................................................... 39 


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9.2.1. 
Prohibited Concomitant Medications ........................................................... 39 
9.3. 
Restrictions .............................................................................................................. 40 
9.4. 
Blinding ................................................................................................................... 40 
9.4.1. 
Blinding of study medications..................................................................... 40 
9.4.2. 
Method and Maintenance of Blinding .......................................................... 40 
9.5. 
Unblinding ............................................................................................................... 40 
10. 
SCHEDULE AND SEQUENCE OF PROCEDURES............................................................. 42 
10.1. 
Informed consent ..................................................................................................... 42 
10.2. 
Subject Confinement ................................................................................................ 42 
10.2.1. 
Screening Period (Days -28 to -1) ............................................................... 42 
10.2.2. 
Check-in Procedures (Day -1) ..................................................................... 43 
10.2.3. 
Randomization (Day 1) .............................................................................. 43 
10.2.4. 
First Single-dose Treatment (Day 1) ............................................................ 43 
10.2.5. 
Day 2 Procedures ....................................................................................... 44 
10.2.6. 
Day 3 Procedures ....................................................................................... 45 
10.2.7. 
Day 4 Procedures ....................................................................................... 45 
10.2.8. 
Days 5, 7, and 9 Procedures ........................................................................ 46 
10.2.9. 
Days 6 and 8 Procedures ............................................................................ 46 
10.2.10. 
Day 10 Procedures ..................................................................................... 46 
10.2.11. 
Second/Final Single-dose Treatment (Day 11) ............................................. 47 
10.2.12. 
Day 12 Procedures ..................................................................................... 47 
10.2.13. 
Day 13 Procedures ..................................................................................... 48 
10.2.14. 
Discharge (Day 14) .................................................................................... 48 
10.2.15. 
Follow-up Phone Call (Day 17) .................................................................. 48 
10.2.16. 
Early Termination ...................................................................................... 49 
11. 
PROTOCOL ASSESSMENTS .............................................................................................. 50 
11.1. 
Assessment of Safety ................................................................................................ 50 
11.1.1. 
Data Review Meetings ............................................................................... 50 
11.1.2. 
Stopping Rules .......................................................................................... 50 
11.1.3. 
Adverse Events ......................................................................................... 51 
11.1.4. 
Body Mass Index (BMI) ............................................................................. 51 
11.1.5. 
Vital Signs ................................................................................................ 51 
11.1.6. 
Physical Exam ........................................................................................... 51 
11.1.7. 
ECG ......................................................................................................... 51 
11.1.8. 
Clinical Laboratory Tests ........................................................................... 52 
11.1.8.1. 
Hematology ........................................................................... 52 
11.1.8.2. 
Chemistry .............................................................................. 52 
11.1.8.3. 
Urinalysis .............................................................................. 53 
11.1.8.4. 
Human Chorionic Gonadotropin (Pregnancy Test) .................... 53 
11.1.8.5. 
Urine Testing for Drugs of Abuse ............................................ 53 
11.1.8.6. 
Breath Alcohol Testing ........................................................... 53 
11.1.8.7. 
Creatinine Clearance .............................................................. 53 


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11.1.9. 
Meals ....................................................................................................... 53 
11.2. 
Assessment of Efficacy ............................................................................................. 53 
11.3. 
Assessment of Pharmacokinetics .............................................................................. 53 
11.3.1. 
Sampling and Processing ............................................................................ 54 
11.3.2. 
Urine Sampling and Processing .................................................................. 54 
12. 
ADVERSE EVENTS ............................................................................................................. 55 
12.1. 
Definitions ................................................................................................................ 55 
12.1.1. 
Adverse Event ........................................................................................... 55 
12.1.1.1. 
AE Severity ........................................................................... 55 
12.1.1.2. 
Study Drug Causality ............................................................. 56 
12.1.2. 
Serious Adverse Event ............................................................................... 56 
12.1.3. 
Medication Errors ...................................................................................... 57 
12.1.4. 
Adverse Event of Special Interest (AESIs) ................................................... 58 
12.1.5. 
Special Situations ...................................................................................... 58 
12.2. 
Procedure for Non-Serious Adverse Event Recording .............................................. 59 
12.3. 
Procedure for Serious Adverse Event Reporting ...................................................... 59 
12.4. 
Procedure for Medication Error Reporting for Study Drugs .................................... 59 
12.5. 
Procedure for Reporting Adverse Events of Special Interest (AESI’s) ...................... 60 
12.6. 
Procedure for Reporting Pregnancies/Lactation Exposure ....................................... 60 
12.7. 
Procedure for Reporting Special Situations .............................................................. 60 
12.8. 
Procedure for SUSARs ............................................................................................. 60 
13. 
DATA COLLECTION .......................................................................................................... 61 
14. 
STATISTICAL PLAN ........................................................................................................... 62 
14.1. 
Sample size ............................................................................................................... 62 
14.2. 
Randomization ......................................................................................................... 62 
14.3. 
General Statistical Considerations and Definitions ................................................... 62 
14.3.1. 
General Statistical Methods ........................................................................ 62 
14.3.2. 
Analysis Population ................................................................................... 63 
14.3.2.1. 
Intent-to-Treat (ITT) Population .............................................. 63 
14.3.2.2. 
Modified Intent-to-Treat (mITT) Population ............................. 63 
14.3.2.3. 
Pharmacokinetics (PK) Population .......................................... 63 
14.3.2.4. 
Per-Protocol (PP) Population .................................................. 63 
14.3.2.5. 
Safety Population ................................................................... 63 
14.3.3. 
Missing Data Handling .............................................................................. 63 
14.4. 
Statistical Analyses ................................................................................................... 64 
14.4.1. 
Demographic and Background Characteristics ............................................. 64 
14.4.2. 
Study Drug and Concomitant Medications ................................................... 64 
14.4.2.1. 
Adverse Events ...................................................................... 64 
14.4.3. 
Laboratory Tests ........................................................................................ 64 
14.4.4. 
Vital Signs ................................................................................................ 65 


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14.4.5. 
ECGs ........................................................................................................ 65 
14.4.6. 
Pharmacokinetic Parameters ....................................................................... 65 
15. 
RECORDS RETENTION ..................................................................................................... 66 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 67 
16.1. 
Auditing ................................................................................................................... 67 
16.2. 
Protocol Deviations .................................................................................................. 67 
17. 
ETHICS AND RESPONSIBILITY ........................................................................................ 69 
17.1. 
Informed Consent .................................................................................................... 69 
17.2. 
Institutional Review Board/Ethics Committee .......................................................... 69 
18. 
CONFIDENTIALITY ........................................................................................................... 71 
19. 
INVESTIGATOR AGREEMENT ......................................................................................... 72 
20. 
REFERENCES ..................................................................................................................... 73 
 
 
 


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4. 
LIST OF ABBREVIATIONS 
A. baumannii  
Acinetobacter baumannii 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AM 
Ante meridiem, morning 
aPTT 
Activated partial thromboplastin time 
ARO 
Academic Research Organization 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
ºC 
Degrees Celsius 
CDAD 
Clostridium difficile-associated diarrhea 
CDC  
Centers for Disease Control and Prevention 
C. difficile 
Clostridium difficile 
CFR 
Code of Federal Regulations 
Cmax 
Maximum observed drug concentration 
CS 
Clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCC 
Clinical Trials Center Cologne 
d 
Day(s) 
DBP 
Diastolic blood pressure 
DMC 
Data monitoring committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 


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eDC 
Electronic Data Capture 
EOS 
End of study 
ET 
Early termination  
EU 
European Union 
FDA 
Food and Drug Administration 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GPV 
Global pharmacovigilance 
h 
Hour 
Hg 
Mercury 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals  
IEC 
Independent Ethics Committee 
IH 
Intracranial hypertension 
IMI 
Innovative Medicines Initiative 
IMP 
Investigational medicinal product 
IMSIE 
Institute of Medical Statistics, Informatics and Epidemiology 
ITT 
Intent-to-treat 
IU 
International Units 
IV 
Intravenous 
kg 
Kilogram(s) 
L 
Liter 
m2 
Meters squared 
MAA 
Marketing Authorization Application 
max 
Maximum 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 


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MI 
Myocardial infarction 
mITT 
Modified intent to treat 
mL 
Milliliter(s) 
min 
Minute(s) 
n 
Number 
NCS 
Not clinically significant 
NDA 
New drug application 
OTC 
Over-the-counter 
PCS 
Potentially clinically significant  
PD 
Pharmacodynamics 
pH 
Power of hydrogen 
PI 
Principal Investigator 
PK 
Pharmacokinetic or pharmacokinetics 
PP 
Per-protocol (population) 
PR 
PR interval (time from onset of P wave to start of QRS complex) 
PT 
Prothrombin time 
Q 
Quartile 
q12h 
Every twelve hours 
QTc 
Corrected QT interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan  
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
Tmax 
Time of the maximum drug concentration 
UA 
Urinalysis 
UKK 
University Hospital of Cologne 
ULN 
Upper limit of normal 
US, USA 
United States of America 


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USP 
United States Pharmacopeia 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
This study will evaluate the safety, tolerability and PK of Minocin IV 
(Minocycline) for Injection. 
Minocycline was first approved in the United States (US) as both oral and IV 
formulations in the 1970s. Only oral dosage formulations of minocycline have 
been approved for use in countries in the EU. A new formulation of Minocin IV 
has been approved in the US that enables administration of minocycline in a 
smaller volume of fluid. The Medicines Company plans to conduct a development 
program in the EU for Minocin IV for the treatment of infections due to A. 
baumannii, and this new formulation supports the planned study of higher doses 
of minocycline. 
This study will be conducted in compliance with Good Clinical Practices (GCP) 
including the Declaration of Helsinki and all applicable regulatory requirements. 
Additional details regarding Minocin IV can be found in the Investigator’s 
Brochure. 
5.1. Background 
Minocycline is a tetracycline derivative. The approved indication for Minocin IV 
in the United States includes the treatment of infections due to susceptible strains 
of several important Gram-positive and Gram-negative pathogens, including 
Acinetobacter species. 
Acinetobacter infections are associated with high morbidity and mortality 
[Munoz-Price and Weinstein, 2008]. Antibacterial agents frequently used to treat 
Acinetobacter infections include aminoglycosides, cephalosporins, and 
carbapenems; however, resistance to these first-line agents is increasing, leaving 
only unproven agents available for treatment [Shlaes et al, 2013; Munoz-Price and 
Weinstein, 2008]. In view of this increasing resistance, both EU and US 
governments have identified multi-drug resistant Acinetobacter infections as a 
public health risk [EU MEMO/08/788, 2008; US Generating Antibiotic Incentives 
Now (GAIN) Act, 2012; and Centers for Disease Control (CDC) Antibiotic 
Resistance Threats Report, 2013]. 
It is noteworthy that while minocycline has been approved since the 1970s, recent 
studies indicate that minocycline remains highly active in vitro against 
Acinetobacter species. Importantly, minocycline has been found to be active 
against strains that are resistant to doxycycline or tigecycline [Munoz-Price and 
Weinstein, 2008]. 


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The original IV formulation of minocycline, Minocin (minocycline) for Injection, 
was approved in the US on 26 October 1972. Only oral dosage formulations of 
minocycline and Minocin have been approved for use in countries in the EU since 
the 1970s [Minocycline tablets SmPC, 2011; Minocin MR Capsules SmPC, 
2014]. The new formulation of Minocin IV was approved in the US on 
17 April 2015 (NDA 50,444). The new formulation is comprised of minocycline 
hydrochloride with magnesium sulfate to improve the solubility and stability of 
minocycline solutions at a more physiological pH, which enables administration 
of minocycline in a smaller volume of fluid. 
The Medicines Company plans to conduct three Phase I safety and pharmacology 
studies (including this study) and one Phase III study to support the overall 
development strategy for Minocin IV in the EU. 
5.2. Minocin IV (minocycline) for Injection 
Minocin® (minocycline) for Injection, and referred to as Minocin IV in this 
protocol, is an intravenous (IV) formulation of minocycline, a derivative of 
tetracycline. 
Minocin IV is supplied as a sterile lyophilized cake in a single-use 10 mL glass 
vial with a rubber stopper and an aluminum over-seal. Each vial contains 108 mg 
of minocycline hydrochloride equivalent to 100 mg minocycline, 269 mg of 
magnesium sulfate heptahydrate equivalent to 27 mg of magnesium (an inactive 
ingredient), and sodium hydroxide (to adjust pH). 
5.2.1. Nonclinical Studies 
The nonclinical development program for Minocin IV consists of studies of 
antibacterial potency in vitro against clinical isolates and in vivo in mouse and 
rat infection models; in vitro and in vivo pharmacokinetic and metabolism 
studies; and a battery of nonclinical toxicity, safety, and local tolerance 
studies, including 14 day IV repeat-dose studies in rats and dogs, safety 
pharmacology studies in rats and dogs, and local tolerance studies in mice and 
rabbits. 
Additional details regarding the nonclinical development program for Minocin 
IV can be found in the Investigator’s Brochure. 
5.2.2. Clinical Studies 
No clinical studies have been conducted to date by the sponsor with the new 
formulation of Minocin IV. However, clinical pharmacokinetic and safety 
information are available from the US Prescribing Information for Minocin IV 
[Minocin for Injection PI, 2015], and while no randomized controlled trials of 
IV minocycline in patients with A. baumannii infection exist, clinical efficacy 


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data are available from published case report series that indicated successful 
treatment. 
Following a single dose of Minocin IV 200mg administered to 10 healthy 
male subjects, serum concentrations of minocycline ranged from 2.52 μg/mL 
to 6.63 μg/mL (average of 4.18 μg/mL) at the end of infusion and 0.82 μg/mL 
to 2.64 μg/mL (average of 1.38 mcg/mL) after 12 hours [Minocin IV 
Investigator’s Brochure Ed. 2 Addendum, 2017]. 
The serum t½ of minocycline following administration of Minocin IV 100 mg 
every 12 hours or 200 mg once daily was not significantly different and 
ranged from 15 hours to 23 hours [Minocin IV Investigator’s Brochure Ed. 2 
Addendum, 2017. 
IV minocycline has been in use for over four decades and has a well-
established safety profile. Recent clinical safety data have been generated 
from studies of potential non-antimicrobial effects of minocycline [Casha et 
al, 2012; Fagan et al, 2010]. 
Additional details regarding the clinical studies conducted for Minocin IV can 
be found in the Investigator’s Brochure. 
5.2.3. Known and Potential Risks and Benefits 
In general, the risk of significant adverse events related to the Minocin IV is 
minimal and consistent with taking intravenous doses of a tetracycline 
antibiotic. The following adverse reactions have been observed in patients 
receiving tetracyclines and are included in the Minocin® (minocycline) 
Investigator’s Brochure. 
Drug rash with eosinophilia and systemic symptoms, including fatal cases, 
have been reported with minocycline use. If this syndrome is recognized, the 
drug should be discontinued immediately. 
Photosensitivity manifested by an exaggerated sunburn reaction has been 
observed in some individuals taking tetracyclines. This has been reported with 
minocycline. 
Central nervous system side effects including light-headedness, dizziness, or 
vertigo have been reported with minocycline. These symptoms may disappear 
during therapy and usually disappear rapidly when the drug is discontinued. 
Clostridium difficile (C. difficile) associated diarrhea (CDAD) has been 
reported with use of nearly all antibacterial agents, including Minocin, and 
may range in severity from mild diarrhea to fatal colitis. Treatment with 
antibacterial agents alters the normal flora of the colon leading to overgrowth 
of C. difficile. 


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Intracranial hypertension (IH; pseudotumor cerebri) has been associated with 
the use of tetracyclines, including Minocin. Clinical manifestations of IH 
include headache, blurred vision, diplopia, and vision loss; papilledema can be 
found on fundoscopy. Women of childbearing age who are overweight or 
have a history of IH are at greater risk for developing tetracycline-associated 
IH. Concomitant use of isotretinoin and Minocin should be avoided because 
isotretinoin is also known to cause pseudotumor cerebri. Although IH 
typically resolves after discontinuation of treatment, the possibility for 
permanent visual loss exists. 
The anti-anabolic action of the tetracyclines may cause an increase in BUN. 
While this is not a problem in those with normal renal function, in patients 
with significantly impaired function, higher serum levels of tetracycline may 
lead to azotemia, hyperphosphatemia, and acidosis. 
Minocin IV, like other tetracycline-class antibacterials, can cause fetal harm 
when administered to a pregnant woman. The use of drugs of the tetracycline 
class during tooth development (last half of pregnancy, infancy, and 
childhood to the age of 8 years) may cause permanent discoloration of the 
teeth (yellow-gray-brown). Enamel hypoplasia has also been reported. 
All tetracyclines form a stable calcium complex in any bone-forming tissue. A 
decrease in the fibula growth rate has been observed in premature human 
infants given oral tetracycline in doses of 25 mg/kg every 6 hours. 
Results of animal studies indicate that tetracyclines cross the placenta, are 
found in fetal tissues, and can have toxic effects on the developing fetus (often 
related to retardation of skeletal development). Evidence of embryotoxicity 
has been noted in animals treated early in pregnancy. 
As with other antibacterial preparations, use of Minocin may result in 
overgrowth of nonsusceptible organisms, including fungi. 
Because Minocin IV contains magnesium, close monitoring is recommended; 
it should be used with caution in patients with heart block or myocardial 
damage. 
Minocin IV is contraindicated in individuals who have shown hypersensitivity 
to any of the tetracyclines or to any components of the product formulation. 
The safety monitoring practices employed by this protocol (i.e. physical 
examination, vital signs, 12-lead ECG, hematology, serum chemistry, 
urinalysis, and AE collection) are adequate to protect the subjects’ safety and 
should detect adverse events. 


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The approximate volume of blood planned for collection from each subject 
over the course of the study presents no undue risk to the subjects. 
There will be no direct health benefit for trial participants from receipt of 
study drug. An indirect health benefit to the healthy subjects enrolled in this 
trial is the free medical tests received at screening and during the study. 
A complete description of relevant risks of Minocin IV, including reported 
adverse reactions that have been observed in patients receiving tetracyclines, 
can be found in the Investigator’s Brochure Ed. 2 Addendum, 2017. 
5.3. Study Rationale 
The purpose of this study is to collect safety, tolerability and PK data on 
ascending dose regimens of Minocin IV. The safety, tolerability and PK data will 
support the compound as a potential clinical candidate in Europe and allow 
recommendations of dose levels to be used in future registration studies. 
Minocin IV is similar to other drugs developed in the era prior to the maturation 
of the field of pharmacodynamics, in that human doses were not systematically 
determined or optimized. An updated development program for Minocin IV 
would enable the availability of a new agent in the European Union (EU) to 
address highly resistant strains of Acinetobacter baumannii. The program will 
build on recently acquired information in preclinical studies and allow for 
optimization of the dosage regimen prior to use in controlled studies.  
The overall development strategy in the EU is summarized below: 
 Establish safety, tolerability, and PK of escalating doses of Minocin IV in 
normal subjects 
 Link PK data in human subjects with PK-PD efficacy targets in animal 
models of infection to select dosage regimen 
 Conduct a pathogen-directed clinical study of Minocin IV in infections 
due to Acinetobacter baumannii, assisted by the use of a rapid diagnostic 
test 
PK-PD and Dosing Strategy. Studies of minocycline in 2 animal models of 
infection have been completed and identified the 24h free (non-protein bound) 
minocycline plasma AUC: MIC ratio as the PK-PD index associated with 
antimicrobial effects. These findings are consistent with studies with other 
tetracyclines/glycylcyclines. Studies in lung models of infection in rats show that 
an AUC:MIC ratio of 11 is required for bacterial stasis and a ratio of 18 is 
required for a 1 log drop in bacterial counts; these data and the current approved 
dosage regimens are consistent with the CLSI and US FDA breakpoint of 4 ug/ml.  


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There has been interest in the potential clinical uses of higher doses of 
minocycline for its properties unrelated to its antimicrobial effects (Garrido-Mesa, 
2013), and resulted in studies of the pharmacokinetics and safety of intravenous 
minocycline at higher doses than those currently approved for treatment of 
infections.  In a Phase 1 study in subjects with acute traumatic spinal cord injury, 
52 subjects received IV minocycline in a dose escalation protocol (Casha, 2011).  
Treatment was given for 7 days (14 doses).  The first five patients received 200 
mg twice daily for 7 days.  Steady state minocycline concentrations were 4.2 
µg/mL within 48 hours.  Subsequent patients were treated with a loading dose of 
800 mg, with subsequent doses tapered by 100 mg every 12 hours until a dose of 
400 mg was reached; the dose of 400 mg every 12 hours was maintained through 
Day 7.  A mean steady-state serum minocycline concentration of 12.7 µg/mL was 
reported on this regimen.  Two subjects died in the study, one in the placebo 
group (multiorgan failure and acute respiratory distress syndrome at Day 20) and 
one in the minocycline group (narcotic drug overdose at 6 months).  The 
incidence of adverse events was not significantly different between the 
minocycline and placebo groups.  One subject on minocycline developed elevated 
liver enzymes that normalized after discontinuation of drug, but was 
asymptomatic.   
Sixty patients with acute ischemic stroke received total daily intravenous doses of 
up to 700 mg for 72 hours and serum PK data obtained (Fagan, 2010).  No dose-
limiting toxicities were observed.  The plasma concentrations and exposure to 
minocycline increased in proportion to dose and were well-tolerated with doses 
up to 10 mg/kg/day (highest tested), or approximately 3.5x the current maximum 
labelled IV dose in the US; the mean 24h AUC was in the high dose group 348 
mg-h/L. Adverse events were predominantly mild in severity, self-limiting, and 
were unrelated to minocycline dose.  The most commonly reported adverse events 
outside of the cardiovascular system were headache (10%), 
nausea/vomiting/diarrhoea (9%), and local infusion reactions (8%).  
The results of these studies indicate that doses of minocycline higher than those 
currently approved for the IV in the US (and oral in the US and EU) appear to be 
safe and well tolerated in humans.  Based on these data, the sponsor believes it is 
rational to investigate higher doses of minocycline to optimize PK-PD properties 
for treatment of serious gram-negative pathogens, particularly non-fermenting 
organisms such as Acinetobacter baumannii complex. 
This study is the first in the EU development program described above and will 
start with doses already approved in the US, namely 100 mg and 200 mg, in order 
to build a population PK model. Doses will be increased up to 600 mg if safety is 
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5.4. Study Population 
Healthy male and female volunteer subjects between 18 and 50 years of age, 
inclusive, will participate in the study. Six cohorts of approximately 10 subjects 
are planned. Each cohort should include at least three men and three women, with 
at least 1 man and 1 woman each receiving placebo. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. Primary Objective 
The primary objective is to assess the safety and tolerability of single and multiple 
intravenous doses of Minocin IV when administered to healthy adult subjects. 
6.2. Secondary Objective 
The secondary objective is to assess the pharmacokinetics of single and multiple 
intravenous doses of Minocin IV when administered to healthy adult subjects. 


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7. 
TRIAL DESIGN 
7.1. Type/Design of Trial 
This is a double-blind, randomized, placebo-controlled, single- and multiple 
ascending dose study of up to 5 doses/cohorts of Minocin IV. 
Each cohort will consist of 10 subjects (8 active drug and 2 placebo). 
Planned Cohorts: 
 Cohort 1: 100 mg* 
 Cohort 2: 200 mg* 
 Cohort 3: 300 mg 
 Cohort 4: 400 mg 
 Cohort 5: 500/300 mg 
 Cohort 6: 600/300 mg 
* Cohorts 1 and 2 may be run concurrently as they are the approved doses of 
minocycline IV in the US. Cohorts 3, 4, 5 and 6 will be run sequentially. 
 
Within each cohort, subjects will receive a single dose on Day 1, followed by 7 
days of multiple-doses (Days 4-10), followed by a single dose on Day 11. 
Subjects will be discharged from the clinic on Day 14 and follow-up phone call 
will occur on Day 17 (See Schedule of Events for details). 
 
Subjects are required to remain admitted in the research unit from the time of 
randomization until discharge on Day 14. 
 
Subjects that discontinue the study early are required to complete Early 
Termination procedures. 
 
Safety will be assessed throughout the study and serial blood and urine samples 
will be collected for the safety and PK assessment of Minocin IV. 
 
 
7.2. Study Endpoints 
The endpoints of this trial are:  
o Assess the safety and tolerability of single and multiple intravenous doses 
of Minocin IV when administered to healthy adult subjects. 
o Assess the pharmacokinetics of single and multiple intravenous doses of 
Minocin IV when administered to healthy adult subjects. 


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7.3. Measures to Minimize/Avoid Bias 
7.3.1. Blinded Study Where Pharmacist is Unblinded 
The study will be conducted using a double-blind design, with a placebo 
comparator. Specifics on how the blind for the study drug is maintained are 
provided in Section 9.4.  Allocation of treatment is not disclosed to the 
blinded study team and subject. Study drug will be prepared by an unblinded 
pharmacist (or qualified designee) and will be provided to the blinded team in 
such a way that the appearance, volume, and infusion rate is the same for both 
study groups. Unblinded pharmacists (and qualified designees) will be 
required by signature to keep the study personnel blinded and will be 
prohibited from performing any study duties other than prepare study drug 
and associated tasks (e.g., drug accountability, etc.). 


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8. 
SUBJECT POPULATION 
8.1. Number of Subjects  
Sixty subjects will be studied at one study center. Each randomized subject can be 
part of one cohort only, i.e. cannot be randomized twice. Subjects who drop-
out/are withdrawn before taking any study drug may be replaced at the discretion 
and agreement of the site and Sponsor. 
8.2. Inclusion Criteria 
Subjects must meet all of the following criteria in order to be eligible for the study: 
1. A signed informed consent form, the ability to understand the study conduct 
and tasks that are 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; 
2. Male or female between 18 and 50 years of age inclusive; 
3. Subject has a body mass index (BMI) ≥18 kg/m2 and ≤ 30kg/m2; 
4. Subject is non-smoker or smokes up to 5 cigarettes per day (or equivalent); 
5. Subject is in good health based on medical history and physical examination 
findings and has no clinically meaningful safety laboratory abnormalities 
(Hematology, blood chemistry, and urinalysis) or 12-lead ECG results, as 
assessed by the Principal Investigator (PI); 
6. Vital signs (BP, pulse and temperature) measured at screening/baseline must be 
within the following ranges: SBP ≥90 to ≤150 mm Hg, DBP ≥45 to ≤90 mm 
Hg; Heart Rate ≥ 45 to ≤90 bpm (taken after resting in a supine position for at 
least 5 minutes); 
7. Expectation that intravenous access will be sufficient to allow for ease of study 
drug infusion, and for all protocol required blood sampling to take place; 
8. Subject commits to remaining admitted in the research unit for the course of 
the study; 
9. Female subject is surgically sterile, postmenopausal: period of amenorrhea for 
at least 2 years, or if of childbearing potential, agrees to abstinence or to use at 
least 2 acceptable methods of birth control (e.g. prescription oral 
contraceptives, contraceptive injections, contraceptive patch, intrauterine 
device, barrier methods, etc.) or male partner sterilization alone, between the 
first dose (Day 1) and for 90 days after the completion of the study. 
8.3. Exclusion Criteria 
Subjects who meet any of the following exclusion criteria at baseline will not be 
enrolled in the study: 


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1. Has any condition, including findings in the medical history or in pre-study 
assessments that constitutes a risk or a contraindication for the participation in 
the study or completing the study; 
2. Positive breath test for alcohol and/or positive urine test for drugs of abuse at 
Screening and Day -1 Visits; 
3. Has a history or presence of alcohol/drug abuse within 2 years. Alcohol abuse 
is defined as regularly consuming >3 units/day (21 units per week for men), >2 
units/day (14 units/week) for women. A unit is 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); 
4. Subject shows positive hepatitis B surface antigen (HBsAg), hepatitis C virus 
antibodies (anti-HCV), or human immunodeficiency virus (HIV) I/II antibodies 
and antigen tests; 
5.  Subject has active or ongoing candida infection; 
6. Blood or plasma donation within past 2 months; 
7. Females who are pregnant or nursing or who have a positive pregnancy test 
result at the Screening or Day -1 Visits; 
8. Males who are 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 (i.e. condom with spermicide, where locally available); 
9. Presence of known raised intracranial pressure; 
10. Use of retinoids (e.g., Isotretinoin); 
11. History of significant hypersensitivity or allergic reaction to any of the 
tetracycline class of antibiotics or the components of those antibiotics; 
12. Receipt of any investigational medication or investigational device during the 
last 30 days prior to randomization; 
13. Treatment with any prescription, vitamins or OTC drugs, within 2 weeks or 
five half-lives, whichever is longer, or herbal nutritional supplements within 2 
weeks of screening, with the exception of acetaminophen/paracetamol for 
minor headache. Subjects will not be allowed to receive medications for the 
duration of the study (except the abovementioned 
acetaminophen/paracetamol). Birth control or other hormone replacement is 
also permitted as long as it has been taken at a stable dose for at least three 
months before the Screening Visit and remains stable for the duration of the 
study; 
14. A  QTcF of >480 msec; 
15. Calculated creatinine clearance less than 50 mL/min (Cockcroft-Gault method) 
at screening or check-in (Day -1); 


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16. Unable or unwilling, in the judgment of the investigator, to comply with the 
protocol; 
17. 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; 
18. Prior enrollment in any minocycline study including prior cohorts in this trial. 
 
8.4. Withdrawal Criteria 
All subjects have the right to withdraw at any point during treatment without 
prejudice. The investigator can discontinue any subject at any time if medically 
necessary. It will be documented whether or not each subject completed the 
clinical study. If for any subject, study treatment or observations were 
discontinued, the reason will be recorded and the Sponsor should be notified 
promptly. Reasons that a subject may discontinue participation in a clinical study 
are considered to constitute one of the following: 
1. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the PI that continued 
participation is not in the best interest of the subject, that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements 
of the protocol. 
2. Subject's decision to withdraw. 
3. Requirement of prohibited concomitant medication. 
4. Physician’s decision. 
5. Subject’s failure to comply with protocol requirements or study related 
procedures. 
6. Lost to follow-up. 
7. Termination of the study by the Sponsor, or designee, ARO or regulatory 
authorities. 
It is imperative to obtain complete follow-up data for all subjects whether or not 
they receive their assigned treatment or have discontinued study drug. All data 
collected up until the time of subject withdrawal is to be entered into the eCRF. In 
addition, every attempt should be made to collect follow-up information except 
for those subjects who specifically withdraw consent for release of such 
information. All procedures and laboratory specimens or tests requested for 
evaluation following administration of the study drug should be carried out when 
possible whether or not a subject continues to receive treatment according to the 
protocol. 


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The clinical report will include reason(s) for subject withdrawals as well as details 
relevant to the subject withdrawal. If a subject is withdrawn from the trial prior to 
study completion, the subject will undergo all procedures scheduled for study 
completion (end of study evaluations) as appropriate (see Section 10.2.14). Any 
subject withdrawn due to an AE (whether serious or non-serious) or clinically 
significant abnormal laboratory test values will be evaluated by the PI or a 
monitoring physician and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the PI. 
Subjects who drop-out/are withdrawn may be replaced at the discretion and 
agreement of the site and Sponsor. Randomization numbers for replacements will 
be generated by Biostatistics. 


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9. 
TREATMENT OF SUBJECTS 
9.1. Study Medications 
Each subject will receive a single dose of Minocin IV or placebo, followed by 
multiple doses of Minocin IV or placebo, given q12h (+/- 1 h) over 60 minutes in 
0.9% Sodium Chloride Injection (referred to as Normal Saline for the remainder 
of the document) for 7 days and then a single dose on day 11. 
9.1.1. Minocin IV 
Minocin IV will be supplied as a sterile lyophilized powder in single-use 10 
mL glass vials. Each vial contains 108 mg of minocycline hydrochloride 
equivalent to 100 mg of minocycline. 
Each dose will be reconstituted and prepared in Sodium Chloride Injection 
USP bag per the Table below and administered as a constant rate IV infusion 
over 1 hour via a single dedicated peripheral venous line. Details of Minocin 
IV preparation and administration are included in the study Pharmacy Manual. 
9.1.2. Placebo 
Sodium Chloride Injection USP (placebo) is administered at a rate and volume 
matching the rate and volume of Minocin IV for each respective Cohort. 
Dosing is to the same schedule as subjects randomized to Minocin IV. Details 
of placebo preparation and administration are included in the study Pharmacy 
Manual. 
9.1.3. Packaging and Labeling 
Minocin IV will be provided by the Sponsor. Infusion bags of normal saline 
will be provided by the study site pharmacy. 
Medication labels will comply with regulatory requirements. 
9.1.4. Storage 
Minocin IV will be stored in a secure area at a controlled room temperature of 
20° to 25°C. Once diluted into an IV bag, Minocin IV may be stored at either 
room temperature for up to 4 hours or refrigerated at 2 to 8C for up to 24 
hours. Access should be strictly limited to the study pharmacists or designees. 
Normal Saline should be stored per the manufacturer’s instructions. Normal 
saline used as placebo should be treated the same as Minocin IV once it leaves 
the pharmacy to ensure blinding is maintained (e.g., refrigerate, etc.).   
Further details of Minocin IV and normal saline storage can be found in the 
Pharmacy Manual. 


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9.1.5. Accountability 
The investigator or designee must maintain an inventory record of Minocin IV 
received and all doses administered to assure the regulatory authorities and the 
Sponsor that the study drug will not be dispensed to any person who is not a 
subject under the terms and conditions set forth in this protocol. Study drug 
accountability forms and specific instructions can be found in the Pharmacy 
Manual. 
The Minocin IV supplied for use in this study is to be prescribed only by the 
Principal Investigator or designated sub-investigators and may not be used for 
any purpose other than that outlined in this protocol. 
During the study all used Minocin IV vials will be kept until the monitor has 
reviewed the accountability records. 
All unused Minocin IV will be destroyed on site once it has been inventoried 
and the monitor has reviewed the accountability records. In the event that 
Minocin IV needs to be returned for any other reason, the site will receive a 
written request listing the lot number(s) to be returned and the reason for the 
return request. 
9.1.6. Product Complaints 
Sites are required to report any product complaints to MDCO immediately but 
no later than 24 hours from the time of awareness, by phone or e-mail as 
follows: 
United States of America: +1-888-977-6326 
Contact information for all other geographic areas: 
www.themedicinescompany.com/contact/global-medical-info 
Email: Medical.information@themedco.com 
 
Product Complaint: Is defined as any written, electronic, or oral 
communication that alleges deficiencies related to the identity, durability, 
reliability, quality, safety, effectiveness or performance of a product, after it is 
released for distribution (EU DIR 2001/83/EC). (Derived from Ref US 21 
CFR 211.198). 
There are two types of Product Complaints: Technical Quality Complaints: 
A report of dissatisfaction with product with regard to its efficacy, strength, 
integrity, purity, or quality; thus a potential failure to meet product 
specifications. Preference Complaints: A report of dissatisfaction with 
service, delivery, packaging or other preference. 


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Technical Quality Complaint: A report of dissatisfaction with the product 
with regard to its efficacy, strength, integrity, purity, or quality; thus a 
potential failure to meet product specifications. Examples include: 
 An indication that there is an unexpected physical change in the drug 
product such as discoloration, change in shape of the drug product, 
presence of particulates or any other physical change that might 
indicate contamination, a manufacturing defect or any other event that 
might indicate a compromise in product quality. 
 An indication that the content does not meet its labeled volume, count, 
etc. 
 An indication that there is an unexpected physical change in any part 
of the container (this includes the bottle, any part of the seal, the cap or 
the label). 
 An indication that the product is mislabeled. 
 An indication that there is an unexpected physical change of the 
product or container once the product is diluted or reconstituted (the 
container includes the vial, bag, IV line, syringe or any other item that 
is in contact with the product). 
 An indication that the product is falsified, tampered with or 
adulterated. 
 
9.2. Concomitant Medications 
All medications taken during the 14 days prior to dosing will be recorded and 
reviewed by the PI or their designee. 
9.2.1. Prohibited Concomitant Medications 
During the study, 2 grams per day or less of acetaminophen/paracetamol may 
be administered orally at the discretion of the PI or their designee for 
intercurrent illness or AEs. If needed on dosing day, 
acetaminophen/paracetamol should not be taken until at least 2 hours after 
dosing. 
Vitamin supplements will be prohibited for 14 days prior to Day 1 until 
discharge. 
All medication (other than study drug, acetaminophen/paracetamol or birth 
control and hormone replacement therapy) is prohibited during the study. If 


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drug therapy other than that specified by the protocol is taken, a joint decision 
will be made by the PI and Sponsor to continue or discontinue the subject. 
9.3. Restrictions 
Beverages containing alcohol should not be consumed 48 hours or less prior to 
Day -1 until the end of the study. 
Subjects that smoke more than 5 cigarettes per day will be excluded from the 
study. 
Subjects participating in strenuous exercise or sports as assessed by the PI will be 
excluded from the study. 
Extreme exposure to the sun or sunbathing has to be avoided, as well as the use of 
tanning devices (e.g. sunbed, solarium) from screening until 7 days after 
discharge. 
9.4. Blinding 
9.4.1. Blinding of study medications 
The study drug will be prepared by an unblinded pharmacist (or qualified 
unblinded designee) in a secure area where blinded staff are not present. Once 
prepared, the IV bags containing the study drug will be labeled without 
revealing the treatment. Additional steps may be required to ensure that the 
blinded staff do not become unblinded by the color of the IV solution (e.g., 
colored IV tubing, IV bag covers, etc.) which are described in detail in the 
study Pharmacy Manual. 
9.4.2. Method and Maintenance of Blinding 
This is a double-blind study, other than the unblinded statistician (or designee) 
who prepares the randomization list and the unblinded study pharmacist (and 
designee(s). All others will be blinded, including, but not limited to: PI, site 
staff, subjects, Sponsor and third party vendors. 
9.5. Unblinding 
One set of sealed, printed code break slips containing the randomization code for 
each subject will be supplied. 
Breaking of the blind is expressly forbidden except in the event of a medical 
emergency where the identity of the drug must be known to properly treat the 
subject or to assess the stopping rules. 
In  the  event  of  a  medical  emergency,  it  is  requested  that  the  investigator  make 
every effort to contact the study  Medical Monitor or designee prior to breaking 
the blind. If breaking the blind is required because of a medical emergency, the 


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treatment identity would be  revealed  for that subject only.  In the event  that the 
emergency is one in which it appears that the other subjects may be at imminent 
risk, the blind may be broken for all subjects dosed at that dose level. 
In  all  cases  where  the  blind  is  broken,  the  investigator  should  record  the  date, 
reason for blind breaking and sign his/her name. 
At  the  end  of  the  study,  the  envelopes  will  be  reviewed  by  the  sponsor  at  a 
designated unblinded monitoring visit. 
The study will be unblinded at the end of the study post clinical database lock or 
as needed after the completion of a cohort for review of AEs. 


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10. 
SCHEDULE AND SEQUENCE OF PROCEDURES 
The Study Schematic Tables are outlined in Sections 2 and 3, which summarize 
the study assessments by time point. 
10.1. Informed consent 
Prior to any study-related activities, an Informed Consent Form (ICF) and subject 
information sheet, if applicable, approved by a regional ethical or institutional 
review board must be signed and personally dated by the subject. The format and 
content of the ICF and subject information sheet must be agreed upon by the 
Principal Investigator(s), appropriate regional ethical or institutional review 
board, and MDCO, or designee. The subject’s original signed and dated ICF 
(together with any subsequent amended versions approved by the regional ethical 
or institutional review board) must be retained by the investigator in the subject’s 
file. A copy of the original signed and dated ICF and subject information sheet 
must be given to the subject. 
10.2. Subject Confinement 
Subjects will be admitted to the study on Day 1 and will remain in the research 
unit through completion of all scheduled procedures on Day 14. Subjects who 
leave the research unit prior to Day 14 will be considered Early Terminations 
unless permission is granted by the PI and sponsor due to extraordinary 
circumstances. 
10.2.1. Screening Period (Days -28 to -1) 
Once consent is obtained, screening may begin within 28 days prior to first 
dosing. The subject informed consent form will be obtained prior to any study 
procedures being performed. Subjects will have to meet all eligibility criteria 
before being enrolled in the study. 
 
The following assessments/procedures will be performed at the screening 
visit:  
o Informed consent administered 
o Inclusion/exclusion criteria assessment 
o Medical history and Demographics will be recorded 
o Review of concomitant medications 
o Height, weight, and BMI calculated 
o Physical examination 


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o Vital signs: systolic and diastolic blood pressure, pulse, respiratory 
rate, and temperature 
o 12-lead ECG 
o Hematology, serum chemistry, and urinalysis 
o Urine drug/alcohol screen 
o Serum pregnancy test (women of childbearing potential only) 
10.2.2. Check-in Procedures (Day -1) 
Day -1 procedures should be completed within approximately 24 hours before 
dosing on Day 1 to obtain baseline values. Baseline data may be captured pre-
dose on Day 1 at the site’s discretion. 
Subject  eligibility  will  be  reviewed  for  each  subject  to  ensure  that  subjects 
remain eligible for the study since the Screening Visit. 
The following assessments/procedures will occur on Day -1: 
o Review of inclusion/exclusion criteria 
o Review of concomitant medications 
o Review medical history and demographics 
o Weight and BMI (calculated using height from Screening) 
o Physical examination 
o Vital  signs:  systolic  and  diastolic  blood  pressure,  pulse,  temperature 
and respiratory rate 
o 12-lead ECG (performed in triplicate) 
o Hematology, serum chemistry, and urinalysis collection 
o Urine drug screen 
o Alcohol screen  
o Serum pregnancy test (women of childbearing potential only) 
10.2.3. Randomization (Day 1) 
Randomization  should  only  occur  once  subject  eligibility  is  confirmed  and 
after  all  screening  and  Day  -1  medical/physical  assessments  and  laboratory 
tests have been completed (with lack of exclusion criteria or contraindications 
to treatment identified). 
 
10.2.4. First Single-dose Treatment (Day 1) 
Within each cohort, subjects will receive a single dose of either study drug or 
placebo (prepared by an unblinded pharmacist or qualified designee) on Day 


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1.  
Day 1 Pre-Dose Assessments: 
o Ensure all baseline procedures noted in Section 10.2.2 (Day -1) have 
been completed within 24 hours of dosing 
o Urine pregnancy test (women of childbearing potential only) 
o Blood collection for pharmacokinetic assessment within 24 h of dosing 
o Urine collection for pharmacokinetic assessment within 24 h of dosing 
o Dose administration 
 
Day 1 Post-Dose assessments: 
o Vital signs at: 1, 3, and 6 h after the start of dosing 
o Blood  collection  for  pharmacokinetic  assessment  at:  1  h  (end-of-
infusion),  2,  4,  8,  12,18,  24,  36,  48  and  72  hours  after  the  start  of 
dosing (ongoing Days 1-4) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 
4-8, 8-12, 12-24*, 24-48 and 48-72 hours after dosing (ongoing Days 
1-4) 
o Urine collected will also be used to determine 24 h creatinine 
clearance 
o 12-lead  ECG  at  1  hour  (+/-10  minutes)  after  dosing/end  of  infusion 
(performed in triplicate) 
o Review of adverse events 
o Review of concomitant medications 
 
 
10.2.5. Day 2 Procedures 
The following procedures will occur on Day 2: 
o Vital signs, collected once in the morning: systolic and diastolic blood 
pressure, pulse, temperature and respirations 
o Hematology, serum chemistry, and urinalysis 
o Blood  collection  for  pharmacokinetic assessment  at:  1  h  (end-of-
infusion),  2,  4,  8,  12,  18,  24,  36,  48  and  72  hours  after  the  start  of 
dosing (ongoing Days 1-4) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 
4-8, 8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing Days 1-
4) 
o Review of adverse events 


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o Review of concomitant medications 
10.2.6. Day 3 Procedures 
The following procedures will occur on Day 3: 
o Vital signs, collected once in the morning: systolic and diastolic blood 
pressure, pulse, temperature and respirations 
o Blood  collection  for  pharmacokinetic assessment  at:  1  h  (end-of-
infusion),  2,  4,  8,  12,  18,  24,  36,  48  and  72  hours  after  the  start  of 
dosing (ongoing Days 1-4) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 
4-8, 8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing Days 1-
4) 
o Physical examination 
o Review of adverse events 
o Review of concomitant medications 
10.2.7. Day 4 Procedures 
The following procedures will occur on Day 4: 
o Vital  signs  before  and  at  1,  3,  and  6  h  after  the  start  of  the 
morning  dose  and  before  and  at  1  hour  after  the  start  of  the 
evening dose: systolic and diastolic blood pressure, pulse, 
temperature and respirations12-lead ECG: before and 1 h (+/-
10 minutes)/end of infusion after the start the first dose 
(performed in triplicate) 
o Dose administration q12 hours (+/- 1 h) (Note: the first dose on Day 4 
will  occur  once  the  72  h  post-  (Day  1)  dose  PK  collection  has  been 
completed) 
o Hematology, serum chemistry, and urinalysis:  approximately 4 hours 
after the start of the morning dose 
o Blood collection for pharmacokinetics assessment. Note: The 72-hour 
sample  for  Day  1  dosing  is  also  the  pre-dose  sample  for  the  Day  4 
morning dose. Samples are also taken at 1 h (end-of-infusion), 2, 4, 8, 
and 12 hours after the start of the Day 4 morning dosing (the 12-hour 
post-dose  PK  collection  should  occur  before  the  start  of  the  second 
infusion on Day 4). 
o Final  urine  collection  for  pharmacokinetics  assessment  of  the  Day  1 
dosing (this is the end of the Day 1 dosing collection period, 48-72 h. 
There is no requirement for Urine PK to be collected for the multiple-
dose period). 
o Review of adverse events 


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o Review of concomitant medications 
 
10.2.8. Days 5, 7, and 9 Procedures 
The following procedures will occur on Days 5, 7, and 9: 
o Vital signs before and at 1, 3, and 6 h after the start of the morning dose 
and before and at 1 hour after the start of the evening dose: systolic and 
diastolic blood pressure, pulse, temperature and respirations 
o 12-lead ECG: before and 1 h/end of infusion (+/-10 minutes) after the start 
of the morning (AM) dosing 
o Dose administration (q12h - +/- 1 h) 
o Physical examination (Day 9 only) 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.9. Days 6 and 8 Procedures 
The following procedures will occur on Days 6 and 8: 
o Vital signs before and at 1, 3, and 6 h after the start of the morning dose 
and before and at 1 hour after the start of the evening dose: systolic and 
diastolic blood pressure, pulse, temperature and respirations 
o 12-lead ECG: before and 1 h/end of infusion (+/-10 minutes) after the start 
of the morning (AM) dosing 
o Hematology,  serum  chemistry,  and  urinalysis:  approx.  4  hours  after  the 
start of the morning (AM) dose 
o Dose administration (q12h - +/- 1 h) 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.10. Day 10 Procedures 
The following procedures will occur on Day 10: 
o Weight and BMI (calculated using height from Screening) 
o Vital signs before and at 1, 3, and 6 h after the start of the morning dose 
and before and at 1 hour after the start of the evening dose: systolic and 
diastolic blood pressure, pulse, temperature and respirations 
o 12-lead ECG: before and 1 h/end of infusion (+/-10 minutes) after the start 


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of the morning (AM) dosing 
o Hematology,  serum  chemistry,  and  urinalysis:  approx.  4  hours  after  the 
start of the morning dose 
o Dose administration (q12h - +/- 1 h) 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.11. Second/Final Single-dose Treatment (Day 11) 
The following procedures will occur on Day 11: 
o Vital signs before and at 1, 3, and 6 h after the start of dose: systolic and 
diastolic blood pressure, pulse, temperature and respirations 
o 12-lead ECG: before and 1 h/end of infusion  (+/-10 minutes) after the start 
of dosing 
o Blood  collection  for  pharmacokinetics  assessment:  taken  before  the  Final 
Dose and at 1 h (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48 and 72 hours 
after the start of dosing (ongoing Days 11-14) 
o Urine collection for pharmacokinetic assessment pre-dose and during 
intervals: 0-4, 4-8, 8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing 
Days 11-14) 
o Dose administration 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.12. Day 12 Procedures 
The following procedures will occur on Day 12: 
o Vital  signs:  systolic  and  diastolic  blood  pressure,  pulse,  temperature  and 
respirations 
o Blood  collection  for  pharmacokinetics  assessment:  taken  before  the  Final 
Dose and at 1 h (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48 and 72 hours 
after the start of dosing (ongoing Days 11-14) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 4-8, 
8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing Days 11-14) 
o Review of adverse events 
o Review of concomitant medications 
 


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10.2.13. Day 13 Procedures 
The following procedures will occur on Day 13: 
o Vital  signs:  systolic  and  diastolic  blood  pressure,  pulse,  temperature  and 
respirations 
o Hematology, serum chemistry, and urinalysis 
o Blood  collection  for  pharmacokinetics  assessment:  taken  before  the  Final 
Dose and at 1 h (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48 and 72 hours 
after the start of dosing (ongoing Days 11-14) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 4-8, 
8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing Days 11-14) 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.14. Discharge (Day 14) 
Subjects will be discharged from the clinic on Day 14. Prior to discharge, the 
following procedures will occur: 
o Weight and BMI (calculated using height from Screening) 
o Physical examination 
o Vital  signs:  systolic  and  diastolic  blood  pressure,  pulse,  temperature  and 
respirations 
o 12-lead ECG 
o Hematology, serum chemistry, and urinalysis 
o Serum pregnancy test (women of childbearing potential only) 
o Blood  collection  for  pharmacokinetics  assessment:  taken  before  the  Final 
Dose and at 1 h (end-of-infusion), 2, 4, 8, 12, 18, 24, 36, 48 and 72 hours 
after the start of dosing (ongoing Days 11-14) 
o Urine collection for pharmacokinetic assessment during intervals: 0-4, 4-8, 
8-12, 12-24, 24-48 and 48-72 hours after dosing (ongoing Days 11-14) 
o Review of adverse events 
o Review of concomitant medications 
 
10.2.15. Follow-up Phone Call (Day 17)  
A  Day  17  follow-up  phone  call  will  be  performed  to  evaluate  safety  by  the 
assessment of adverse events and serious adverse events. A subject’s 
participation in the study is complete when: 


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o All procedures at the last study visit (Day 14) have been completed 
o All procedures for the follow-up phone call (Day 17) have been completed 
o All AEs/SAEs have been followed to resolution 
 
10.2.16. Early Termination 
An Early Termination Visit is required for any subject that discontinues the 
study prior to Day 14. All Day 14 visit procedures should occur during the 
Early Termination Visit, as well as the collection of any PK samples (if 
applicable). A follow-up phone call should occur approximately 3 days from 
the Early Termination Visit. 
 


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11. 
PROTOCOL ASSESSMENTS 
11.1. Assessment of Safety 
11.1.1. Data Review Meetings 
Intra-Cohort Data Review:  
For Cohorts 3-6, single dose safety data will be reviewed by the Medical 
Monitor and Principal Investigator on Day 3 prior to the start of the multi- 
dosing on Day 4. During the review, blinded safety data from the single 
dose infusions will be assessed and one of the following will be decided 
before the start of the Multiple Dose Phase on Day 4: 
o To continue with the Multi-dose phase as planned, 
o To continue with the Multi-dose phase and add additional safety 
evaluations, 
o To not continue with the Multi-dose phase. 
Between- Cohort Data Monitoring Committee Review: 
Safety data will be reviewed by the Data Monitoring Committee (DMC) 
following each cohort and prior to the start of the next cohort. 
After completion of cohorts 1 and 2, which may run concurrently, and prior 
to dosing of each cohort 3, 4, 5 and 6, the DMC Sponsor will review all 
pertinent blinded safety data (e.g., physical examinations, vital signs, 
electrocardiograms (ECGs), clinical laboratory tests, and AEs) from the 
preceding cohort to determine one of the following: 
o To continue with the next cohort as planned, 
o To continue with the next cohort and add additional safety 
evaluations, 
o To continue with the next cohort by adjusting the planned dose of 
Minocin IV, or 
o To not continue with the next cohort. 
11.1.2. Stopping Rules 
The study will be terminated if ≥ 2 subjects in a cohort meet any of the 
following criteria and the subject was determined to have received active 
drug after unblinding (see 9.5 Unblinding): 
o Has a drug related SAE 
o Experiences a drug related AE grade > 3 toxicity 


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A written statement fully documenting the reasons for study termination will 
be provided to the HREC/IEC. 
11.1.3. Adverse Events 
Subjects will be carefully monitored for adverse events by the investigator 
during the designated study period (see Section 12 for details). 
11.1.4. Body Mass Index (BMI) 
BMI will be calculated using the following equation: 
BMI= Weight (kg)/Height (m2) 
11.1.5. Vital Signs 
Vital signs assessments will include systolic and diastolic blood pressure, 
pulse, body temperature, and respirations. 
Subjects should be resting in a supine position for at least 5 minutes prior to 
and during vital signs measurements. 
A +/- 10 minute time window is permitted. 
11.1.6. Physical Exam 
Physical examinations include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, 
cardiovascular system, gastrointestinal system, neurological condition, 
blood and lymphatic systems, and the musculoskeletal system. A licensed 
physician will conduct the examinations. 
Physical examination may be performed at various unscheduled time points 
if deemed necessary by the investigator. 
11.1.7. ECG 
12-lead ECGs will be assessed. 
Triplicate 12-lead ECGs each separated by at least 1 minute will be taken at 
Day -1 and post- dose at Day 1. Triplicate 12-lead will also be taken at Day 
4 pre-dose and post-dose (for the morning dose). ECGs will be taken 
following resting in the supine position for 5 minutes. The average value for 
the triplicate will be utilized for assessing QTcF exclusion criteria. 
All subsequent post-dose ECGs will be single readings. However, if one of 
the following occurs, then the ECG will be repeated in triplicate (separated 
by at least 1 minute): 
 QTcF increase from baseline triplicate average > 30msec 


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 QRS duration > 130ms 
 PR interval > 240ms 
If the “recheck” triplicate’s average is still above these parameters, then the 
investigator shall be notified for decision on further action. 
The same model of ECG machine should be used for check-in and post-dose 
readings for all subjects. 
A +/- 10 minute time window is permitted, -1 hour for pre-dose assessment. 
ECGs will be interpreted and signed and dated by the PI, or qualified 
designee. The ECGs will be classified as normal, having a clinically 
insignificant abnormality (NCS), or having a clinically significant 
abnormality (CS). In addition, ECG parameters of ventricular rate, PQ or PR 
interval, QRS duration, and QT interval (corrected and uncorrected) will be 
noted on the eCRF. 
All CS findings will be recorded as AEs. 
11.1.8. Clinical Laboratory Tests 
Clinical laboratory tests will be conducted at the site’s local lab. Lab results 
and lab reports will be kept as source documents. Subjects will be required 
to fast for at least 4 hours before the clinical laboratory tests. Abnormal lab 
ranges must be documented as clinically significant or non-clinically 
significant by a study investigator and filed with the source documents. 
At a minimum the following lab tests should be performed at the designated 
time points: 
11.1.8.1. Hematology 
Hemoglobin, Hematocrit, White blood cell count (with automated 
differential), Red blood cell count, Platelet count, Prothrombin time 
(PT), Activated partial thromboplastin time (aPTT). 
11.1.8.2. Chemistry 
Blood urea nitrogen, Serum creatinine, Total bilirubin, Direct bilirubin, 
Alkaline phosphatase, Aspartate aminotransferase, Alanine 
aminotransferase, Albumin, Total protein, Glucose, Calcium, Chloride, 
Sodium, Magnesium, Potassium, Uric acid, Lactate dehydrogenase, 
Bicarbonate, Phosphorus. 


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11.1.8.3. Urinalysis 
Midstream urine sample analyzed by dipstick (Note: microscopic 
examination of sediment will only occur if a strong positive result is 
observed). 
11.1.8.4. Human Chorionic Gonadotropin (Pregnancy 
Test) 
Pregnancy tests are required for women of childbearing potential only. 
Serum pregnancy should be performed during Screening, Day -1 and 
14. Urine pregnancy test should be performed before dosing on Day 1. 
11.1.8.5. Urine Testing for Drugs of Abuse 
Amphetamines,  barbiturates,  benzodiazepines,  cannabinoids,  cocaine, 
methadone and opiates. 
11.1.8.6. Breath Alcohol Testing 
Breath alcohol test will be performed on all subjects. 
11.1.8.7. Creatinine Clearance 
Urine will be obtained to measure 24-hour creatinine clearance on Day 
1 only. Serum creatinine concentrations will also be measured from the 
clinical laboratory tests. 
11.1.9. Meals 
Standard meals will be provided uniformly to all subjects at approximately 1 
hour prior to dosing, and at approximately 4 and 9 hours after dosing on Day 
1 and Day 11. On all other study days, breakfast, lunch, dinner, and evening 
snacks will be served at appropriate times. 
Water will be allowed as desired at all times. To encourage urine 
production, subjects will be asked to drink ~240 mL of water at 2 hours after 
start of dosing on Days 1 and 11. 
11.2. 
Assessment of Efficacy  
Efficacy will not be assessed in this study. 
11.3. 
Assessment of Pharmacokinetics  
The PK sample collection times are all from the start of the study drug 
infusion. 


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11.3.1. Sampling and Processing 
For the PK blood samples, the following deviation windows from the actual 
sampling times are permitted: 
Nominal Time  
Reporting Standard 
0-4 h      
+/- 2 minutes 
>4 h      
+/- 5 minutes 
>12 h 
+/- 10 minutes 
After collection of the PK samples, blood will be centrifuged and plasma 
collected, and frozen. For specific collection and storage procedures, please 
refer to the Study PK Manual. 
11.3.2. Urine Sampling and Processing 
Urine PK samples will be collected at designated time points. To begin the 
0-4 h post-dose collection, subjects will void completely within 15 min prior 
to dosing. Subjects will be encouraged to void at the end of each collection 
interval. The time of each void should be documented. 
A +/- 20 minute time window is permitted following scheduled collection 
time. 
Subjects should be encouraged to drink water during the urine PK collection 
periods. 
Urine will be refrigerated during the collection intervals. At the end of each 
interval, total urine volume will be measured and recorded. For specific 
collection and storage procedures, please refer to the Study PK Manual. 


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12. ADVERSE EVENTS 
12.1. Definitions 
12.1.1. Adverse Event 
Adverse Event (AE): Any untoward medical occurrence in a patient or 
clinical trial subject administered a medicinal product and that does not 
necessarily have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal 
product. 
Planned hospital admissions and/or surgical operations for an illness or 
disease that existed before the study drug was given or the subject was 
randomized in a clinical study are not to be considered AEs. 
Adverse events or abnormal test findings will be followed until the event (or 
its sequelae) or the abnormal test finding resolves or stabilizes at a level 
acceptable to the Sponsor/Investigator. 
12.1.1.1. AE Severity 
The severity of an AE will be assessed by the investigator. 
The investigator should ensure that any subject 
experiencing an AE receives appropriate medical support 
until the event resolves. 
The investigator and/or sub investigator will classify the 
severity of AEs according to the current version of 
Common Terminology Criteria for Adverse Events 
(CTCAE) as follows: 
Grade 1 = mild 
Grade 2 = moderate 
Grade 3 = severe 
Grade 4 = life-threatening 
Grade 5 = death related to AE 
If a condition cannot be identified in the CTCAE, the 
following definitions will be used: 
Mild: asymptomatic or mild symptoms OR clinical or 
diagnostic observations only OR intervention not indicated. 


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Moderate: minimal, local or noninvasive intervention 
indicated OR limiting age appropriate instrumental 
activities of daily living (e.g., preparing meals, shopping 
for groceries or clothes, using the telephone, managing 
money, etc.). 
Severe or medically significant but not immediately life-
threatening: hospitalization or prolongation of 
hospitalization indicated OR disabling OR limiting self-
care activities of daily living (e.g., bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, not being bedridden). 
Life-threatening: urgent intervention indicated. 
12.1.1.2. Study Drug Causality 
The relationship of an AE to study drug will be assessed 
with consideration to the following criteria: 
 Temporal relationship to the initiation of study 
medication 
 Response of the event to withdrawal of study 
medication 
 AE profile of concomitant therapies 
 Clinical circumstances during which the AE occurred 
 Subject’s clinical condition and medical history 
Categorization of causality will be designated by the 
investigator as stated below: 
Reasonable possibility - There are facts (evidence) or 
arguments to suggest a causal relationship between the 
event and the IMP. 
No Reasonable possibility - There are few to no facts 
(evidence) or arguments to suggest a causal relationship 
between the event and the IMP. 
12.1.2. Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence 
that at any dose: 
o Results in death, 
o Is life-threatening, i.e. the subject was, in the opinion of the 
investigator, at immediate risk of death from the event as it 


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occurred (it does not include an event that, had it occurred in a 
more severe form, might have caused death), 
o Results in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject's body 
function/structure, physical activities and/or quality of life, 
o Requires in-subject hospitalization or prolongs hospitalization, 
o Is a congenital anomaly/birth defect, or 
o Is another medically significant event where medical and 
scientific judgement should be exercised in deciding whether 
other situations should be considered serious reactions, such as 
important medical events that might not be immediately life 
threatening or result in death or hospitalization but might 
jeopardize the patient or might require intervention to prevent 
one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or 
abuse. Any suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction. 
A distinction should be drawn between serious and severe AEs. 
Severity is an estimate or measure of the intensity of an AE, while 
the criteria for serious AEs are indications of adverse subject 
outcomes for regulatory reporting purposes. A severe AE need not 
necessarily be considered serious and a serious AE need not be 
considered severe. For example, nausea that persists for several 
hours may be considered severe nausea, but not an SAE. On the 
other hand, a myocardial infarction (MI) that may be considered 
minor could also be an SAE if it prolonged hospitalization. 
12.1.3. Medication Errors 
Medication error refers to any unintended error in the dosing and/or 
administration of the study drug as per instructions in the protocol. 
Medication errors generally fall into 4 categories as follows: 
o wrong study drug 
o wrong dose (including dosing regimen, strength, form, 
concentration, amount); 
o wrong route of administration; 
o wrong patient (i.e. not administered to the intended patient) 


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Medication Errors include occurrences of overdose and under dose 
of the study drug, and abuse and misuse. 
Overdose: Unintentional administration of a quantity of the study 
drug given per administration or per day which is above the 
maximum recommended dose according to the reference safety 
information or protocol for the study drug. This also takes into 
account cumulative effects due to overdose. 
Under dose: Unintentional administration of a quantity of the study 
drug given per administration or per day which is under the 
minimum recommended dose according to the reference safety 
information or protocol. 
Abuse of a medicinal product: Persistent or sporadic, intentional 
excessive use of medicinal products which is accompanied by 
harmful physical or psychological effects. 
Misuse: Intentional and inappropriate use of a study drug not in 
accordance with the prescribed or authorized dose, route of 
administration, or not within the legal status of its supply. 
12.1.4. Adverse Event of Special Interest (AESIs) 
An adverse event of special interest (serious or non-serious) is one of 
scientific and medical concern specific to the Sponsor’s study drug 
or program, which warrants ongoing monitoring and rapid 
communication by the investigator to the sponsor. Such an event 
might warrant further investigation in order to characterize and 
understand it. 
There are no AESIs identified for the study drug Minocin IV in this 
protocol. 
12.1.5. Special Situations 
Special Situations is a comprehensive term that encompasses 
safety information related to products for which global 
regulations require collection, evaluation, and/or reporting to 
regulatory authorities. 
Additional special situations not previously defined include the 
following: 
o Suspected transmission via a medicinal product of an 
infectious agent 
o Drug interactions 
o Occupational exposure 


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12.2. 
Procedure for Non-Serious Adverse Event Recording 
All non-serious AEs that occur between first administration of study 
medication and the completion of the Day 17 follow up must be assessed 
and recorded on the source documents and eCRF, regardless of causal 
relationship to the study drug. 
12.3. 
Procedure for Serious Adverse Event Reporting 
Note: This procedure may need also to be followed for reporting Special 
Situations. 
All SAEs that occur between first administration of study medication and 
the completion of the Day 17 follow up must be reported to the Sponsor’s 
Global Pharmacovigilance Department (GPV) within 24 hours of awareness 
of the event using the provided study specific SAE Report Form. In addition 
to completing the SAE Report Form, each SAE must be entered on the 
appropriate page of the eCRF. 
When death occurs with an SAE, the cause of death must be reported as an 
SAE. “Fatal” will be reported as the outcome for these events. 
The investigator must assess the causality for each SAE. 
The Sponsor will contact the investigator, if necessary, to clarify any of the 
event information. The investigator should provide any follow-up 
information for the event to the Sponsor on an updated SAE report form as 
soon as it becomes available. 
If the investigator is notified of a SAE that occurs post-study period, that he 
or she wishes to report to the Sponsor (e.g., an event suspected to be 
causally related to study drug), the event should be reported through the 
process described above. 
Where appropriate, if required by local regulations or procedures, the 
investigator should report these events to the Ethics Committee (EC) and/or 
national regulatory authority in addition to the Sponsor. 
12.4. 
Procedure for Medication Error Reporting for Study 
Drugs 
Medication errors with or without an associated AE need to be recorded as 
medication errors in the eCRF as described in Section 12.1.3. 
Medication errors with an associated SAE need to be recorded as medication 
errors in the eCRF and reported to the Sponsor’s Global Pharmacovigilance 
Department as described in Section 12.3. 


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A mis-dosing protocol deviation (refer to Section 16.2) would need to be 
reported as a medication error if it was an “unintended error” as defined in 
Section 12.1.3. 
12.5. 
Procedure for Reporting Adverse Events of Special 
Interest (AESI’s) 
There are no AESIs identified for the study drug, Minocin IV, in this 
protocol. 
12.6. 
Procedure for Reporting Pregnancies/Lactation 
Exposure 
Occurrences of pregnancy/lactation exposure in a study subject or study 
subject’s partner should be reported within 24 hours using the 
Pregnancy/Lactation Exposure Reporting form. In cases where a 
pregnancy/lactation exposure occurs with a Serious Adverse Event, the 
Serious Adverse Event reporting form should be used to report the SAE and 
the Pregnancy Reporting form should be used to report the pregnancy. 
When a pregnancy occurs without any concurrent SAE, the Pregnancy 
Reporting form may be submitted alone. The pregnancy must be followed 
through to outcome of pregnancy. Any pregnancy discovered from study 
drug administration until 30 days after last dose needs to be reported. 
12.7. Procedure for Reporting Special Situations 
If there is an occurrence of a Special Situation event, defined in 12.1.5, 
report this occurrence to the Sponsor as per Section 12.3, Procedure for 
Serious Adverse Event Reporting. Note: The Special Situations event does 
not need to be serious to be reported on the SAE Report form. 
12.8. Procedure for SUSARs 
Suspected unexpected serious adverse reactions (SUSAR or EIGI), new 
Safety Development or the requirement of Urgent Safety Measures will be 
reported to the Central Committee on Research Involving Human Subjects 
(CCMO) in accordance with agency timelines.  


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13. DATA COLLECTION 
An electronic data capture (EDC) system will be used for this trial. The IT 
infrastructure and data management staff will be supplied by CTC Cologne. All 
users will be trained on the technical features of the EDC by performing an 
eLearning program prior to gaining access to the EDC. A data entry guideline will 
cover training of the content of the eCRF. A UserID/Password will be granted for 
eLearning. After successful completion of the training access to the study eCRF is 
granted. This UserID and Password is not to be shared amongst the study staff. All 
users must have a unique account to enter or review data. The eCRF should be 
filled out by the site continuously during study within 3 business days, basic safety 
data AEs, safety lab) within 1 business day. All subject data until day 14 within 1 
business day from day 14, until day 17 within 3 business days. Discrepancies and 
implausible values are queried by data management electronically. The trial site 
should answer these queries without unreasonable delay. 
It is not expected that the eCRF will serve as source for any data collected in this 
trial. If there is a reason for a site to do so, it must be approved by Sponsor and 
documented in the site files. 
Prior to the database being locked, the investigator or designee will review, approve 
and sign/date each completed eCRF. This signature serves as attestation of the 
Investigator’s responsibility for ensuring that all data entered into the eCRF are 
complete, accurate and authentic. After the end of the trial, a copy of the data will 
be provided to the site. This copy will contain the final data, an audit trail of activity 
on the data, and any queries and answers that were posted for data clarification. 


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14. STATISTICAL PLAN 
Detailed methodology for summary and statistical analyses of the data collected in 
this trial will be documented in a Statistical Analysis Plan (SAP). The SAP will be 
prepared by Institute of Medical Statistics, Informatics and Epidemiology (IMSIE) 
and agreed upon with the Sponsor. This document may modify the plans outlined in 
the protocol; however, any major modifications of the primary endpoints definition 
and/or its analysis will also be reflected in a protocol amendment. Additional 
statistical analyses other than those described in this section may be performed if 
deemed appropriate and included in the plan. 
14.1. Sample size 
Ten subjects per cohort are planned, hence n = 60 subjects in total. This sample 
size was selected based on previous experience attempting to minimize the 
number of subjects on study drug while obtaining sufficient PK data from 
different subjects to produce a good estimate of exposure. 
 
14.2. Randomization  
Subjects will be allocated to Minocin IV or placebo arm based on permuted 
blocks of varying length after written informed consent. The randomization 
will be stratified by sex. A randomization list for each cohort is provided to 
the pharmacy by the statistician. At the time of inclusion (day 1 of each 
cohort) the pharmacist assigns treatment according to the randomization list 
to the subjects indicated by the investigator 
Within each cohort, 8 subjects will receive Minocin IV (at least 2 male and 
2 female) and 2 placebo (1 male and 1 female). Based on the study center’s 
capabilities, subjects in Cohorts 1 and 2 may be run concurrently where 
subjects are randomly assigned to receive either 100 mg, 200 mg Minocin 
IV or placebo. 
In case any randomized subject needs to be replaced (see section 8.4), the 
replacement subject gets the treatment (kit) as already assigned. 
14.3. General Statistical Considerations and Definitions 
14.3.1. General Statistical Methods 
Descriptive statistical analyses will be performed. Number of 
subjects (n), arithmetic mean, standard deviation (SD), median, first 
quartile (Q1), third quartile (Q3), minimum (min) and maximum 
(max) will be given for quantitative variables. Absolute and relative 


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frequencies are given for qualitative variables. If variables are 
measured over time, each time point will be summarized. Summaries 
of the number and frequency and/or raw data listings of AEs will be 
presented. 95% confidence intervals will be given where reasonable. 
No interim analysis is planned. 
14.3.2. Analysis Population 
The following populations will be used for data analyses and/or 
presentation. 
14.3.2.1. Intent-to-Treat (ITT) Population  
All subjects randomized into the trial. Treatment 
classification will be based on the randomized treatment. 
14.3.2.2. Modified Intent-to-Treat (mITT) Population 
All ITT subjects who receive at least one dose of study 
drug. 
14.3.2.3. Pharmacokinetics (PK) Population 
All subjects who have any valid samples measured for 
study drug levels. This will be used for PK analysis (on an 
as-treated basis). 
14.3.2.4. Per-Protocol (PP) Population 
All mITT subjects who received their assigned study drug 
without major protocol violations. The PP population will 
be finalized during a treatment-blind data review before 
database lock. 
14.3.2.5. Safety Population 
All subjects who received at least one dose of study drug. 
Treatment classification will be based on the actual 
treatment received. This will be the primary population for 
the safety analyses. 
14.3.3. Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and 
will be excluded from the associated analysis. 


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14.4. Statistical Analyses 
14.4.1. Demographic and Background Characteristics 
Subject demographics and baseline characteristics will be 
summarized descriptively by treatment group using ITT, mITT, PK, 
PP, and safety populations. 
14.4.2. Study Drug and Concomitant Medications 
Listings and frequency counts of each prior (pre-baseline) 
medication and concomitant (baseline or later) medication will be 
provided by treatment. Medications will be coded using the most 
updated version of the WHO Drug Dictionary available (e.g. version 
WHODDE DEC. 1, 2015 or later). 
14.4.2.1. Adverse Events 
The MedDRA dictionary will be used for coding adverse events 
(AEs). The current version will be used when coding is started. 
All AEs are listed by subject with severity, relationship to study 
drug, cohort (dose), treatment. 
The number (percentage) of subjects reporting AEs and the total 
number (percentage) of AEs will be tabulated by each preferred 
term, system-organ class, severity, relationship to study drug, cohort 
(dose), treatment. AE analysis is done for Safety Population. 
14.4.3. 
Laboratory Tests 
Laboratory values will be summarized descriptively by treatment 
group and cohort, including changes and percent changes from 
baseline at each time point. Analyses will also be performed for each 
lab parameter by treatment group for incidence rates of potentially 
clinical significant (PCS) values for subjects without PCS value at 
baseline. 
Numerical values of laboratory parameters from different (if any) 
local laboratories with different units and normal ranges (if any) will 
be converted to the conventional units and normalized to a standard 
set of reference/normal ranges. The normalization process will be 
performed and separated by each of the laboratory parameters. A 
shift analysis by normal range will be done which counts the number 
of patients with a low, normal or high value at baseline and a low, 
normal or high value post baseline. 


Minocin® (minocycline) for Injection 
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 65 
14.4.4. 
Vital Signs 
Change and percent change from baseline in vital signs will be 
summarized descriptively at each scheduled time point by treatment 
group. 
14.4.5. 
ECGs 
PR, QRS, QT, and QTc intervals will be summarized descriptively. 
A normal-abnormal shift table will be presented for ECGs. ECG 
results will be classified using frequency counts for normal, 
abnormality that is not clinically significant (NCS), and clinically 
significant abnormality (CS) by dose cohort and time point of 
collection. 
14.4.6. 
Pharmacokinetic Parameters 
The plasma concentration-time data for Minocin IV will be analyzed 
by non-compartmental methods. Treatment arms (doses, placebo) are 
compared regarding plasma AUC0-t, AUC0-inf, Cmax, and Tmax. 
Individual as well as mean time-concentration profiles will be 
graphed. Statistical analysis of dose proportionality of exposure 
parameters will be performed. 
Urine PK parameters such as amount excreted and % dose excreted 
will be calculated from urinary excretion data. 
Detailed methods used and the results obtained will be included in a 
separate PK report. 


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Confidential 
 66 
15. RECORDS RETENTION 
Current EU Directives / Regulations and ICH guidelines collectively require that 
essential clinical trial documents (including case report forms) other than patient’s 
medical files must be retained for the following time period: 
 for at least 15 years after completion or discontinuation of the trial, 
 or for at least two years after the granting of the last marketing 
authorization in the European Community and when there are no pending 
or contemplated marketing applications in the European Community, 
 or for at least two years after formal discontinuation of clinical 
development of the study drug. 
Subject's medical files should be retained in accordance with applicable 
legislation and in accordance with the maximum period of time permitted by the 
hospital, institution or private practice. The documents can be retained for a 
longer period, however, if required by the applicable regulatory requirements or 
by agreement with the sponsor.  
To comply with these requirements, the Investigator will not dispose of any 
records relevant to this study without either (1) written permission from the 
Sponsor or (2) providing an opportunity for the Sponsor to collect such records. 
The Investigator shall take responsibility for maintaining adequate and accurate 
hard copy source documents of all observations and data generated during this 
study, including the hard copy or discs received from the sponsor of the final data. 
Such documentation is subject to inspection by the Sponsor or its agents, the 
Competent Authority, FDA and/or other regulatory agencies. 


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 67 
16. QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor has ethical, legal and scientific obligations to carefully follow 
this study in accordance with established research principles and applicable 
regulations. The Investigator, as part of his/her responsibilities, is expected 
to cooperate with the Sponsor (and designees) in ensuring that the study 
adheres to the protocol and ICH GCP requirements. 
As part of a concerted effort to fulfill these obligations, the Sponsor's (or 
Sponsor designees’) monitor will visit the center(s) during the study in 
accordance with the Monitoring Plan set forth for this trial. The Investigator 
will permit the Sponsor (and designees) to monitor the study as frequently 
as is deemed necessary and provide access to medical records/source 
documents to ensure that data are being recorded adequately, that data are 
verifiable and that protocol adherence is satisfactory. 
16.1. Auditing 
The Sponsor (and designees) may conduct audits at the study center(s). 
Audits will include, but not be limited to, study drug supply, presence of 
required documents, the informed consent process, and comparison of 
eCRFs with source documents. The Investigator agrees to permit audits 
conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also inspect the Investigator during 
or after the study. The Investigator should contact the Sponsor (and 
designees) immediately if this occurs, and must permit regulatory authority 
inspections. 
16.2. Protocol Deviations 
This study will be conducted as described in this protocol, except for an 
emergency situation in which the protection, safety, and well-being of the 
subject requires immediate intervention, based on the judgment of the 
Investigator (or a responsible, appropriately trained professional designated 
by the Investigator). In the event of a significant deviation from the protocol 
due to an emergency, accident, or mistake, the Investigator or designee must 
contact the Sponsor (and designees), or their agent, at the earliest possible 
time by telephone. This will allow an early joint decision regarding the 
subject’s continuation in the study. The Investigator and the Sponsor will 
document this decision. The EC will be informed of all protocol changes by 
the Investigator in accordance with the EC established procedure. No 
deviations from the protocol of any type will be made without complying 
with all the EC established procedures. 


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 68 
The following Protocol Deviations will require additional information in the 
eCRF explaining why the deviation occurred and what will be done to 
prevent it from re-occurring: 
 Inclusion criteria violation 
 Exclusion criteria violation 
 Dosing errors 
 Unintentional unblinding 


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 69 
17. ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s 
standard operating procedures and/or guidelines, the United States Food and Drug 
Administration (FDA) regulations, the International Conference on Harmonization 
(ICH) GCP guidelines, the Declaration of Helsinki and other local regulations, as 
applicable. 
17.1. Informed Consent 
Written informed consent will be obtained from all subjects before any 
study-related procedures (including any pre-treatment procedures) are 
performed. The Investigator(s) has both ethical and legal responsibility to 
ensure that each subject (and their guardian or legally authorized 
representative) being considered for inclusion in this study is given a full 
explanation of the protocol. This shall be documented on a written informed 
consent form, which shall be approved by the same EC responsible for 
approval of this protocol. Each informed consent form shall include the 
elements required by ICH, Part E6, Section 4.8 and any applicable local 
regulations. The Investigator agrees to obtain approval from the Sponsor of 
any written informed consent form used in the study, preferably prior to 
submission to the EC. 
Once the appropriate essential information has been provided to the subject 
and fully explained by the Investigators (or a qualified designee) and it is 
felt that the subject understands the implications of participating, the subject 
and the Investigator (or designee) shall sign the EC-approved written 
informed consent form. The subject shall be given a copy of the signed 
informed consent form, and the original shall be filed appropriately, 
according to the institution. A second copy may be filed in the subject's 
medical record, if allowed by the institution. 
17.2. Institutional Review Board/Ethics Committee 
This protocol, the written informed consent form and any materials 
presented to subjects shall be submitted to the EC identified with this 
responsibility. Notification in writing of approval must come from the EC 
chairman or secretary, to the Investigator, either as a letter or as a copy of 
the appropriate section of the EC meeting minutes where this protocol and 
associated informed consent form were discussed. The Investigator will not 
participate in the decision. If the Investigator is an EC member, the written 
approval must indicate such non-participation in the voting session. The 
Investigator will submit status reports to the EC as required by the 


Minocin® (minocycline) for Injection 
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The Medicines Company 
Confidential 
 70 
governing body. The EC must be notified by the Investigator in writing of 
the interruption and/or completion of the study; the Investigator must 
promptly report to the EC all changes in research (protocol amendments) 
and will not make such changes without EC approval, except where 
necessary to eliminate apparent immediate hazards to human subjects. In 
cases where it is necessary to eliminate immediate hazards to subjects, the 
EC must then be notified of the change as per local requirements. The 
Investigator is required to maintain an accurate and complete record of all 
written correspondence to and received from the EC and must agree to share 
all such documents and reports with the Sponsor. 


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Confidential 
 71 
18. CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and 
must not be disclosed to any persons not directly concerned with the study without 
written prior permission from the Sponsor. However, authorized regulatory officials 
and Sponsor personnel will be allowed full access to the records. All medications 
provided and subject bodily fluids and/or other materials collected shall be used 
solely in accordance with this protocol, unless otherwise agreed to in writing by the 
Sponsor. 
Only unique subject numbers in eCRFs will identify subjects. Their full names may, 
however, be made known to a product regulatory agency or other authorized official 
if necessary. 
With respect to the clinical trial data that is received from countries in the European 
Economic Area and Switzerland, MDCO has certified adherence to the US-EU and 
the US-Swiss Safe Harbor Principles. 


Minocin® (minocycline) for Injection 
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 72 
19. INVESTIGATOR AGREEMENT 
I have read and understand the protocol (including the Investigator’s Brochure) and 
agree that it contains all the ethical, legal and scientific information necessary to 
conduct this study. I will personally conduct the study as described. 
I will provide copies of the protocol to all physicians, nurses and other professional 
personnel responsible to me who will participate in the study. I will discuss the 
protocol with them to assure myself that they are sufficiently informed regarding 
Minocin IV, safety parameters and the conduct of the study in general. I am aware 
that this protocol must be approved by the Ethics Committee (EC) responsible for 
such matters in the Clinical Study Facility where Minocin IV will be tested prior to 
commencement of this study. I agree to adhere strictly to the attached protocol. I 
understand that this EC approved protocol will be submitted to relevant regulatory 
authorities by the Sponsor, as appropriate. I agree that clinical data entered on case 
report forms by me and my staff will be utilized by the Sponsor in various ways 
such as for submission to governmental regulatory authorities and/or in 
combination with clinical data gathered from other research sites, whenever 
applicable. I agree to allow Sponsor monitors and auditors full access to all medical 
records/source documents at the research facility for subjects screened or 
randomized in the study. 
I agree to provide all subjects with informed consent forms, as required by 
government and ICH regulations. I further agree to report to the Sponsor any 
adverse experiences in accordance with the terms of this protocol, ICH guideline, 
Part E6, Section 4.11 and applicable local regulations. 
 
 
Principal Investigator  (Signature) 
 
Date 
 
Principal Investigator  (Printed Name) 
 
Protocol Version: 
Original Version 
 
 
Institution Name 
 
 


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20. REFERENCES 
Antibiotic Resistance Threats in the United States. Centers for Disease Control and 
Prevention (CDC). 2013. 
Casha, S. et al. Results of a phase II placebo-controlled randomized trial of 
minocycline in acute spinal cord injury. Brain 135, 1224-1236 (2012). 
Fagan, S. C. et al. Minocycline to improve neurologic outcome in stroke (MINOS): a 
dose-finding study. Stroke 41, 2283-2287 (2010). 
Garrido-Mesa, N, A Zarzuelo and J Gálvez. Minocycline: far beyond an antibiotic. 
British Journal of Pharmacology 2013; 169: 337-352. 
Generating Antibiotic Incentives Now (GAIN) Act, United States, 2012. 
Memo/08/788, European Commission Press Release Database, 15 Dec 2008. 
MINOCIN® (minocycline) for Injection 100 mg/vial [US Prescribing Information]. 
The Medicines Company; Parsippany, NJ. April 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050444s049lbl.pdf. 
Accessed 1 February 2016. 
Minocin IV Investigator’s Brochure, Edition 2 Addendum, October 2017. 
MINOCIN® MR 100 mg Modified Release Capsules [Summary of Product 
Characteristics]. Meda Pharmaceuticals; Bishop’s Stortford, UK. March 2014. 
Available at: http://www.medicines.org.uk/emc/medicine/21139. Accessed 1 
February 2016. 
Minocycline Tablets 100 mg [Summary of Product Characteristics]. Actavis UK Ltd; 
Devon UK. August 2011. Available at: 
http://www.medicines.org.uk/emc/medicine/24177. Accessed 1 February 2016. 
Munoz-Price LS, Weinstein RA. Acinetobacter Infection. New Engl J Med. 
2008;358:12. 
Shlaes DM, Sahm D, Opiela C et al. The FDA reboot of antibiotic development. 
Antimicrobial Agents and Chemotherapy. 2013;57:4605-07. 

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Minocin 701  
Statistical Analysis Plan 
Page 3 of 29 
SAP_Minocin_701_V03 
 
V03 
Content 
1 
Background ....................................................................................................................... 4 
1.1 
Trial objective ............................................................................................................. 4 
1.2 
Trial design ................................................................................................................ 4 
1.3 
Assessment of Safety ................................................................................................ 7 
1.4 
Timing of Analyses ..................................................................................................... 7 
2 
Analysis populations ......................................................................................................... 8 
2.1 
Definitions .................................................................................................................. 8 
2.2 
Application ................................................................................................................. 8 
2.3 
Major protocol violations / Withdrawals ...................................................................... 8 
3 
Trial centers ...................................................................................................................... 8 
4 
Analysis variables ............................................................................................................. 9 
4.1 
Demography and baseline characteristics ................................................................. 9 
4.2 
Variables for safety and tolerability analysis ............................................................ 11 
4.3 
PK Variables ............................................................................................................ 14 
5 
Handling of missing values and outliers .......................................................................... 15 
5.1 
Missing values ......................................................................................................... 15 
5.2 
Outliers ..................................................................................................................... 15 
6 
Statistical analyses / methods ......................................................................................... 15 
6.1 
Patient / Subject Disposition .................................................................................... 16 
6.2 
Demography and baseline characteristics ............................................................... 16 
6.3 
Prior or concomitant medication and diseases ........................................................ 16 
6.4 
Study drug administration ........................................................................................ 16 
6.5 
Exposition to treatment/Compliance ........................................................................ 16 
6.6 
Analysis of safety and tolerability ............................................................................. 17 
6.6.1 
Adverse events/Serious adverse events .......................................................... 17 
6.6.2 
Laboratory tests (Hematology, Chemistry, Urinalysis) ...................................... 18 
6.6.3 
Vital signs ......................................................................................................... 18 
6.6.4 
ECGs ................................................................................................................ 18 
6.7 
Pharmacokinetic analyses ....................................................................................... 18 
6.8 
Planned subgroup analyses ..................................................................................... 18 
6.9 
Interim analyses ....................................................................................................... 18 
7 
Deviations from the protocol ........................................................................................... 18 
8 
Interpretation of results ................................................................................................... 18 
9 
Data problems ................................................................................................................. 19 
10  Software .......................................................................................................................... 19 
11  References ...................................................................................................................... 19 
12  Appendices ..................................................................................................................... 20 
12.1 
Reference ranges of laboratory parameters ......................................................... 20 
12.2 
Planned tables ...................................................................................................... 22 
12.3 
Planned listings .................................................................................................... 26 
12.4 
Planned graphics .................................................................................................. 28 
12.5 
List of abbreviations ............................................................................................. 29 
 
 
 


Minocin 701  
Statistical Analysis Plan 
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SAP_Minocin_701_V03 
 
V03 
1 
Background 
1.1 
Trial objective 
The primary objective is to assess the safety and tolerability of single and multiple 
intravenous doses of Minocin IV when administered to healthy adult subjects.  
The secondary objective is to assess the pharmacokinetics of single and multiple intravenous 
doses of Minocin IV when administered to healthy adult subjects. 
1.2 
Trial design 
This is a double-blind, randomized, placebo-controlled, single- and multiple ascending dose 
study of up to 6 doses/cohorts of Minocin IV. 
Each cohort will consist of 10 subjects (8 active drug (at least 2 male and 2 female) and 2 
placebo (1 male and 1 female)). 
Planned Cohorts: 
 
Cohort 1: 100 mg* 
 
Cohort 2: 200 mg* 
 
Cohort 3: 300 mg 
 
Cohort 4: 400 mg 
 
Cohort 5: 500/300 mg 
 
Cohort 6: 600/300 mg 
* Cohorts 1 and 2 may be run concurrently as they are the approved doses of minocycline IV 
in the US. Cohorts 1/2, 3, 4, 5 and 6 will be run sequentially. Additional/replacement cohorts 
(e.g. due to dosing errors) will be presented as separate cohorts. 
Within each cohort, subjects will receive a single dose on Day 1, followed by 7 days of 
multiple-doses (Days 4-10), followed by a single dose on Day 11. Subjects will be discharged 
from the clinic on Day 14 upon having an EOS evaluation and follow-up phone call will occur 
on Day 17. 
Subjects are required to remain admitted in the research unit from the time of randomization 
(Day 1) until discharge on Day 14. Subjects that discontinue the study early are required to 
complete Early Termination procedures.  
Safety will be assessed throughout the study and serial blood and urine samples will be 
collected for the safety and PK assessment of Minocin IV. 
Adverse events and serious adverse events will be collected and recorded. Safety will be 
evaluated by the assessment of clinical safety laboratory results, vital sign measurements, 
ECG and physical examination findings. A Day 17 follow up phone call will be performed to 
evaluate safety by the assessment of adverse events and serious adverse events. 
The estimated study period will be approximately 25 weeks from screening of the first subject 
to completion of the last subject. 


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Minocin 701  
Statistical Analysis Plan 
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SAP_Minocin_701_V03 
 
V03 
1.3 
Assessment of Safety 
Intra-Cohort Data Review 
For Cohorts 3-6, single dose safety data will be reviewed by the Medical Monitor and 
Principal Investigator on Day 3 prior to the start of the multi- dosing on Day 4.  During the 
review, blinded safety data from the single dose infusions will be assessed and one of the 
following will be decided before the start of the Multiple Dose Phase on Day 4: 
 
To continue with the Multi-dose phase as planned, 
 
To continue with the Multi-dose phase and add additional safety evaluations, 
 
To not continue with the Multi-dose phase. 
 
Between-Cohort Data Monitoring Committee Review 
Safety data and PK data will be reviewed by the DMC following each cohort and prior to the 
start of the next cohort. 
After completion of cohorts 1 and 2, which may run concurrently, and prior to dosing of each 
cohort 3, 4, 5 and 6, the DMC will review all pertinent blinded safety data (e.g., physical 
examinations, vital signs, electrocardiograms (ECGs), clinical laboratory tests, and AEs) from 
the preceding cohort to determine one of the following: 
 
To continue with the next cohort as planned 
 
To continue with the next cohort and add additional safety evaluations 
 
To continue with the next cohort by adjusting the planned dose of Minocin IV 
 
To not continue with the next cohort 
 
Stopping Rules 
The study will be terminated if ≥ 2 subjects in a cohort meet any of the following criteria and 
the subject was determined to have received active drug after unblinding: 
 
Has a drug related SAE. 
 
Experiences a drug related AE grade > 3 toxicity. 
A written statement fully documenting the reasons for study termination will be provided to 
the HREC/IEC. 
1.4 
Timing of Analyses 
After completion of the last visit of the last subject data will be cleaned and approved by 
CTCC according to their SOPs. The cleaned data will then be transferred to the statistician 
and the final analysis will be performed after the finalization and approval of this statistical 
analysis plan (SAP).  
Number of patients in the final dataset is not known and depends on DMC decision on 
involved cohorts. 


Minocin 701  
Statistical Analysis Plan 
Page 8 of 29 
SAP_Minocin_701_V03 
 
V03 
2 
Analysis populations 
2.1 
Definitions 
The following populations will be used for data analyses and/or presentation. 
Intent-to-Treat (ITT) Population 
All subjects randomized into the trial. Treatment classification will be based on the 
randomized treatment. 
Modified Intent-to-Treat (mITT) Population 
All enrolled subjects who receive at least one dose of study drug. Treatment classification will 
be based on the randomized treatment. 
Pharmacokinetics (PK) Population 
All mITT subjects who receive the active study drug and have any valid samples measured 
for study drug levels. Treatment classification will be based on the actual treatment received. 
This population will be used for PK analysis. 
Safety Population 
The safety set will be the mITT population. 
2.2 
Application 
Decision on the analysis populations is made prior data lock and before the study is 
unblinded. 
The safety population will be used for the evaluation of safety and tolerability of Minocin IV. 
The pharmacokinetic analysis will be conducted in the PK population. 
2.3 
Major protocol violations / Withdrawals 
Withdrawals are included at least in the ITT population. If they receive any study medication 
they are included in mITT and safety as well. The drop-outs will be listed with group, time 
and reason. 
3 
Trial centers 
This clinical trial will be carried out at a single study site: 
QPS Netherlands BV 
Petrus Campersingel 123  
Groningen, 9713 AG 
The Netherlands  


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SAP_Minocin_701_V03 
 
V03 
The planned sample size is 10 subjects per cohort for all 5 cohorts. Each randomized subject 
can be part of one cohort only, i.e. cannot be randomized twice. 
4 
Analysis variables 
4.1 
Demography and baseline characteristics 
The demographic and baseline variables will be measured during screening period (day -28 
to -1), during check-in procedure (day -1) or pre-dose on Day 1. 
The following demographic variables will be analyzed: 
 
Age [years] 
 
Sex [M, F] 
 
Race [White (White), Black (Black or African American), Asian (Asian), Hawai (Native 
Hawaiian or Other Pacific Islander), Indian (American Indian or Alaska Native), Other 
(Other)] 
The following baseline variables will be analyzed: 
 
Physical Examination 
o Height [cm] 
o Weight [kg] 
o BMI [kg/m2] 
o Skin [normal, abnormal, not done; clinical significant] 
o Head [normal, abnormal, not done; clinical significant] 
o Ears, eyes, nose and throat [normal, abnormal, not done; clinical significant] 
o Respiratory system [normal, abnormal, not done; clinical significant] 
o Cardiovascular system [normal, abnormal, not done; clinical significant] 
o Gastrointestinal system [normal, abnormal, not done; clinical significant] 
o Neurological condition [normal, abnormal, not done; clinical significant] 
o Blood and lymphatic system [normal, abnormal, not done; clinical significant] 
o Musculoskeletal system [normal, abnormal, not done; clinical significant] 
o Other [normal, abnormal, not done; clinical significant] 
 
Vital Signs 
o Systolic Blood Pressure [mmHg] 
o Diastolic Blood Pressure [mmHg] 
o Pulse rate [beats/min] 
o Respiratory rate [breaths/min] 
o Temperature [°C] 
 
 


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SAP_Minocin_701_V03 
 
V03 
 
12-lead-ECG 
o ECG result [normal, clinically insignificant abnormality, clinically significant 
abnormality, not assessable] 
o ECG Mean Ventricular Rate [beats/min] 
o PR Interval [msec] 
o QRS Duration [msec] 
o QT Interval, corrected [msec] 
o QT Interval, uncorrected [msec] 
 
Hematology 
o Hemoglobin [g/dL; clinical significant] 
o Hematocrit [%; clinical significant] 
o White blood cell count [x10^-9/l; clinical significant] 
o Neutrophils abs. [x10^-9/l; clinical significant] 
o Neutrophils % [%; clinical significant] 
o Eosinophils [x10^-9/l; clinical significant] 
o Basophils [x10^-9/l; clinical significant] 
o Monocytes [x10^-9/l; clinical significant] 
o Lymphocytes [x10^-9/l; clinical significant] 
o Red blood cell counts [x10^-12/l; clinical significant] 
o Platelet count [x10^-9/l; clinical significant] 
o Prothrombin Intl. Normalized Ratio (INR) [clinical significant] 
o Activated partial thromboplastin time (aPTT) [sec; clinical significant] 
 
Chemistry 
o Blood urea nitrogen [mg/dL; clinical significant] 
o Serum Creatinine [mg/dL; clinical significant] 
o Total Bilirubin [mg/dL; clinical significant] 
o Direct Bilirubin [μmol/L; clinical significant] 
o Alkaline phosphatase [U/L; clinical significant] 
o Aspartate transaminase [U/L; clinical significant] 
o Alanine transaminase [U/L; clinical significant] 
o Albumin [g/L; clinical significant] 
o Total protein [g/L; clinical significant] 
o Glucose [mg/dL; clinical significant] 
o Calcium [mmol/L; clinical significant] 
o Chloride [mmol/L; clinical significant] 
o Sodium [mmol/L; clinical significant] 
o Magnesium [mmol/L; clinical significant] 


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Statistical Analysis Plan 
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SAP_Minocin_701_V03 
 
V03 
o Potassium [mmol/L; clinical significant] 
o Uric acid [mg/dL; clinical significant] 
o Lactate dehydrogenase [U/L; clinical significant] 
o Bicarbonate [mmol/L; clinical significant] 
o Phosphorus [mmol/L; clinical significant] 
 
Urinalysis 
o Protein [negative, positive; clinical significant] 
o Blood [negative, positive; clinical significant] 
o Leucocytes [negative, positive; clinical significant] 
o Nitrite [negative, positive; clinical significant] 
o Glucose [negative, positive; clinical significant] 
o Ketones [negative, positive; clinical significant] 
o Bilirubin [negative, positive; clinical significant] 
o pH [clinical significant] 
o Specific gravity [g/L; clinical significant] 
o Urobilinogen [clinical significant] 
o Additional microscopic exam [yes, no] 
 
Alcohol and drug screening 
o Alcohol test not done [yes, no] 
o Alcohol test result [negative, positive] 
o Drug test not done [yes, no] 
o Drug test result [negative, positive] 
 
Pregnancy test 
o Pregnancy test done [yes, no] 
o Pregnancy test not done reason [post-menopausal, surgically sterilized, other] 
o Pregnancy test result [negative, positive] 
4.2 
Variables for safety and tolerability analysis 
The following variables will be used to analyze safety and tolerability of Minocin IV versus 
placebo: 
 
Adverse Events (Cumulative) 
o Start date [DD/MM/YYYY] 
o Start time [HH:MM] 
o End date [DD/MM/YYYY] 
o End time [HH:MM] 
o Ongoing at the End of Study [yes, no] 
o Severity of AE [Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 


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o Causality to Study Drug [reasonable possibility, no reasonable possibility, 
unclassified, unclassifiable] 
o Action taken with Study Drug [dose not changed, dose reduced, drug 
withdrawn, na (not applicable)] 
o Therapy of Event [yes/no] 
o Outcome of Event [recovered/resolved, recovered/resolved with sequelae, 
recovering/resolving, fatal, unknown] 
o Serious Adverse Event [yes/no] 
o Date AE turned serious [DD/MM/YYYY] 
o Time AE turned serious [HH:MM] 
o Results in Death [yes/no] 
o Life-threatening [yes/no] 
o Results in significant, persistent, … [yes/no] 
o Requires in-patient hospitalization or … [yes/no] 
o Congenital Anomaly or Birth Defect [yes/no] 
o Another medically significant event … [yes/no] 
 
Laboratory Tests (Day 2, 4, 6, 8, 10, 13, 14) 
o Safety Lab: Hematology 
 
Hemoglobin [g/dL; clinical significant] 
 
Hematocrit [%; clinical significant] 
 
White blood cell count [x10^-9/l; clinical significant] 
 
Neutrophils abs. [x10^-9/l; clinical significant] 
 
Neutrophils % [%; clinical significant] 
 
Eosinophils [x10^-9/l; clinical significant] 
 
Basophils [x10^-9/l; clinical significant] 
 
Monocytes [x10^-9/l; clinical significant] 
 
Lymphocytes [x10^-9/l; clinical significant] 
 
Red blood cell counts [x10^-12/l; clinical significant] 
 
Platelet count [x10^-9/l; clinical significant] 
 
Prothrombin Intl. Normalized Ratio (INR) [clinical significant] 
 
Activated partial thromboplastin time (aPTT) [sec; clinical significant] 
o Safety Lab: Chemistry 
 
Blood urea nitrogen [mg/dL; clinical significant] 
 
Serum Creatinine [mg/dL; clinical significant] 
 
Total Bilirubin [mg/dL; clinical significant] 
 
Direct Bilirubin [μmol/L; clinical significant] 
 
Alkaline phosphatase [U/L; clinical significant] 


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 
Aspartate transaminase [U/L; clinical significant] 
 
Alanine transaminase [U/L; clinical significant] 
 
Albumin [g/L; clinical significant] 
 
Total protein [g/L; clinical significant] 
 
Glucose [mg/dL; clinical significant] 
 
Calcium [mmol/L; clinical significant] 
 
Chloride [mmol/L; clinical significant] 
 
Sodium [mmol/L; clinical significant] 
 
Magnesium [mmol/L; clinical significant] 
 
Potassium [mmol/L; clinical significant] 
 
Uric acid [mg/dL; clinical significant] 
 
Lactate dehydrogenase [U/L; clinical significant] 
 
Bicarbonate [mmol/L; clinical significant] 
 
Phosphorus [mmol/L; clinical significant] 
o Urinalysis 
 
Protein [negative, positive; clinical significant] 
 
Blood [negative, positive; clinical significant] 
 
Leucocytes [negative, positive; clinical significant] 
 
Nitrite [negative, positive; clinical significant] 
 
Glucose [negative, positive; clinical significant] 
 
Ketones [negative, positive; clinical significant] 
 
Bilirubin [negative, positive; clinical significant] 
 
pH [clinical significant] 
 
Specific gravity [g/L; clinical significant] 
 
Urobilinogen [clinical significant] 
 
Additional microscopic exam [yes, no] 
 
Vital Signs (Day 1 - Day 14, each: pre-dose, 1h, 3h and 6h post-dose; except Day 1: 
1h, 3h and 6h post-dose and Day 2, 3, 12, 13, 14: only once in the morning) 
o Systolic Blood Pressure [mmHg] 
o Diastolic Blood Pressure [mmHg] 
o Pulse rate [beats/min] 
o Respiratory rate [breaths/min] 
o Temperature [°C] 
 
ECGs (Day 1, 4, 5, 6, 7, 8, 9, 10, 11, 14, each: pre-dose and 1h post-first-dose; 
except Day 1: 1h post-dose and Day 14 no fixed time point) 
o ECG result [normal, clinically insignificant abnormality, clinically significant 
abnormality, not assessable] 


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o ECG Mean Ventricular Rate [beats/min] 
o PR Interval [msec] 
o QRS Duration [msec] 
o QT Interval, corrected [msec] 
o QT Interval, uncorrected [msec] 
 
Physical Examination (Day 3, 9, 14) 
o Height [cm] (only  at screening) 
o Weight [kg] (only Day 9, 14) 
o BMI (only Day 9, 14) 
o Skin [normal, abnormal, not done; clinical significant] 
o Head [normal, abnormal, not done; clinical significant] 
o Ears, eyes, nose and throat [normal, abnormal, not done; clinical significant] 
o Respiratory system [normal, abnormal, not done; clinical significant] 
o Cardiovascular system [normal, abnormal, not done; clinical significant] 
o Gastrointestinal system [normal, abnormal, not done; clinical significant] 
o Neurological condition [normal, abnormal, not done; clinical significant] 
o Blood and lymphatic system [normal, abnormal, not done; clinical significant] 
o Musculoskeletal system [normal, abnormal, not done; clinical significant] 
o Other [normal, abnormal, not done; clinical significant] 
4.3 
PK Variables 
Pharmacokinetic data will be analyzed by non-compartmental methods with WinNonlin 
(version 6.3, Pharsight Corporation, Mountain View, California) and modelled for constant 
intravenous infusion. The pharmacokinetic parameters calculated will be Cmax (maximum 
concentration observed), tmax (time at which Cmax occurs), AUC0-tlast (area under the curve 
from time 0 to the last time point), AUC0- (area under the curve from time 0 extrapolated to 
infinity), t1/2 (half life), CL (plasma clearance), and VSS (volume of distribution). Renal 
clearance (CLR) will be calculated as the amount of minocycline excreted into urine divided 
by the AUC and non-renal clearance will be calculated as the difference between plasma 
clearance and renal clearance. 
For the calculation of summary pharmacokinetic parameters and all analyses of derived 
pharmacokinetic parameters, Cmax and Vss values will be normalized for the weight of the 
subject and expressed as a standardized dose per kg. Continuous variables will be 
summarized using n, mean, median, standard deviation and range (minimum and maximum). 
Categorical variables will be summarized using proportions (counts and percentages). 
 


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The pharmacokinetic parameters Cmax, AUC0-tlast and AUC0- will be loge transformed prior to 
statistical analyses and presented as geometric means in summary output. 
No interim analyses, other than for safety purposes, are planned and no imputation or 
carrying forward of earlier observations will be used for the analyses of data. 
For calculations and statistical analysis of pharmacokinetic variables, missing concentrations 
(either genuinely missing concentrations or below the limit of quantification (BLQ)) measured 
between two concentrations above the lower limit of quantification (LLOQ)) will be deleted, 
resulting in an interpolation between the nearest two concentration values. 
 
Cmax 
Maximum concentration in plasma 
tmax 
Time of Cmax in plasma 
AUC0-t 
Area under the concentration-time curve from time zero to last 
quantifiable concentration in plasma 
AUC0-inf 
AUC extrapolated to infinity in plasma, (AUC0-t + last quantifiable 
concentration/ λz) 
 
5 
Handling of missing values and outliers 
5.1 
Missing values 
Missing values will not be imputed. Instead, if subjects drop-out before the first dose was 
given they will be replaced by additionally randomized trial subjects. If subjects drop-out after 
first dose but before end of study an Early Termination Visit is performed. 
5.2 
Outliers 
For safety, a special outlier handling is not applicable. 
6 
Statistical analyses / methods 
A descriptive statistical analysis will be performed. No tests will be conducted. 
Unless stated otherwise, descriptive statistics will include: 
Quantitative variables and variables with ordered response categories, will be described by 
their number of observations (n), arithmetic mean, standard deviation (SD), median, first 
quartile (Q1), third quartile (Q3), minimum (min) and maximum (max) (see sample Table 
12-1). Qualitative variables will be described by their absolute and relative frequencies (see 
sample Table 12-2). 


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6.1 
Patient / Subject Disposition 
First, the application of the inclusion and exclusion criteria to all included subjects will be 
verified. 
Definition of ITT population: All subjects included in the database (eligible for trial, with given 
written informed consent and randomization ID). 
Definition of mITT population: All ITT subjects with number of administered infusions ≥ 1. 
Definition of PK population: All subjects with any valid PK blood or urine sampling and 
number of administered infusions of Minocin > 0. 
Definition of safety population: All subjects of the mITT population. 
Absolute and relative frequencies of patients per treatment arm and cohort will be calculated 
for each population. Frequencies will be shown in a subject flow diagram. The diagram will 
include consent, allocation, follow-up and analysis. Number of and reasons for drop-outs will 
be included. See sample Figure 12-1 in appendix. 
6.2 
Demography and baseline characteristics 
The last measurement before the first dose (Screening, Day -1 or Day 1) is the baseline 
value. Demographic and baseline variables will be summarized descriptively by treatment 
arm, cohort and in total for safety population. 
6.3 
Prior or concomitant medication and diseases 
Medications will be coded using the most updated version of the WHO Drug Dictionary 
available (e.g. version WHODDE DEC. 1, 2015 or later). 
Listings of each prior (pre-baseline) medication and concomitant (baseline or later) 
medication per treatment group, cohort and patient will be given (see 12.3, 1.). Frequency 
counts of each prior medication (pre-baseline) and concomitant medication (baseline or later) 
(according to WHO) will be provided by cohort. 
6.4 
Study drug administration 
Doses not administered per protocol are listed. Infusion administered, Start date, Start time, 
End date, End time, Reasons for dose administration not per protocol and Residual volume 
(ml) will be given (see 12.3, 2.). 
6.5 
Exposition to treatment/Compliance 
Number of subjects in the mITT population with number of administered infusions <16 will be 
calculated per treatment group and cohort. 
Listing of drop-outs with reason, treatment group and time (Day 1 - Day 17) will be given (see 
12.3, 3.). 


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6.6 
Analysis of safety and tolerability 
Variables for the analysis of safety and tolerability will be evaluated in the safety population. 
Note: For analysis of adverse events two dosing conditions are defined based on 
corresponding study day: day 1 to 3 are assigned to single dosing and day 4 to 17 are 
assigned to multiple dosing. In the following this will be referred to as dosing condition. 
6.6.1 Adverse events/Serious adverse events 
All AEs occurring from the time when first dose is administered up to the last follow-up visit 
(phone call on Day 17) are listed by subject with cohort (dose), treatment group, AE number, 
AE Term, preferred term (MedDRA dictionary), primary system-organ class, study day, 
dosing condition, start date, start time, end date, end time, ongoing at study end, severity, 
causality, therapy, therapy specification, outcome and seriousness (see 12.3, 4.). 
Additionally, all SAEs will be listed by subject with cohort (dose), treatment group, SAE 
number, AE number, preferred term (MedDRA dictionary), primary system-organ class, date 
and time when AE turned serious, SAE diagnosis, results in death, life-threatening, results in 
significant damage, hospitalization, congenital anomaly or birth defect, another medically 
significant event and description of event (see 12.3, 5.). 
The total number (percentage) of AEs will be tabulated by cohort, treatment group and total, 
classified by preferred term (MedDRA dictionary), primary system-organ class, severity and 
causality (see Table 12-3). Even if several AEs are from the same subject, they are counted 
at subject level. 
The absolute and relative frequencies of subjects reporting AEs will be tabulated by cohort 
and treatment group and classified by: 
1. any AE, related AE, unrelated AE, any SAE, related SAE, unrelated SAE (see Table 
12-4) 
2. each preferred term (MedDRA dictionary) within each primary system-organ class 
(see Table 12-5) 
3. severity within each preferred term (MedDRA dictionary) within each primary system-
organ class (see Table 12-6) 
If a subject has multiple AEs or SAEs, related and not related to study drug, then the subject 
is counted as related (‘causality’ = yes). If a subject has multiple AEs/SAEs with the same 
preferred term, it is counted only once. Likewise, if a subject has multiple AEs with the same 
preferred term but different severities, the maximal severity is used and the subject is 
counted only once. 
Tables are presented in three versions: all AEs, AEs occurred during single dosing and AEs 
occurred during multiple dosing. 


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6.6.2 Laboratory tests (Hematology, Chemistry, Urinalysis) 
Laboratory values will be summarized descriptively by treatment group and cohort including 
mean change and mean percent changes from baseline at each time point where 
appropriate (see Table 12-7). Shift tables by reference range (see 12.1), which count the 
number of subjects with a low, normal or high value at baseline and a low, normal or high 
value at each time point, of each parameter will be given by cohort. 
6.6.3 Vital signs 
Vital signs will be summarized descriptively by cohort and treatment group including mean 
change and mean percent change from baseline at each scheduled time point where 
appropriate (see Table 12-7). 
6.6.4 ECGs 
Ventricular rate, PR, QRS, QT and QTc intervals will be summarized descriptively by cohort 
and treatment group for each scheduled time point. If a triplicate measurement was 
performed the average of the triplicate per subject will be computed and used for analysis.  
Furthermore, ECG results are assessed as normal, clinically insignificant abnormal, and 
clinically significant abnormal. This information will be summarized descriptively by cohort for 
each scheduled time point. Additionally, a normal-abnormal shift table (see Table 12-8) will 
be presented for ECGs results for each cohort and treatment group, comparing baseline to 
each scheduled time point. 
6.7 
Pharmacokinetic analyses 
Pharmacokinetic variables will be evaluated in the PK population. 
6.8 
Planned subgroup analyses 
Not applicable. 
6.9 
Interim analyses 
Not applicable. 
7 
Deviations from the protocol 
Not applicable. 
8 
Interpretation of results 
Because of the small sample size a careful interpretation of the results is essential.  


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9 
Data problems 
Not expected. Will be recorded in a separate document. 
10 Software 
The analyses will be programmed in SAS 9.3 or higher (SAS Institute Inc., Cary, NC, USA). 
Mainly SAS procedure PROC TABULATE, PROC REPORT and PROC SGPLOT will be 
used to generate the TFL. Own macros will be validated according to IMSIE SOPs before 
using them for the analysis. 
11 References 
Clinical Study Protocol MDCO-MIN-16-02, Version 2.2, Final 07-Apr-17 
 


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12 Appendices 
12.1 Reference ranges of laboratory parameters 
 
Activated partial thromboplastin time (aPTT): 24 – 35 sec 
 
Prothrombin time (PT): 6.7 – 14.8 sec 
 
Hemoglobin (male): 8.5 – 11 g/dl 
 
Hemoglobin (female): 7.5 – 10 g/dl 
 
Hematocrit (male): 0.41 – 0.51 l/l 
 
Hematocrit (female): 0.36 – 0.47 l/l 
 
Red blood cell count (male): 4.3 – 5.9 x10^12/l 
 
Red blood cell count (female): 3.8 – 5.4 x10^12/l 
 
White blood cell count: 4.0 – 11.0 x10^9/l 
 
Platelet count: 150 – 400 x10^9/l 
 
Basophils: <0.2 x10^9/l 
 
Eosinophils: <0.4 x10^9/l 
 
Lymphocytes: 0.8 – 3.2 x10^9/l 
 
Monocytes: 0.3 – 0.9 x10^9/l 
 
Glucose: 3.5 – 7.8 mmol/l 
 
Sodium: 135 – 145 mmol/l 
 
Potassium: 3.5 – 5.0 mmol/l 
 
Chloride: 97 – 107 mmol/l 
 
Bicarbonate: 23 – 29 mmol/l 
 
Serum Creatinine (male): 50 – 110 µmol/l 
 
Serum Creatinine (female): 50 – 90 µmol/l 
 
Urea: 2.5 -.7.5 mmol/l 
 
Lactate dehydrogenase: <250 U/l 
 
Total protein: 60 – 80 g/l 
 
Albumin: 35 – 50 g/l 
 
Total Bilirubin: <17 µmol/l 
 
Direct Bilirubin: <5 μmol/l 
 
Alanine transaminase: <45 U/l 
 
Aspartate transaminase: <40 U/l 
 
Alkaline phosphatase: <120 U/l 
 
Uric acid (male): 0.20 – 0.45 mmol/l 
 
Uric acid (female): 0.15 – 0.35 mmol/l 
 
Calcium: 2.2 – 2.6 mmol/l 


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 
Magnesium: 0.7 – 1.0 mmol/l 
 
Phosphorus: 0.8 – 1.4 mmol/l 
 
Neutrophils: 2 – 7.5 x10^9/l 
 
pH: 5 – 8 
 
Specific gravity: 1.002 - 1.035 g/l 
 
 
 


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12.2 Planned tables  
Table 12-1 Table of quantitative demographic. 
 
 
Cohort 1 …
Cohort 6
Placebo 
Total 
Quantitative 
Variable 1 
n 
 
 
 
 
 
mean 
 
 
 
 
 
SD 
 
 
 
 
 
min 
 
 
 
 
 
Q1 
 
 
 
 
 
median 
 
 
 
 
 
Q3 
 
 
 
 
 
max 
 
 
 
 
 
Quantitative 
Variable 2 
n 
 
 
 
 
 
mean 
 
 
 
 
 
SD 
 
 
 
 
 
min 
 
 
 
 
 
Q1 
 
 
 
 
 
median 
 
 
 
 
 
Q3 
 
 
 
 
 
max 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Table 12-2 Table of qualitative demographic. 
 
 
Cohort 1
…
Cohort 6
Placebo 
Total 
Total 
n 
 
 
 
 
 
Qualitative Variable 1 
 
 
 
 
 
 
Expression 1 
n 
 
 
 
 
 
 
c% 
 
 
 
 
 
Expression 2 
n 
 
 
 
 
 
 
c% 
 
 
 
 
 
Qualitative Variable 2 
 
 
 
 
 
 
Expression 1 
n 
 
 
 
 
 
 
c% 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 


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Table 12-3 AE tabulation. 
 
 
Cohort 1
…
Cohort 6
Placebo 
Total 
Preferred 
term 
Term 1 
n (%) 
 
… 
 
 
Term 2 
… 
 
 
 
 
… 
 
 
 
 
 
System-
organ 
class 
SOC 1 
 
 
 
 
 
SOC 2 
 
 
 
 
 
… 
 
 
 
 
 
Severity 
Grade 1 
 
 
 
 
 
… 
 
 
 
 
 
Grade 5 
 
 
 
 
 
Causality 
Reasonable 
possibility 
 
 
 
 
 
No reasonable 
possibility 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Table 12-4 AE tabulation (version 1). 
 
 
Cohort 1 … Cohort 6
Placebo 
Total 
AE 
any 
n (%) 
 
… 
 
 
 
related 
… 
 
 
 
 
 
unrelated 
 
 
 
 
 
SAE 
any 
 
 
 
 
 
 
related 
 
 
 
 
 
 
unrelated 
 
 
 
 
 
 
Table 12-5 AE tabulation (version 2). 
 
 
Cohort 1
…
Cohort 6
Placebo 
Total 
SOC 1 
Preferred term 1 
n (%) 
 
… 
 
 
 
Preferred term 2 
… 
 
 
 
 
 
… 
 
 
 
 
 
SOC 2 
Preferred term 1 
 
 
 
 
 
 
Preferred term 2 
 
 
 
 
 
 
… 
 
 
 
 
 
… 
… 
 
 
 
 
 


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Table 12-6 AE tabulation (version 3). 
System-
organ class 
Preferred 
term 
Severity 
Cohort 1
…
Cohort 6
Placebo 
Total 
SOC 1 
Term 1 
Grade 1 
n (%) 
 
… 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
Grade 5 
 
 
 
 
 
 
Term 2 
Grade 1 
… 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
Grade 5 
 
 
 
 
 
 
… 
 
 
 
 
 
 
SOC 2 
Term 1 
Grade 1 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
Grade 5 
 
 
 
 
 
 
Term 2 
Grade 1 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
Grade 5 
 
 
 
 
 
 
… 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 


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Table 12-7 Change table for quantitative variables (mean (percent) change from baseline). 
 
 
Cohort 1
…
Cohort 6
Placebo 
Total 
Quantitative 
Variable 1 
n 
 
 
 
 
 
mean 
 
 
 
 
 
SD 
 
 
 
 
 
min 
 
 
 
 
 
Q1 
 
 
 
 
 
median 
 
 
 
 
 
Q3 
 
 
 
 
 
max 
 
 
 
 
 
mean change 
 
 
 
 
 
mean % change 
 
 
 
 
 
Quantitative 
Variable 2 
n 
 
 
 
 
 
mean 
 
 
 
 
 
SD 
 
 
 
 
 
min 
 
 
 
 
 
Q1 
 
 
 
 
 
median 
 
 
 
 
 
Q3 
 
 
 
 
 
max 
 
 
 
 
 
mean change 
 
 
 
 
 
mean % change 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Table 12-8 Shift table for qualitative variables. 
 
Baseline 
Category 1 
Category 2 
… 
Day x 
Category 1 
n (%) 
… 
 
Category 2 
… 
 
 
… 
 
 
 
Day y 
Category 1 
 
 
 
Category 2 
 
 
 
… 
 
 
 
… 
 
 
 
 
 
 
 


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12.3 Planned listings 
1. 
Prior or concomitant medication by subject (see 6.3) 
Cohort Treatment 
Group 
ID 
Medication 
(tradename)
WHO 
drug 
name 
Indication
Total 
daily 
dose 
Unit 
xx 
xxx 
xxx xxxxx 
xxxxx 
xxxxx 
xxx 
xx 
 
Route of 
administration 
Start date 
More than 2 weeks 
before dosing 
End date 
Ongoing at 
study end 
xxxxx 
dd.mm.yyyy 
x 
dd.mm.yyyy 
x 
2. 
Study Drug Administration (see 6.4) 
ID Cohort 
Infusion 
administered 
Start date 
Start 
time 
End date 
End 
time 
xx xx 
x 
dd.mm.yyyy
hh:mm
dd.mm.yyyy
hh:mm 
 
 
3. 
Drop-outs with cohort, treatment group, time, reason (Day 1 - 17) (see 6.5) 
ID 
Cohort 
Treatment 
Group 
Time 
Reason 
xxx 
xx 
xxx 
dd.mm.yyyy 
xxxxxxxxxxxxxxx 
 
4. 
All AEs occurring from administration of first dose up to the last follow-up visit by subject 
with severity, relationship to study drug, cohort (dose) and treatment group (see 6.6.1)  
ID Cohort Treatment 
Group 
AE 
No. 
AE 
Term 
Preferred 
term 
(MedDRA)
System-
organ 
class 
Study 
day 
Dosing 
condition
xx xx 
xxx 
xx 
xxxxx
xxxxx 
xxxxx 
xx 
xxxxx 
 
Start date 
Start time 
End date 
End time 
Ongoing at the 
end of study 
Severity
dd.mm.yyyy 
hh:mm 
dd.mm.yyyy 
hh:mm 
x 
xx 
 
 
Dose administered 
per protocol 
Reasons for not 
per protocol 
Residual 
volume (ml) 
x 
xxxxx 
xx 
Causality Therapy 
Therapy 
specification 
Outcome 
Seriousness 
CRF 
comment 
xx 
x 
xxxxx 
xx 
 
xxxxx 


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5. 
All SAEs occurring from the time when informed consent is obtained at screening up to 
the last follow-up visit by subject with severity, relationship to study drug, cohort (dose) 
and treatment group (see 6.6.1) 
ID Cohort Treatment 
Group 
SAE 
No. 
AE 
No.
Preferred term 
(MedDRA) 
System-
organ class 
Date AE 
turned serious 
xx xxx 
xxx 
xx 
xx 
xxxxx 
xxxxx 
dd.mm.yyyy 
 
Time AE turned 
serious 
SAE 
diagnosis 
Results in 
death 
Life-
threatening 
Results in significant 
damage 
hh:mm 
xxxxx 
x 
x 
x 
 
 
 
 
Hospitalization Congenital anomaly 
or birth defect 
Another medically 
significant event 
Description 
of event 
CRF 
comment 
x 
x 
x 
xxxxx 
xxxxx 


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12.4 Planned graphics 
 
Figure 12-1: Flow diagramm 
Cohort 3
Cohort 4
Cohort 5
Allocation
Analysis
Analysed for mITT (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed for mITT (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed for PP (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed for PP (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed for PP (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Analysed for PP (n= )
‐ Excluded from analysis (give reasons) 
(n= )
Allocated to Minocin (n= )
‐ Received at least one allocated 
intervention (n= )
‐ Did not receive allocated intervention 
(give reasons) (n= )
Allocated to Placebo (n= )
‐ Received at least one allocated 
intervention (n= )
‐ Did not receive allocated intervention 
(give reasons) (n= )
Allocated to Minocin (n= )
‐ Received at least one allocated 
intervention (n= )
‐ Did not receive allocated intervention 
(give reasons) (n= )
Allocated to Placebo (n= )
‐ Received at least one allocated 
intervention (n= )
‐ Did not receive allocated intervention 
(give reasons) (n= )
Follow‐Up
Lost to follow‐up (give reasons) (n= )
Discontinued intervention (give 
reasons) (n= )
Lost to follow‐up (give reasons) (n= )
Discontinued intervention (give 
reasons) (n= )
Lost to follow‐up (give reasons) (n= )
Discontinued intervention (give 
reasons) (n= )
Lost to follow‐up (give reasons) (n= )
Discontinued intervention (give 
reasons) (n= )
Written informed consent (n= )
Excluded (n= )
‐ Declined to participate (n= )
‐ Other reasons (n= )
Randomization
Cohort 1
Randomized (n= )
Cohort 2
Randomized (n= )
Consent


Minocin 701  
Statistical Analysis Plan 
Page 29 of 29 
SAP_Minocin_701_V03 
 
V03 
12.5 List of abbreviations 
AE 
Adverse Event 
BMI 
Body mass index 
c% 
Column percent 
CS 
Clinically significant 
CTCC 
Clinical Trial Centre Cologne 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiography 
IMSIE 
Institute for Medical Statistics, Informatics and Epidemiology 
University of Cologne 
ITT 
Intent-To-Treat 
max 
Maximum 
min 
Minimum 
mITT 
modified Intent-To-Treat 
MedDRA  
Medical Dictionary for Regulatory Activities 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
Q1 
First quartile 
Q3 
Third quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization