Conditions: Renal Insufficiency, Acute Renal Insufficiency, Chronic Healthy Subjects
Keywords: Bacterial infections
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: yes

Brief summary:
This is a Phase 1, open-label, single-dose study of the safety, tolerability, and pharmacokinetics of Minocin® (minocycline) for injection in subjects with renal insufficiency.

Detailed description:
The purpose of this study is to collect safety, tolerability, and pharmacokinetics (PK) data on a single dose of Minocin® (minocycline) for Injection in subjects with renal insufficiency and in subjects receiving hemodialysis therapy. The safety, tolerability, and PK data will support the compound as a potential clinical candidate in Europe and will inform the development of future Phase 2/3 studies.

Arms:
arm 1: Minocin (minocycline) for Injection 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 cohort receives a single 200-mg dose of Minocin (minocycline) for Injection except for the hemodialysis therapy/end stage renal disease cohort, which receives two 200-mg doses.

Interventions: intervention 1: Minocin (minocycline) for Injection
Intervention descriptions: intervention 1: 200mg IV Minocin given over 1 hour

Protocol document:
Prot_000.pdf: 
Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
Confidential 
1 
Investigational New Drug 
Minocin® (minocycline) for Injection 
A PHASE I, OPEN-LABEL, SINGLE-DOSE TRIAL TO DETERMINE 
THE SAFETY AND PHARMACOKINETICS OF MINOCIN® 
(MINOCYCLINE) FOR INJECTION IN SUBJECTS WITH RENAL 
INSUFFICIENCY 
Protocol No.: MDCO-MIN-16-03 
Minocin 702 
U.S.  NDA No.: 50-444/S-047 
EuDRACT No.: 2016-002247-41 
PROTOCOL VERSION: 3.0 
Development Phase 
Phase I 
Sponsor 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054, USA 
Sponsor Representative in the 
European Union 
The Medicines Company – UK 
Medical.Information@THEMEDCO.com 
+44 1235 448 500 
Principal Investigator 
Volker Burst, MD 
University Hospital Cologne 
Department II for Internal Medicine 
Kerpener Str. 62 
50937 Koeln, Germany 
Sponsor Representatives 
 
Medical Director 
Name: 
Jeffery Loutit, MBChB 
Project Lead 
Name: 
David Sylvester 
Global Safety Officer 
Name: 
Isabelle Degeyter, MD 
IMI/Combacte NET 
 
 
Medical Lead 
Name: 
Oliver Cornely, MD 
Project Lead 
Name:  
Vassiliki Dimitriou 
Issue Date 
Date:  
           28 July 2017 
CONFIDENTIAL 
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 IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
Medical Director 
Jeffery Loutit, MBChB 
+1-650-888-5007 
Global Safety Officer 
Isabelle Degeyter, MD 
+1-973-290-6120 
 
 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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KEY CONTACTS 
Role in Study 
Name 
Contact Information 
Academic Lead/ Medical 
Monitor 
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 
 
Sponsor Medical Lead 
Jeffery Loutit, MBChB 
The Medicines Company 
Health Science Infectious Disease 
Care 
3033 Science Park Road 
San Diego, CA 92121 
USA 
tel +1 650 888-5007 
 
+1 858 875-6665 
jeff.loutit@themedco.com 
 
Trial Statistician 
Stefanie Hamacher 
University Hospital of Cologne 
(UKK) 
Institute of Medical Statistics, 
Informatics and Epidemiology 
(IMSIE) 
Kerpener Str. 62 
50937 Koeln 
Germany 
tel +49 221 478-6517 
stefanie.hamacher@uni-koeln.de 
 
Sponsor Project Lead 
David Sylvester 
The Medicines Company 
3033 Science Park Road 
San Diego, CA 92121 
USA 
tel +61-488-100-096 
david.sylvester@themedco.com 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
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Role in Study 
Name 
Contact Information 
UKK Project Lead 
Vassiliki Dimitriou 
University Hospital of Cologne 
(UKK) 
Department I for Internal Medicine 
Kerpener Str. 62 
50937 Koeln 
Germany 
tel +49 221 478-98302 
vassiliki.dimitriou@uk-koeln.de 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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5 
INSTITUTIONS INVOLVED 
 
Responsibility 
Address 
Bioanalytical Laboratory and Pharmacokinetic 
Analysis 
North Bristol NHS Trust 
Southmead Hospital Bristol 
Department of Medical Microbiology 
Westbury on Trym 
Bristol, BS10 5NB 
United Kingdom 
 
Clinical Laboratory 
 
University Hospital of Cologne (UKK) 
Institute of Clinical Chemistry 
Kerpener Str. 62 
50937 Koeln 
Germany 
 
Data Management 
 
University Hospital of Cologne (UKK) 
Clinical Trials Center Cologne (CTCC) 
Kerpener Str. 62 
50937 Koeln 
Germany 
 
 
 




Minocin IV (Minocycline for Injection) 
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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 I, Open-Label, Single-Dose Trial To Determine The Safety And 
Pharmacokinetics Of Minocin® (Minocycline) For Injection In Subjects With Renal 
Insufficiency 
Phase of Development: Phase I 
Study Centers: A single German study site is planned  
Number of Subjects: The study is designed to enroll approximately 40 subjects. There 
will be approximately 24 subjects with varying degrees of renal insufficiency, 
approximately 8 subjects with normal renal function, and 8 subjects receiving 
hemodialysis (HD) therapy. 
Principal Investigator: Volker Burst, MD 
Study Period: 
The study is planned to take place over approximately 24 weeks depending on rate of 
enrollment. 
 
Objectives: 
 To evaluate the safety and tolerability of Minocin IV in subjects with 
renal insufficiency and in subjects receiving HD therapy 
 
To assess the pharmacokinetics (PK) of Minocin IV in subjects with renal 
insufficiency and in subjects receiving HD therapy 
Methodology: 
This is a Phase I, open-label, single-dose study to assess the safety, tolerability, and PK 
of Minocin IV in adults with varying degrees of renal insufficiency and in adult subjects 
receiving HD therapy as compared to subjects with normal renal function. 
There will be at least 8 subjects assigned to each of the following groups based on 
estimated glomerular filtration rate [eGFR] calculated at screening, using CKD-EPI 2009 
for Groups 1-3, and using Cockroft-Gault for Group 4 (normal renal function). Group 5 
is instead assigned by the requirement for HD therapy. 
 
Group 1: Mild renal insufficiency (eGFR 60-89 mL/min/1.73m2) 
 
Group 2: Moderate renal insufficiency (eGFR 30 to < 60 mL/min/1.73m2) 
 
Group 3: Severe renal insufficiency (eGFR < 30 mL/min/1.73m2) not receiving 
HD therapy 
 
Group 4: Healthy subjects with normal renal function (eGFR ≥ 90 
mL/min/1.73m2) 
 
Group 5: Subjects with end stage renal disease (ESRD) receiving HD therapy 3 
times a week for at least 3 months prior to Day 1 


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Analysis of data will be based on Creatinine Clearance measurement by 24 h urine 
collection on Day 1. 
Subjects with mild, moderate, and severe renal insufficiency (Groups 1, 2, and 3, 
respectively) will be enrolled in the study concurrently. 
Once the mild, moderate, and severe renal insufficiency groups are fully enrolled, healthy 
subjects (Group 4) will be matched to the pooled mean values of age (± 10 years), body 
mass index (BMI; ± 20%), and gender. 
Group 5 will be enrolled after completion of Groups 1-4. It will include subjects who 
require HD therapy 3 times a week for at least 3 months prior to Day 1. Subjects in 
Group 5 will receive Minocin IV twice over the course of the study, once before HD 
therapy (Period 1) and once after (Period 2). Periods 1 and 2 do not have to occur in 
sequence for any given subject. A Washout Period will occur between the 2 Periods 
regardless of the sequence of the Periods. The Washout Period will be scheduled to 
ensure that study drug administration is at least 6 days apart and no more than 14 days 
apart. 
Inclusion Criteria: 
Subjects will be included in the study if they meet all of the following criteria: 
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 
hospital or after discharge, for the duration of the study; 
2. Adult male or female between 18 and 85 years of age (inclusive) at the time of 
screening; 
3. Subject has a BMI ≥ 18.5 kg/m2 and ≤ 45 kg/m2; 
4. Pulse measured at screening/baseline must be within the ranges ≥ 45 to ≤ 115 
beats per minute (bpm, taken after resting in a semi-recumbent position for at 
least 5 minutes); 
5. Have sufficient peripheral vascular access, based on the Investigator’s 
assessment, for all PK blood sample collections to take place (Central venous 
access may be possible for HD subjects, please refer to Section 9.3.2 and 
Section 9.5.2); 
6. Female subject is surgically sterile (bilateral tubal occlusion), postmenopausal, or 
if of childbearing potential, agrees to abstinence or to use a highly efficient 
method of birth control (i.e., intrauterine device [IUD] or intrauterine hormone-
releasing system [IUS] or vasectomized male partner, or hormonal 
contraceptives [estrogen and progestogen combined or progestogen only] with 
inhibition of ovulation, oral hormonal contraceptives must be supplemented with 
the use of condoms), between inclusion and for 7 days after the completion of the 
study; 
7. Subject agrees to limit exposure or use protective measures (e.g., to wear 
sunglasses, protective clothing, sunscreen with high light protection factor, etc.) 
when in sunlight or ultraviolet light throughout the study; 
Subjects with Renal Insufficiency: 


Minocin IV (Minocycline for Injection) 
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The Medicines Company 
 
 
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8. Assessment of renal insufficiency for assignment to study groups will be based 
on measurements of eGFR calculated by CKD-EPI 2009 equation at the 
screening visit to determine eligibility; 
Subjects with Normal Renal Function: 
9. Normal volunteers matched by age (± 10 years), BMI (± 20%), and gender to the 
pooled mean values of the mild, moderate, and severe renal insufficiency groups; 
10. Have a eGFR ≥ 90 mL/min calculated by Cockcroft-Gault equation at the 
screening visit to determine eligibility; 
Hemodialysis Subjects: 
11. Receiving stable HD (Kt/V > 1.2, determined within 6 months before inclusion) 
at least 3 times a week for at least 3 months; 
12. Otherwise considered to be clinically stable with respect to underlying renal 
impairment, as determined by the Investigator, and based upon a medical 
evaluation that includes a medical history, physical examination, laboratory tests, 
and electrocardiogram (ECG); 
13. Have clinical laboratory test results that are considered clinically stable in the 
opinion of the Investigator, especially if the clinical abnormality or laboratory 
parameter is deemed associated with the subject’s underlying renal impairment; 
14. A stable medication regimen is required, defined as not starting new drug(s) or 
significant changes in dosage(s) within 3 weeks prior to Day -1, or during the 
conduct of the study. Changes of medications in HD subjects are subject to 
dialysis site protocols such that erythropoiesis-stimulating agents (ESAs), iron, 
and vitamin D can be changed based on the then current subject status and 
dialysis unit standard practice and subject safety prior to screening. 
Exclusion Criteria: 
Subjects will be excluded from the study if there is evidence of any of the following at 
screening or check-in, as appropriate: 
1. 
Subject with normal renal function has any condition, including findings in 
the medical history or in pre-study assessments, that are capable of altering 
the distribution, metabolism, or elimination of drugs or that constitute a risk 
or a contraindication for the participation in the study or completing the 
study; 
2. 
Current evidence or history of malignancy, excluding basal cell carcinoma, 
requiring active treatment or management; 
3. 
Positive breath test for alcohol and/or positive urine or saliva test for drugs 
of abuse at screening or baseline; 
4. 
Has a history or presence of alcohol/drug abuse within the 30 days prior to 
enrollment. 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); 
5. 
Blood or plasma donation within past 2 months;  
6. 
Vigorous exercise from 48 hours prior to Day -1 until the day of discharge 
from the study; 
7. 
Surgery within 48 hours prior to inclusion or surgery planned during the 
study period;  


Minocin IV (Minocycline for Injection) 
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8. 
Liver function abnormalities at screening (or Day -1) (defined by an 
elevation in bilirubin, aspartate aminotransferase [AST], or alanine 
aminotransferase [ALT] 1.5 x upper limit of normal [ULN] of the normal 
range for subjects based on age and sex); 
9. 
Raised magnesium levels at screening or Day -1 (defined by an elevation in 
magnesium above the ULN); 
10. 
Females who are pregnant or nursing or who have a positive pregnancy test 
result at the Screening Visit or Day -1; 
11. 
Males who are unwilling to practice abstinence or use an acceptable method 
of birth control during the entire study period (i.e., condom with spermicide, 
where locally available); 
12. 
Presence of known raised intracranial pressure; 
13. 
Use of isotretinoin; 
14. 
History of significant hypersensitivity or allergic reaction to tetracycline 
antibiotics; 
15. 
History of seizures (e.g., epilepsy), head injury, or meningitis requiring 
ongoing anti-seizure medications; 
16. 
Receipt of any investigational medication or investigational device during 
the last 30 days prior to inclusion; 
17. 
QTc >500 msec or history of prolonged QT syndrome; 
18. 
Use of products containing alcohol within 48 hours before dosing; 
19. 
Unable or unwilling, in the judgment of the Investigator, to comply with the 
protocol; 
20. 
Subjects that have known active hepatitis B (HBV) or C (HCV), or human 
immunodeficiency virus (HIV) infection or have known immune deficiency 
disease at screening; 
21. 
Concurrent use of medications known to affect the elimination of serum 
creatinine (e.g., trimethoprim/sulfamethoxazole [Bactrim®] or cimetidine 
[Tagamet®]. See Section 8.2.2 for full list) within 30 days prior to the first 
dose of study drug, or anticipated need for these therapies through the last 
PK sample; 
22. 
An employee of the Investigator or study center or Sponsor, with direct 
involvement in the proposed study or other studies under the direction of that 
Investigator or study center or the Sponsor, or a family member of the 
employee or the Investigator; 
Subjects with Renal Insufficiency: 
23. 
Have a sitting systolic blood pressure (BP) > 180 mm Hg or < 90 mm Hg or 
have a sitting diastolic BP > 110 mm Hg or < 50 mm Hg at the Screening 
Visit; for HD subjects with BP outside these limits before HD, measurement 
can be repeated; 
24. 
Use of any other prescription or nonprescription drugs, grapefruit/grapefruit 
juice, or dietary or herbal supplements within 14 days prior to Day -1 other 
than those listed below: 
a. Medications required to treat underlying renal disease or medical 
conditions related to renal disease are permitted; 


Minocin IV (Minocycline for Injection) 
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b. Medications required to treat other pre-existing comorbidities and 
medical conditions (not related to renal disease) are permitted, provided 
that dosing is stable for 3 weeks prior to Day -1; 
c. Oral contraceptives are permitted for birth control; 
d. Doses of concomitant medications (except hormonal contraceptives, 
hormone replacement therapy for females, and insulin) must be stable for 
3 weeks prior to Day -1. Minor dose changes consistent with treatment 
practices may be permitted at the discretion of the Sponsor’s Medical 
Monitor; 
e. Acetaminophen/paracetamol (≤ 1 g/day) and low-dose acetylsalicylic 
acid (ASA; i.e., ≤ 325 mg per day) are permitted; 
Subjects with Normal Renal Function: 
25. 
Abnormal and clinically significant findings on physical examination, 
medical history, serum chemistry, hematology, or urinalysis per Investigator 
discretion; 
26. 
Have a sitting systolic BP > 150 mm Hg or < 90 mm Hg or have a sitting 
diastolic BP > 90 mm Hg or < 50 mm Hg at the Screening Visit; 
27. 
Use of any prescription or nonprescription drugs, grapefruit/grapefruit juice, 
or dietary or herbal supplements within 14 days prior to Day -1 other than 
those listed below: 
a. Oral contraceptives are permitted for birth control; 
b. Acetaminophen/paracetamol (≤ 1 g/day), ibuprofen, and low-dose ASA 
(i.e., ≤ 325 mg per day) are permitted. 
Test Drug/Device, Dose, and Mode of Administration:   
Minocin IV doses should be prepared by a pharmacist (or qualified designee). Minocin 
IV 200 mg will be administered intravenously into a peripheral vein over 60 minutes in 
100 ml 0.9% Sodium Chloride Injection (referred to as Normal Saline for the remainder 
of the document). Central venous access may be possible for HD subjects; please refer to 
Section 9.3.2 and Section 9.5.2. 
Duration of Treatment: 
The planned length of participation in the study for each subject with mild, moderate, or 
severe renal insufficiency and normal renal function (excluding screening) is 
approximately 5 days from check-in on Day -1 (Day -1 procedures can also be completed 
pre-dose on Day 1 at the site’s discretion) through completion of the Day 4 post-dose 
procedures. Subjects will remain within the clinic for the duration of the single-dose 
period until completion of the post-dose procedures on Day 4. Subjects will receive a 
follow-up phone call on Day 6 (with a window of + ≤2 days). The total duration of 
participation, excluding screening period and including follow-up call, for each subject 
will be approximately 7-9 days. 
Subjects with HD will participate in two 5 day periods; Periods 1 and 2, each from 
check-in on Day -1 (Day -1 procedures can also be completed pre-dose on Day 1 at the 
site’s discretion) through completion of the Day 4 post-dose procedures. During each 
period, subjects will be confined to the clinic during Day -1 through Day 4. To separate 
Periods 1 and 2, a Washout Period will be scheduled to ensure that study drug 
administration is at least 6 days apart and no more than 14 days apart. Subjects will 
receive a follow-up phone call on Day 6 (with a window of + ≤ 2 days) after their second 


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dosing. The total duration of participation, excluding screening period, for each subject 
will be approximately 12-23 days. 
Reference Therapy, Dose, and Mode of Administration: This is an open-label study 
with no reference treatment or placebo. 
Criteria for Evaluation: 
Endpoints: 
 
To evaluate the safety and tolerability of Minocin IV in subjects with renal 
insufficiency and in subjects receiving HD therapy (see below section Safety) 
 
To assess the PK of Minocin IV in subjects with renal insufficiency and in 
subjects receiving HD therapy (see below section Pharmacology) 
Efficacy: Efficacy will not be assessed in this study. 
Safety: 
Assessment of Adverse Events (AEs) will be performed from the first administration of 
Investigational Medicinal Product (IMP) on Day 1 through end-of-study. 
Changes from baseline in physical examination findings, safety laboratory test results, 
ECGs, and vital signs will be evaluated. 
A Data Monitoring Committee (DMC) will review safety data as described in the DMC 
Charter. 
Pharmacology:  
Serial plasma samples will be collected to determine concentrations of minocycline (see 
Section 1.1 Schedule of Events Flowchart). 
Plasma concentrations and PK parameters for Minocin IV will be summarized by time 
point using descriptive statistics (n, mean, standard deviation, coefficient of variation, 
median, minimum, and maximum). Plasma minocycline concentration versus time data 
will be analyzed to estimate the following PK parameters: area under concentration-time 
curve (AUC) from time zero to the time of the last measurable concentration (AUC0-last), 
AUC from time zero to infinity (AUC0-inf), maximum measured plasma concentration 
(Cmax), minimum plasma concentration (Cmin), time to Cmax (Tmax), elimination half-life 
(t1/2), total body clearance (CL), and volume of distribution (VSS) for each subject. 
Methods: 
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 demographic and medical baseline 
characteristics, medications, laboratory values, vital signs and ECG results. Additional 
shift tables will be provided for laboratory values and ECG results. 
AEs will be listed, and number (percentage) of subjects reporting AEs and number 
(percentage) of AEs will be tabulated. Other safety data will be summarized as 
appropriate.   
An analysis of the PK and AEs will be performed based on gender. 


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1.1. 
SCHEDULE OF EVENTS/ASSESSMENTS  
Schedule of Events for Subjects with Mild, Moderate, and Severe Renal Insufficiency and Healthy Volunteers - Groups 1-4 
STUDY DAY► 
SCREEN 
(<28) 
-1[1] 
1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
4  
Final 
Visit 
6 (+≤2) 
Follow-Up 
Call 
STUDY HOUR ► 
 
 
0 
1 
2 
4 
8 
12 
18 
24 
36 
48 
72 
EVENT▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. History / Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Conmed Review 
X 
X-------------------------------------------------------------------------------------------------------------------------- 
BMI 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PE / Charlson Comorbidity Index 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
RR/BP/HR/Temperature 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
ECG (12-lead)[2] 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
Hem/Coag/Chem/UA[3] 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Drug/Alcohol Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test[4] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
 
 
X------------------------------------------------------------------------------------------------------------------ 
CrCl / 24 h urine collection 
 
 
X--------------------------------------------------------------------- 
 
 
 
 
PK Blood Collection 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dose (1 h infusion) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations:  Conmed=concurrent medications; BMI=Body Mass Index; RR=respiratory rate; BP=blood pressure; HR=heart rate; ECG=electrocardiogram; Hem=hematology; 
 Coag=coagulation; Chem=chemistry; UA=urinalysis; CrCl=creatinine clearance; PE=physical examination; PK=pharmacokinetics; h=hour 
1 Day -1 procedures, with the exception of triplicate ECG and assessment of Adverse Events, only need to be repeated if screening was >3 days prior to Day 1.  
Day -1 procedures can also be completed pre-dose on Day 1 at the site’s discretion. 
2 On Day -1, ECGs should be performed in triplicate and may be repeated if necessary at the Investigator or Sponsor’s discretion. 
3 Serum Creatinine from Screening Chemistry will be used for calculation of CrCl for renal function determination. Cockcroft-Gault will be used for Group 4 
(normal renal function) and CKD-EPI 2009 for Groups 1-3 (renal insufficiency). 
4 Serum pregnancy should be performed during screening and Day -1. Urine pregnancy test should be performed before dosing on Day 1. 
 
 


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Schedule of Events for Subjects with End Stage Renal Disease - Group 5 
 
 
Period 1[1]  
Washout Period[2] 
Period 2 [1] 
 
STUDY DAY► 
Screening Period 
(<28) 
-1 
1 
 
2 
3 
(48 h) 
4 
(72 h) 
(Duration 1-9 days) 
-1 
1 
2 
3 
(48 h) 
4 
(72 h) 
6 (+≤2) 
Follow-up Call 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History / Demographics 
X 
X 
 
 
 
 
X 
 
 
 
 
 
Conmed Review 
X 
X-------------------------------------- 
X---------------------------------------- 
X 
BMI 
X 
X 
 
 
 
 
X 
 
 
 
 
 
PE / Charlson Comorbidity Index 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
RR/BP/HR/Temperature[3] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG (12-lead)[4] 
X 
X 
X 
X 
 
X[10] 
X 
X 
X 
 
X[10] 
 
Hem/Coag/Chem 
X 
X 
 
 
 
X[10] 
X 
 
 
X[10] 
 
Drug Screen 
X 
X 
 
 
 
 
X 
 
 
 
 
 
Alcohol Screen 
X 
X 
 
 
 
 
X 
 
 
 
 
 
Pregnancy Test[5] 
X 
(X) 
 
 
 
X[10] 
(X) 
 
 
 
X[10] 
 
Adverse Events[6] 
 
(X) 
X---------------------------- 
(X) 
X-------------------------------X 
X 
Hemodialysis[7] 
 
 
X 
 
(X) 
(X) 
 
X 
(X) 
(X) 
 
Hourly dialysate aliquots[7] 
 
 
X 
 
 
 
 
X 
 
 
 
 
PK Blood Collection[8] 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X 
X[9] 
 
 
 
 
X[9] 
 
 
 
 
 
Dose (1h infusion) – prior to dialysis (Period 1) 
 
 
X 
 
 
 
 
 
Dose (1h infusion) – after dialysis (Period 2) 
 
 
 
 
 
 
X 
 
 
                                                 
[1] Periods 1 and 2 do not have to occur in sequence, but Washout Period is required regardless of order. Procedures denoted by brackets “(X)” vary by period order / subject (see footnotes for each).  
[2] The Washout Period will occur between the Periods 1 and 2, and will be scheduled to ensure that study drug administration is 6-14 days apart. Any AEs will be reviewed at the time of 2nd check-in. 
[3] Vital signs, including RR/BP/HR/Temperature, will be taken at: pre-dose, 1, 4, 24, 48, and 72 hours after the start of dosing for both Periods 1 and 2. 
[4] ECG (12-lead) will be taken at: Day -1 (in triplicate at Day -1 of the 1st period conducted), then at pre-dose, 4, 24, and 72* hours after the start of dosing for both Periods 1 and 2. (*See footnote 10) 
[5] Serum pregnancy test should be performed during screening, the first Day -1 (whichever period is conducted first), and at the final Day 4 visit (whichever period is completed last). 
[6] AEs will be reviewed from Day 1 time of dosing through to the Day 6 [+ ≤2] Follow-Up Call. AEs during the Washout should be recorded at the second Day -1, upon subject’s return to site. 
[7] HD will be done Day 1 pre- or post-dosing, depending on Period (1 or 2), then at Day 3 OR 4, then as per subject’s usual schedule throughout the Washout Period; In Period 1, Day 1, a pre-spent 
dialysate sample is collected prior to initiating HD, then hourly dialysate samples (with aliquots) through the end of HD; In Period 2, Day 1, only a pre-spent dialysate sample is required. 
[8] Plasma samples will be collected for PK assessments at: 0, 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 hours after the start of dosing for both Periods 1 and 2. 
[9] Inclusion/Exclusion Criteria should be checked at Day -1 of whichever period is conducted first (Day -1 before the subject’s first day of dosing). 
[10] Complete these assessments only if Day 4 is the final, end-of-study visit for a subject.  Because Periods 1 and 2 do not have to occur in sequence, the Day 4 of either period may be a subject’s final 
in-patient visit. For the first period (prior to Washout), do not complete these procedures. For an early termination complete all of these procedures. 


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Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
Confidential 
16 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ................................................................... 7 
1.1. 
SCHEDULE OF EVENTS/ASSESSMENTS .................................. 13 
2. 
SCHEMATIC DIAGRAM OF TRIAL DESIGN............................. 15 
3. 
LIST OF ABBREVIATIONS........................................................... 20 
4. 
INTRODUCTION ............................................................................ 23 
4.1. 
Background ....................................................................................... 23 
4.2. 
Minocin IV (Minocycline for Injection) ........................................... 24 
4.2.1. 
Nonclinical Studies ........................................................................... 24 
4.2.2. 
Clinical Studies ................................................................................. 24 
4.2.3. 
Known and Potential Risks and Benefits.......................................... 24 
4.3. 
Study Rationale ................................................................................. 26 
4.4. 
Study Population ............................................................................... 26 
5. 
TRIAL OBJECTIVES AND PURPOSE .......................................... 27 
5.1. 
Objectives ......................................................................................... 27 
6. 
TRIAL DESIGN ............................................................................... 28 
6.1. 
Type/Design of Trial ......................................................................... 28 
6.2. 
Study Endpoints ................................................................................ 29 
7. 
SUBJECT POPULATION ............................................................... 30 
7.1. 
Number of Subjects .......................................................................... 30 
7.2. 
Inclusion Criteria .............................................................................. 30 
7.3. 
Exclusion Criteria ............................................................................. 31 
7.4. 
Withdrawal Criteria .......................................................................... 33 
8. 
TREATMENT OF SUBJECTS ........................................................ 35 
8.1. 
Study Medications ............................................................................ 35 
8.1.1. 
Minocin IV ........................................................................................ 35 
8.1.2. 
Packaging and Labeling .................................................................... 35 
8.1.3. 
Storage .............................................................................................. 35 
8.1.4. 
Accountability ................................................................................... 35 
8.2. 
Concomitant Medications ................................................................. 36 
8.2.1. 
Permitted Concomitant Medications ................................................ 36 
8.2.2. 
Prohibited Concomitant Medications ............................................... 36 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
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8.3. 
Restrictions ....................................................................................... 37 
8.4. 
Blinding ............................................................................................ 37 
9. 
SCHEDULE AND SEQUENCE OF PROCEDURES ..................... 38 
9.1. 
Screening Period (Day -28 to Day -1) .............................................. 38 
9.1.1. 
Screening .......................................................................................... 38 
9.1.2. 
Informed Consent ............................................................................. 38 
9.1.3. 
Subject Confinement ........................................................................ 39 
9.2. 
Study Conduct for Groups 1-4 .......................................................... 39 
9.2.1. 
Check-in Procedures (Day -1) .......................................................... 39 
9.2.2. 
Single-dose Administration of Minocin IV  (Day 1) ........................ 40 
9.2.3. 
Ongoing Clinical Assessment (Day 2) ............................................. 40 
9.2.4. 
Ongoing Clinical Assessment (Day 3) ............................................. 40 
9.2.5. 
Final In-patient Clinical Assessment (Day 4) ................................... 41 
9.2.6. 
Follow-Up Telephone Call (Day 6 + ≤ 2 days) ................................ 41 
9.3. 
Study Conduct for Group 5 HD Subjects – Period 1: Dose 
Administration Prior to Dialysis ....................................................... 41 
9.3.1. 
Check-in Procedures for HD Subjects (Period 1, Day -1) ................ 42 
9.3.2. 
Single-dose Administration of Minocin IV (Period 1, Day 1) ......... 42 
9.3.3. 
Ongoing Clinical Assessment (Period 1, Day 2) .............................. 43 
9.3.4. 
Ongoing Clinical Assessment (Period 1, Day 3) .............................. 44 
9.3.5. 
Ongoing Clinical Assessment (Period 1, Day 4) .............................. 44 
9.4. 
Washout Period ................................................................................. 45 
9.5. 
Study Conduct for Group 5 HD Subjects – Period 2: Dialysis Prior to 
Dose Administration ......................................................................... 45 
9.5.1. 
Check-in Procedures (Period 2, Day -1) ........................................... 45 
9.5.2. 
Single-dose Administration of Minocin IV (Period 2, Day 1) ......... 46 
9.5.3. 
Ongoing Clinical Assessment (Period 2, Day 2) .............................. 46 
9.5.4. 
Ongoing Clinical Assessment (Period 2, Day 3) .............................. 47 
9.5.5. 
Ongoing Clinical Assessment (Period 2, Day 4) .............................. 47 
9.6. 
Study Conduct for Group 5 HD Subjects – Follow-Up Telephone 
Call (last Period Day 6 + ≤ 2 days)................................................... 47 
9.7. 
Early Termination ............................................................................. 48 
10. 
PROTOCOL ASSESSMENTS ........................................................ 49 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
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10.1. 
Assessment of Safety ........................................................................ 49 
10.1.1. 
Adverse Events ................................................................................. 49 
10.1.2. 
Body Mass Index (BMI) ................................................................... 49 
10.1.3. 
Vital Signs ........................................................................................ 49 
10.1.4. 
Physical Exam and Charlson Comorbidity Index ............................. 49 
10.1.5. 
ECG .................................................................................................. 49 
10.1.6. 
Clinical Laboratory Tests ................................................................. 50 
10.1.6.1. 
Hematology ....................................................................................... 50 
10.1.6.2. 
Coagulation ....................................................................................... 50 
10.1.6.3. 
Chemistry .......................................................................................... 50 
10.1.6.4. 
Urinalysis .......................................................................................... 50 
10.1.6.5. 
Human Chorionic Gonadotropin (Pregnancy Test) .......................... 50 
10.1.6.6. 
Testing for Drugs of Abuse .............................................................. 51 
10.1.6.7. 
Breath Alcohol Testing ..................................................................... 51 
10.1.6.8. 
Creatinine Clearance ......................................................................... 51 
10.1.7. 
Birth Control Measures ..................................................................... 51 
10.2. 
Assessment of Efficacy ..................................................................... 52 
10.3. 
Assessment of Pharmacokinetics ...................................................... 52 
10.3.1. 
Sampling and Processing .................................................................. 52 
11. 
ADVERSE EVENTS........................................................................ 53 
11.1. 
Definitions ........................................................................................ 53 
11.1.1. 
Adverse Event ................................................................................... 53 
11.1.1.1. 
AE Severity ....................................................................................... 53 
11.1.1.2. 
Study Drug Causality ........................................................................ 54 
11.1.2. 
Serious Adverse Event ...................................................................... 54 
11.1.3. 
Medication Errors ............................................................................. 55 
11.1.4. 
Adverse Event of Special Interest (AESIs) ...................................... 56 
11.1.5. 
Special Situations .............................................................................. 56 
11.2. 
Procedure for Non-Serious Adverse Event Recording ..................... 56 
11.3. 
Procedure for Serious Adverse Event Reporting .............................. 56 
11.4. 
Procedure for Medication error reporting for Study Drugs .............. 57 
11.5. 
Procedure For Reporting Adverse Events Of Special Interest ......... 57 
11.6. 
Procedure For Reporting Pregnancies/Lactation Exposure .............. 57 


Minocin IV (Minocycline for Injection) 
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11.7. 
Procedure For Reporting Special Situations ..................................... 57 
12. 
DATA COLLECTION ..................................................................... 58 
13. 
STATISTICAL PLAN...................................................................... 59 
13.1. 
Sample Size ...................................................................................... 59 
13.2. 
Randomization .................................................................................. 59 
13.3. 
General Statistical Considerations and Definitions .......................... 59 
13.3.1. 
General Statistical Methods .............................................................. 59 
13.3.2. 
Analysis Population .......................................................................... 59 
13.3.2.1. 
Intent-to-Treat (ITT) Population ....................................................... 59 
13.3.2.2. 
Modified Intent-to-Treat (mITT) Population .................................... 59 
13.3.2.3. 
PK Population ................................................................................... 60 
13.3.2.4. 
Per-Protocol (PP) Population ............................................................ 60 
13.3.2.5. 
Safety Population .............................................................................. 60 
13.3.3. 
Missing Data Handling ..................................................................... 60 
13.4. 
Statistical Analyses ........................................................................... 60 
13.4.1. 
Demographic and Background Characteristics ................................ 60 
13.4.2. 
Study Drug and Concomitant Medications ....................................... 60 
13.4.2.1. 
Adverse Events ................................................................................. 60 
13.4.2.2. 
Laboratory Tests ............................................................................... 60 
13.4.2.3. 
Vital Signs ........................................................................................ 61 
13.4.2.4. 
ECGs ................................................................................................. 61 
13.4.2.5. 
Pharmacokinetic Parameters ............................................................. 61 
14. 
RECORDS RETENTION ................................................................ 62 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE ............... 63 
15.1. 
Monitoring ........................................................................................ 63 
15.2. 
Auditing ............................................................................................ 63 
15.3. 
Protocol Deviations .......................................................................... 63 
16. 
ETHICS AND RESPONSIBILITY .................................................. 64 
16.1. 
Informed Consent ............................................................................. 64 
16.2. 
Ethics Committee .............................................................................. 64 
17. 
CONFIDENTIALITY ...................................................................... 65 
18. 
INVESTIGATOR AGREEMENT ................................................... 66 
19. 
REFERENCES ................................................................................. 67 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
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3. 
LIST OF ABBREVIATIONS 
A. baumannii  
Acinetobacter baumannii 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-inf 
AUC from time 0 to infinity 
AUC0-last 
AUC from 
time 0 to time of the last quantifiable concentration 
BMI 
Body mass index 
BP 
Blood Pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CDAD 
Clostridium difficile-associated diarrhea 
CDC 
Centers for Disease Control and Prevention 
C. difficile 
Clostridium difficile 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
Clearance 
Cmax 
Maximum observed drug concentration 
Cmin 
Minimum observed drug concentration 
CrCl 
Creatinine clearance 
CS 
Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCC 
Clinical Trials Center Cologne 
CTFG 
Clinical Trial Facilitation Group  
d 
Day(s) 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ESA 
Erythropoiesis-stimulating agent 
ESRD 
End-stage renal disease 
EU 
European Union 
FDA 
Food and Drug Administration 
GAIN 
Generating Antibiotic Incentives Now 
GCP 
Good Clinical Practice 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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GPV 
Global Pharmacovigilance Department 
h 
hour 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HD  
Hemodialysis 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals  
IH 
Intracranial hypertension 
IMP 
Investigational medicinal product 
IMSIE  
Institute of Medical Statistics, computer Science and Epidemiology 
INR 
International Normalized Ratio 
ITT 
Intent-to-treat 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
IV 
Intravenous 
kg 
Kilogram(s) 
max 
Maximum 
MDCO 
The Medicines Company 
MDR 
Multi-drug resistant 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
MI 
Myocardial infarction 
min 
Minute(s), Minimum 
mITT 
Modified intent-to-treat 
mL 
Milliliter(s) 
msec 
Milisecond 
n 
Number 
NCS 
Not clinically significant 
NDA 
New drug application 
PE 
Physical exam 
PI 
Principal Investigator 
PK 
Pharmacokinetics  
PP 
Per-protocol 
 
PT 
Prothrombin time 
Q1 
1st Quarter (of the year) 
Q3 
3rd Quarter (of the year) 
QTc 
Corrected QT interval 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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SD 
Standard deviation 
SOP 
Standard Operating Procedure 
t1/2 
Half-life 
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 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
VSS 
Volume of distribution 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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4. 
INTRODUCTION 
This study will evaluate the safety, tolerability, and pharmacokinetics (PK) of Minocin 
IV (Minocycline for Injection).  
Minocycline was first approved in the United States (US) as both oral and intravenous 
(IV) formulations in the 1970s. Only oral dosage formulations of minocycline have been 
approved for use in countries in the European Union (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 Acinetobacter 
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. 
4.1. Background 
Minocycline is a tetracycline derivative. The approved indication for Minocin IV 
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 
(MDR) Acinetobacter infections as a public health risk [EU MEMO/08/788; US 
Generating Antibiotic Incentives Now (GAIN) Act; and Centers for Disease Control 
(CDC) Antibiotic Resistance Threats Report]. 
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]. 
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 stability of minocycline solutions at a more physiological pH, which enables 
administration of minocycline in a smaller volume of fluid. 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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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.   
4.2. 
Minocin IV (Minocycline for Injection) 
Minocin® (minocycline) for Injection, also known as RPX-602 and referred to as 
Minocin IV in this protocol, is an 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). 
4.2.1. Nonclinical Studies 
The non-clinical development program for Minocin IV consists of in vitro antibacterial 
potency studies 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 non-clinical 
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. 
4.2.2. Clinical Studies 
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 data are available from published case report series that indicated successful 
treatment.   
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, 2011; Fagan et al, 2010], and these studies 
utilized multiple doses, at a higher dose level than that being studied here. 
Additional details regarding the clinical studies conducted for Minocin IV can be found 
in the Investigator’s Brochure. 
4.2.3. Known and Potential Risks and Benefits 
In general, the risk of significant adverse events (SAEs) related to 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. 


Minocin IV (Minocycline for Injection) 
Clinical Study Protocol MDCO-MIN-16-03 
The Medicines Company 
 
 
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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. As this is 
a single-dose study, phototoxic reactions are not expected; however, as a precaution, 
subjects will be instructed to limit their exposure to sunlight and ultraviolet light, to wear 
sunglasses and protective clothing, and to use sun protection products (such as sunscreen) 
with a high light protection factor throughout the course of the study.  
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. 
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 blood urea nitrogen 
(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. 


Minocin IV (Minocycline for Injection) 
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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 electrocardiogram [ECG], hematology, coagulation, serum chemistry, 
urinalysis, and adverse event [AE] collection) are adequate to protect the subjects’ safety 
and should detect AEs. 
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 [see references]. 
4.3. Study Rationale 
The purpose of this study is to collect safety, tolerability, and PK data from a single IV 
infusion of Minocin IV administered to subjects with renal insufficiency and subjects 
receiving hemodialysis (HD) therapy as compared to subjects with normal renal function. 
The safety, tolerability, and PK data will support the compound as a potential clinical 
candidate in Europe and allow recommendations of Minocin IV dose levels to be 
administered to renal insufficiency patients.  
4.4. Study Population 
The study is designed to enroll approximately 40 subjects. There will be approximately 
24 subjects with varying degrees of renal insufficiency, approximately 8 subjects with 
normal renal function, and 8 subjects receiving HD therapy.  
 
 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. Objectives 
 To evaluate the safety and tolerability of Minocin IV in subjects with renal 
insufficiency and in subjects receiving HD therapy 
 To assess the PK of Minocin IV in subjects with renal insufficiency and in subjects 
receiving HD therapy 
 


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6. 
TRIAL DESIGN 
6.1. Type/Design of Trial 
This is a Phase I, open-label, single-dose study to assess the safety, tolerability, and PK 
of Minocin IV in adults with varying degrees of renal insufficiency and in adult subjects 
receiving HD therapy as compared to subjects with normal renal function. 
There will be at least 8 subjects assigned to each of the following groups based on 
estimated glomerular filtration rate [eGFR] calculated at screening, using CKD-EPI 2009 
[Levey, A. S. et al, 2009] for Groups 1-3, and using Cockroft-Gault for Group 4 (normal 
renal function). Group 5 is instead assigned by the requirement for HD therapy. 
 Group 1: Mild renal insufficiency (eGFR 60-89 mL/min/1.73m2) 
 Group 2: Moderate renal insufficiency (eGFR 30 to < 60 mL/min/1.73m2) 
 Group 3: Severe renal insufficiency (eGFR < 30 mL/min/1.73m2) not receiving 
HD therapy 
 Group 4: Healthy subjects with normal renal function (eGFR ≥ 90 
mL/min/1.73m2) 
 Group 5: Subjects with end stage renal disease (ESRD) receiving HD therapy 3 
times a week for at least 3 months prior to Day 1 
Subjects with mild, moderate, and severe renal insufficiency (Groups 1, 2, and 3, 
respectively) will be enrolled in the study concurrently. 
Once the mild, moderate, and severe renal insufficiency groups are fully enrolled, healthy 
subjects (Group 4) will be matched to the pooled mean values of age (± 10 years), body 
mass index (BMI; ± 20%), and gender. 
Within Groups 1-4, subjects will receive a single dose on Day 1. Subjects are required to 
remain admitted in the research unit from Day -1 until discharge on Day 4. A follow-up 
phone call will occur on Day 6 (with a window of + ≤ 2 days). 
Group 5 will be enrolled after completion of Groups 1-4. It will include subjects who 
require HD therapy 3 times a week for at least 3 months prior to Day 1. Subjects in 
Group 5 will receive Minocin IV twice over the course of the study, once prior to HD 
therapy (Period 1) and once after (Period 2). Periods 1 and 2 do not have to occur in 
sequence for any given subject. A Washout Period will occur between the 2 Periods 
regardless of the sequence of Periods. The Washout Period will be scheduled to ensure 
that study drug administration is at least 6 days apart and no more than 14 days apart. 
Group 5 subjects will be required to remain admitted in the research unit from Day -1 
until Day 4 of each period. A follow-up phone call will occur on Day 6 (with a window 
of + ≤ 2 days) of the subject’s second period. 
Subjects that discontinue the study early are required to complete Early Termination 
procedures. 


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Safety will be assessed throughout the study, and serial blood samples will be collected 
for the safety and PK assessment of Minocin IV. 
 
A Data Monitoring Committee (DMC) will be compiled for the work package of the IMI 
COMBACTE-Net project. The DMC will review safety data after inclusion of 12 
subjects within Groups 1, 2, and 3, and after completion of Group 4, before dosing of 
Group 5. Details of the DMC’s roles and responsibilities can be found in the DMC 
Charter. 
 
6.2. Study Endpoints 
The endpoints of this trial are:  
o To evaluate the safety and tolerability of Minocin IV in subjects with renal 
insufficiency and in subjects receiving HD therapy; 
o To assess the PK of Minocin IV in subjects with renal insufficiency and in 
subjects receiving HD therapy. 


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7. 
SUBJECT POPULATION 
7.1. Number of Subjects  
The study is designed to enroll approximately 40 subjects. There will be approximately 
24 subjects with varying degrees of renal insufficiency, approximately 8 subjects with 
normal renal function, and 8 subjects receiving HD therapy. 
7.2. Inclusion Criteria 
Subjects will be included in the study if they meet all of the following criteria: 
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 hospital or after discharge, for the duration of the study; 
2.  Adult male or female between 18 and 85 years of age (inclusive) at the time 
of screening; 
3. Subject has a BMI ≥ 18.5 kg/m2 and ≤ 45 kg/m2; 
4. Pulse measured at screening/baseline must be within the ranges ≥ 45 to ≤115 
beats per minute (bpm, taken after resting in a semi-recumbent position for at 
least 5 minutes); 
5. Have sufficient peripheral vascular access, based on the Investigator’s 
assessment, for all PK blood sample collections to take place; 
6. Female subject is surgically sterile (bilateral tubal occlusion), 
postmenopausal, or if of childbearing potential, agrees to abstinence or to use 
a highly efficient method of birth control (i.e., intrauterine device [IUD] or 
intrauterine hormone-releasing system [IUS] or vasectomized male partner, 
or hormonal contraceptives [estrogen and progestogen combined or 
progestogen only] with inhibition of ovulation, oral hormonal contraceptives 
must be supplemented with the use of condoms), between inclusion and for 7 
days after the completion of the study; 
7. Subject agrees to limit exposure or use protective measures (e.g., to wear 
sunglasses, protective clothing, sunscreen with high light protection factor, 
etc.) when in sunlight or ultraviolet light throughout the study; 
Subjects with Renal Insufficiency: 
8. Assessment of renal insufficiency for assignment to study groups will be 
based on measurements of eGFR calculated by CKD-EPI 2009 equation at 
the screening visit to determine eligibility [Levey, A. S. et al, 2009]; 
Subjects with Normal Renal Function: 
9. Normal volunteers matched by age (± 10 years), BMI (± 20%), and gender to 
the pooled mean values of the mild, moderate, and severe renal insufficiency 
groups; 


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10. Have a eGFR ≥ 90 mL/min calculated by Cockroft-Gault equation at the 
screening visit to determine eligibility; 
Hemodialysis Subjects: 
11. Receiving stable HD (Kt/V > 1.2, determined within 6 months before 
inclusion) at least 3 times a week for at least 3 months; 
12. Otherwise considered to be clinically stable with respect to underlying renal 
impairment, as determined by the Investigator, and based upon a medical 
evaluation that includes a medical history, physical examination, laboratory 
tests, and ECG; 
13. Have clinical laboratory test results that are considered clinically stable in the 
opinion of the Investigator, especially if the clinical abnormality or laboratory 
parameter is deemed associated with the subject’s underlying renal 
impairment; 
14. A stable medication regimen is required, defined as not starting new drug(s) 
or significant changes in dosage(s) within 3 weeks prior to Day -1, or during 
the conduct of the study. Changes of medications in HD subjects are subject 
to dialysis site protocols such that erythropoiesis-stimulating agents (ESAs), 
iron, and vitamin D can be changed based on the then current subject status 
and dialysis unit standard practice and subject safety prior to screening. 
7.3. Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following 
at screening or check-in, as appropriate: 
1. Subject with normal renal function has any condition, including findings in 
the medical history or in pre-study assessments, that are capable of altering 
the distribution, metabolism, or elimination of drugs or that constitute a risk 
or a contraindication for the participation in the study or completing the 
study; 
2. Current evidence or history of malignancy, excluding basal cell carcinoma, 
requiring active treatment or management; 
3. Positive breath test for alcohol and/or positive urine test for drugs of abuse at 
screening; 
4. Has a history or presence of alcohol/drug abuse within the 30 days prior to 
enrollment. 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); 
5. Blood or plasma donation within past 2 months; 
6. Vigorous exercise from 48 hours prior to Day -1 until the day of discharge 
from the study; 


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7. Surgery within 48 hours prior to randomization or surgery planned during the 
study period;  
8. Liver function abnormalities at screening (or Day -1) (defined by an elevation 
in bilirubin, aspartate aminotransferase [AST] or alanine aminotransferase 
[ALT] 1.5 x upper limit of normal [ULN] of the normal range for subjects 
based on age and sex); 
9. Raised magnesium levels at screening or Day -1 (defined by an elevation in 
magnesium above the ULN); 
10. Females who are pregnant or nursing or who have a positive pregnancy test 
result at the Screening Visit or Day -1; 
11. Males who are unwilling to practice abstinence or use an acceptable method 
of birth control during the entire study period (i.e., condom with spermicide, 
where locally available);  
12. Presence of known raised intracranial pressure; 
13. Use of isotretinoin; 
14. History of significant hypersensitivity or allergic reaction to tetracycline 
antibiotics; 
15. History of seizures (e.g., epilepsy), head injury, or meningitis requiring 
ongoing anti-seizure medications; 
16. Receipt of any investigational medication or investigational device during the 
last 30 days prior to randomization; 
17. QTc > 500 msec or history of prolonged QT syndrome; 
18. Use of products containing alcohol within 48 hours before dosing; 
19. Unable or unwilling, in the judgment of the Investigator, to comply with the 
protocol; 
20. Subjects that have known active hepatitis B (HBV) or C (HCV), or human 
immunodeficiency virus (HIV) infection or have known immune deficiency 
disease at screening; 
21. Concurrent use of medications known to affect the elimination of serum 
creatinine (e.g., trimethoprim/sulfamethoxazole [Bactrim®] or cimetidine 
[Tagamet®]. See Section 8.2.2 for full list) within 30 days prior to the first 
dose of study drug or anticipated need for these therapies through the last PK 
sample; 
22. An employee of the Investigator or study center or Sponsor, with direct 
involvement in the proposed study or other studies under the direction of that 
Investigator or study center or the Sponsor, or a family member of the 
employee or the Investigator; 
 
 


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Subjects with Renal Insufficiency: 
23. Have a sitting systolic blood pressure (BP) > 180 mm Hg or < 90 mm Hg or 
have a sitting diastolic BP > 110 mm Hg or < 50 mm Hg at the Screening 
Visit; 
24. Use of any other prescription or nonprescription drugs, grapefruit/grapefruit 
juice, or dietary or herbal supplements within 14 days prior to Day -1; 
a. Concomitant medications required to treat underlying renal disease or 
medical conditions related to renal disease are permitted; 
b. Medications required to treat other pre-existing comorbidities and medical 
conditions (not related to renal disease) are permitted, provided that 
dosing is stable for 3 weeks prior to Day -1; 
c. Oral contraceptives are permitted for birth control; 
d. Doses of concomitant medications (except hormonal contraceptives, 
hormone replacement therapy for females, and insulin) must be stable for 
3 weeks prior to Day -1. Minor dose changes consistent with treatment 
practices may be permitted at the discretion of the Sponsor’s Medical 
Monitor; 
e. Acetaminophen/paracetamol (≤ 1 g/day) and low-dose acetylsalicylic acid 
(ASA; i.e., ≤ 325 mg per day) are permitted; 
Subjects with Normal Renal Function: 
25. Abnormal and clinically significant findings on physical examination, 
medical history, serum chemistry, hematology, or urinalysis per Investigator 
discretion; 
26. Have a sitting systolic BP > 150 mm Hg or < 90 mm Hg or have a sitting 
diastolic BP > 90 mm Hg or < 50 mm Hg at the Screening Visit; 
27. Use of any other prescription or nonprescription drugs, grapefruit/grapefruit 
juice, or dietary or herbal supplements within 14 days prior to Day -1; 
a. Oral contraceptives are permitted for birth control; 
b. Acetaminophen/paracetamol (≤ 1 g/day), ibuprofen and low-dose ASA (i.e., 
≤ 325 mg per day) are permitted. 
 
7.4. 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 the following: 


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1. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition or circumstance that indicates to the 
Principal Investigator (PI) that continued participation is not in the best interest 
of the subject and/or does not allow them 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, 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 electronic case report form 
(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 the protocol. 
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 (Day 
4 - final in-patient clinical assessment) as appropriate (see Section 9.2.5 for subjects in 
Groups 1-4, and Section 9.3.5 / Section 9.5.5 for HD subjects in Group 5). 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 withdrawn for reasons other than drug-related AEs with fewer than 4 PK 
samples within 24 hours of dosing will be replaced. Subjects who drop-out/are withdrawn 
before taking any study drug will be replaced. 


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8. 
TREATMENT OF SUBJECTS 
8.1. Study Medications 
Each subject in Groups 1-4 will receive a single 200 mg dose of Minocin IV over 60 
minutes. Subjects in Group 5 will receive a single dose of Minocin IV in Period 1 and 
another single dose in Period 2. 
8.1.1. 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. Two vials will be prepared for each dose to give 200 mg of minocycline. 
Each dose will be reconstituted and further diluted in 100 mL of 0.9% Sodium Chloride 
Injection and administered as a constant rate IV infusion over 1 hour via a single 
dedicated peripheral venous line. If a peripheral line is not an option and a central line is 
in place then this can be used, provided that an appropriate flush is used. Details of 
Minocin IV preparation and administration are included in the study Pharmacy Manual. 
8.1.2. 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. 
8.1.3. Storage 
Minocin IV will be stored in a secure area at room temperature (20 to 25°C). Once 
reconstituted and diluted into an IV bag, Minocin IV may be stored at either room 
temperature for up to 4 hours or refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours. 
Access should be strictly limited to the study pharmacists or designees. 
Further details of Minocin IV storage can be found in the Pharmacy Manual. 
8.1.4. 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 PI or 
designated sub-investigators and may not be used for any purpose other than that outlined 
in this protocol. 
Used (empty) study drug vials may be destroyed on site following recording of dosing on 
the master and individual subject accountability logs by the pharmacist or designee. 
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 


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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. 
8.2. Concomitant Medications 
All medications taken during the 14 days prior to dosing will be recorded and reviewed 
by the PI or their designee. 
8.2.1. 
Permitted Concomitant Medications 
During the study, 1 gram per day or less of acetaminophen/paracetamol and low dose 
ASA (i.e., ≤ 325 mg per day) are permitted. 
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. 
For subjects with renal insufficiency, concomitant medications required to treat 
underlying renal disease or medical conditions related to renal disease are permitted. 
Medications required to treat other pre-existing comorbidities and medical conditions 
(not related to renal disease) are permitted, provided that dosing is stable for 3 weeks 
prior to Day -1 and the medications are not specified in Section 8.2.2, Prohibited 
Concomitant Medications. 
Oral contraceptives are permitted for birth control. 
Doses of concomitant medications (except hormonal contraceptives, hormone 
replacement therapy for females, and insulin) must be stable for 3 weeks prior to Day -1. 
Minor dose changes consistent with treatment practices may be permitted at the 
discretion of the Sponsor’s Medical Monitor. 
8.2.2. 
Prohibited Concomitant Medications 
With the exception of those medications listed in Section 8.2.1 Permitted Concomitant 
Medications, the use of any other prescription or nonprescription drugs, 
grapefruit/grapefruit juice, or dietary or herbal supplements will be prohibited for 14 days 
prior to Day -1 until discharge. 
Several drugs, such as cimetidine, trimethoprim, corticosteroids, pyrimethamine, 
phenacemide, salicylates, and active vitamin D metabolites, have been reported to 
increase plasma creatinine without influencing its glomerular filtration [Andreev E. et al, 
1999]. These medications are prohibited for 30 days prior to the first dose of study drug 
through the last PK sample. 
If 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. 
 


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8.3. Restrictions  
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
 Alcohol: Beverages containing alcohol should not be consumed 48 hours or 
less prior to Day -1 until the end of the study. 
8.4. Blinding  
This is an open-label study. 
 


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9. 
SCHEDULE AND SEQUENCE OF PROCEDURES 
The Study Schedule of Events Tables are outlined in Section 1.1, which summarize the 
study assessments by time point. A schematic diagram of the trial design is provided in 
Section 2. 
The sample times for assessments/procedures are in relation to the start of drug infusion. 
9.1. Screening Period (Day -28 to Day -1) 
9.1.1. 
Screening 
Screening will begin within 28 days prior to first dosing. The subject informed consent 
will be obtained prior to any study procedures being performed. Screening Visit can be 
combined with Day -1 visit. 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:  
 Informed consent 
 Inclusion/exclusion criteria 
 Medical history and demographics 
 Review of concomitant medications 
 BMI calculation (using recorded height and weight) 
 Physical examination 
 Vital signs assessment (systolic and diastolic blood pressure, pulse, 
respiratory rate, and temperature) 
 12-lead ECG administration 
 Hematology, coagulation, serum chemistry, and urinalysis (for HD subjects, 
urinalysis is not required) 
 Urine drug/alcohol screen (for HD subjects, serum or saliva drug screen is 
acceptable) 
 Serum pregnancy test (women of childbearing potential only) 
 Renal function determination using CrCl (calculated by CKD-EPI 2009); 
however, for HD subjects, study admission will be based on receiving HD 
therapy 3 times a week for at least 3 months prior to Day 1. 
9.1.2. 
Informed Consent 
Prior to any study-related activities, an informed consent form (ICF), approved by a 
regional ethics committee (EC), must be personally signed and dated by the subject. The 
format and content of the ICF must be agreed upon by the Investigator(s), appropriate 
regional EC, and Sponsor or designee. The subject’s original signed and dated ICF 
(together with any subsequent amended versions approved by the regional EC must be 


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retained by the Investigator in the subject’s file. A copy of the original signed and dated 
ICF must be given to the subject. 
9.1.3. 
Subject Confinement 
If a subject meets all of the inclusion and exclusion criteria and provides consent, he/she 
may be enrolled in the study and will be admitted to the research unit the day before the 
first dose of study medication. Subjects will remain within the clinic for the duration of 
the single-dose period until completion of the post-dose procedures on Day 4. 
Subjects with HD will participate in two 4-day periods (Periods 1 and 2), and during each 
period, subjects will be confined to the clinic through Day 4. To separate the periods, a 
Washout Period will be scheduled to ensure that study drug administration is at least 6 
days apart and no more than 14 days apart. Subjects are not required to be in the clinic 
during the  
Washout Period. 
9.2. Study Conduct for Groups 1-4 
9.2.1. 
Check-in Procedures (Day -1) 
Day -1 procedures, with the exception of triplicate ECG, only need to be repeated if 
screening was > 3 days prior to Day 1. 
Day -1 procedures may be performed on Day 1, pre-dose, at the site’s discretion. 
Subject eligibility will be reviewed for each subject to ensure that subjects remain 
eligible for the study since screening.  
The following assessments/procedures will be performed:  
 Review of inclusion/exclusion criteria 
 Review of concomitant medications and changes to medical history 
 Review of medical history and update with any new information since 
screening 
 Weight recorded and BMI calculated (using height from screening) 
 Physical examination including components needed to calculate the Charlson 
Comorbidity Index 
 Vital signs: systolic and diastolic blood pressure, pulse, temperature, and 
respirations 
 12-lead ECG (performed in triplicate) 
 Hematology, coagulation, serum chemistry, and urinalysis 
 Urine drug screen 
 Alcohol breath test (only if subject is suspected of being under the influence 
of alcohol 


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 Serum pregnancy test 
9.2.2. 
Single-dose Administration of Minocin IV  
(Day 1) 
The following assessments/procedures will be performed pre-dose on Day 1 (only 
required if Day -1 procedures are completed outside noted time windows): 
 Review of concomitant medications and changes to medical history 
 Review of AEs; 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature before dosing, and at the following times post-dose: 1 and 4 hours 
 12-lead ECG before dosing and at 4 hours post-dose 
 Urine or serum pregnancy test 
Once all pre-dose assessments are completed, the Minocin IV infusion can begin. All 
subjects will receive 200 mg Minocin IV infused over 1 hour 
 Plasma samples will be collected for PK assessments at the following time 
points: pre-dose (0), 1 (end-of-infusion), 2, 4, 8, 12, and 18 hours after dosing  
 Review of AEs 
 24 hour urine collection for creatinine clearance 
9.2.3. 
Ongoing Clinical Assessment (Day 2) 
The following assessments/procedures will be performed on Day 2: 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 24 hours post-dose 
 12-lead ECG at 24 hours post-dose  
 Review of concomitant medications 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 24 and 36 hours after 
dosing 
9.2.4. 
Ongoing Clinical Assessment (Day 3) 
The following assessments/procedures will be performed on Day 3: 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 48 hours post-dose 
 Review of concomitant medications 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 48 hours after dosing 


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9.2.5. 
Final In-patient Clinical Assessment (Day 4) 
Subjects will remain confined until all assessments have been completed on Day 4, or at 
early termination. Should any subject withdraw or be withdrawn from the study, all the 
end-of-study evaluations scheduled for Day 4 (plus plasma PK sample collection) should 
be performed at the time of discontinuation, if possible (see Section 9.7). 
 Review of concomitant medications 
 Physical examination 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature 
 12-lead ECG 
 Hematology, coagulation, serum chemistry, and urinalysis 
 Serum pregnancy test 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 72 hours post dosing 
9.2.6. 
Follow-Up Telephone Call (Day 6 + ≤ 2 days) 
On Day 6 (plus a ≤ 2 day window), subjects will be contacted once by telephone to 
determine the status of ongoing AEs and concomitant medications. Subject-reported data 
will be documented in the subject’s study-specific files and included in the clinical 
database, as appropriate. 
9.3. Study Conduct for Group 5 HD Subjects – Period 1: Dose 
Administration Prior to Dialysis 
In order to determine the impact of HD on the PK of Minocin IV, PK blood samples will 
be collected in the same subjects (Group 5) at a time when Minocin IV is administered 
immediately prior to HD and again at a time when Minocin IV is administered 
immediately following HD. The two administrations will be separated by a Washout 
Period.  
For Group 5 during Period 1, study drug administration will occur prior to dialysis on 
Day 1, and subjects will remain in the clinical center until completion of all study 
assessments on Day 4. Subsequent dialysis will be done at either Day 3 or Day 4, 
following as close as possible to the subject’s usual HD therapy schedule (when 
applicable).  
For Group 5 during Period 2, dialysis will occur prior to study drug administration on 
Day 1, and subjects will remain in the clinical center until completion of all study 
assessments on Day 4. Subsequent dialysis will be done at either Day 3 or Day 4, 
following as close as possible to the subject’s usual HD therapy schedule (when 
applicable).  


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Periods 1 and 2 do not have to occur in sequence for any given subject. Therefore, the 
final in-patient evaluations will be on Day 4 of Period 1 or 2, whichever period occurs 
second.  
Dialysis will be done following subject’s usual HD therapy schedule throughout the 
Washout Period and follow-up period. 
Should any subject withdraw or be withdrawn from the study, all the end-of-study 
evaluations scheduled for Day 4 (plus plasma PK sample collection) should be performed 
at the time of discontinuation, if possible (see Section 9.7). 
9.3.1. 
Check-in Procedures for HD Subjects (Period 1, Day -1) 
The Day -1 procedures may be performed on Day 1, pre-dose at the site’s discretion. 
 Inclusion/Exclusion Criteria should be reviewed at Day -1 of whichever 
period is conducted first (Day  -1 before the subject’s first day of dosing) 
 AEs that occurred during the Washout Period should be reviewed at Day -1 of 
whichever period is conducted second (Day -1 before the subject’s second day 
of dosing). 
 Review of concomitant medications 
 Review of medical history and update with any new information since 
screening (only for Day  -1 of whichever period is conducted first) 
 Weight recorded and BMI calculated (using height from screening)  
 Physical examination including components needed to calculate the Charlson 
Comorbidity Index 
 Vital signs: systolic and diastolic blood pressure, pulse, temperature, and 
respirations 
 12-lead ECG (to be performed in triplicate at Day -1 of whichever period is 
conducted first [Day  -1 before the subject’s first day of dosing]) 
 Hematology, coagulation, and serum chemistry 
 Saliva drug screen 
 Alcohol breath test (only if subject is suspected of being under the influence 
of alcohol) 
 Serum pregnancy test (only for Day -1 of whichever period is conducted first) 
 
9.3.2. 
Single-dose Administration of Minocin IV (Period 1, Day 1) 
The following assessments/procedures will be performed on Pre-Dose on Day 1 (only 
required if Day -1 procedures are completed outside noted time windows): 
 Review of concomitant medications 


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 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature before dosing, and at the following hours post-dose: 1, and 4 
hours 
 12-lead ECG before dosing and at 4 hours post-dose 
 The study drug IV infusion lock and PK sampling lock should be placed in the 
arm opposite of the HD access. The PK sampling lock should be placed distal 
to the IV infusion lock to prevent contamination of the PK samples. If a 
peripheral line is not an option and a central line is in place then this can be 
used, provided that an appropriate flush is used. Instances where the infusion 
and/or PK lock cannot be placed in this manner should be discussed with the 
Sponsor to ensure the infusion and sample collection is not compromised. 
 Once all pre-dose assessments/procedures are completed, the Minocin IV 
infusion can begin. All subjects will receive 200 mg Minocin IV infused over 
1 hour. 
 The infusion should be scheduled so that infusion ends approximately 2 hours 
BEFORE dialysis is started 
 Plasma samples will be collected for PK assessments at the following time 
points: pre-dose (0), 1 (end-of-infusion), 2, 4, 8, 12, and 18 hours after dosing  
 Transport subject from the clinical center to the dialysis center (if required) 
 Complete HD therapy session using a non-reuse dialyzer 
 Collect a pre-spent dialysate sample prior to initiating HD and then hourly 
dialysate samples (with aliquots) during dialysis and through the end of 
dialysis 
 Upon completion of dialysis, return the subject to the clinical center 
 Review of AEs 
 
9.3.3. 
Ongoing Clinical Assessment (Period 1, Day 2) 
The following assessments/procedures will be performed on Day 2, period 1: 
 Review of concomitant medications 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 24 hours post-dose 
 12-lead ECG at 24 hours post-dose 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 24 and 36 hours after 
dosing 


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9.3.4. 
Ongoing Clinical Assessment (Period 1, Day 3) 
The following assessments/procedures will be performed on Day 3, period 1: 
 Review of concomitant medications 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 48 hours post-dose 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 48 hours after dosing 
 HD therapy can be completed on Day 3 or at Day 4, before or after other 
procedures, per the subject’s usual frequency of HD therapy. 
 Complete HD therapy session using a non-reuse dialyzer 
9.3.5. 
Ongoing Clinical Assessment (Period 1, Day 4) 
Subjects will remain confined until all assessments have been completed on Day 4 of 
period 1. 
The following assessments/procedures will be performed on Day 4: 
 Review of concomitant medications 
 Physical examination 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 72 hours 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 72 hours after dosing 
 HD therapy can be completed on Day 3 or at Day 4, before or after other 
procedures, per the subject’s usual frequency of HD therapy. 
 Complete HD therapy session using a non-reuse dialyzer 
 Release from clinical center 
Because Periods 1 and 2 do not have to occur in sequence, this visit may be a subject’s 
final in-patient clinical assessment visit. If this visit is the final in-patient clinical 
assessment visit for a subject, the following additional assessments should be conducted: 
 12-lead ECG at 72 hours post-dose 
 Hematology, coagulation, and serum chemistry 
 Serum pregnancy test 
 


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9.4. Washout Period 
The Washout Period will occur between the 2 periods regardless of the sequence of 
periods. Therefore, subjects will be released from the clinical center after completion of 
all study assessments on Day 4 of Period 1 or 2, whichever period is first. The Washout 
Period will be scheduled to ensure that study drug administration is at least 6 days apart 
and no more than 14 days apart, so it will be between 1 and 9 days in duration. 
Subjects will be encouraged to contact the site and provide details of any AEs that occur 
during the Washout Period. Adverse events that occurred during the Washout Period will 
be reviewed at the time of check-in for whichever period is second. 
9.5. Study Conduct for Group 5 HD Subjects – Period 2: Dialysis 
Prior to Dose Administration 
9.5.1. 
Check-in Procedures (Period 2, Day -1) 
The following assessments/procedures will be performed:  
 Inclusion/Exclusion Criteria should be reviewed at Day -1 of whichever 
period is conducted first (Day -1 before the subject’s first day of dosing) 
 AEs that occurred during the Washout Period should be reviewed at Day -1 of 
whichever period is conducted second (Day -1 before the subject’s second day 
of dosing). 
 Review of adverse events (only AEs related to the study should be captured 
on Day -1 of whichever period is conducted first for a subject, and unrelated 
events should be captured as medical history) 
 Review of concomitant medications 
 Review of medical history and update with any new information since 
screening (only for Day -1 of whichever period is conducted first) 
 Weight recorded and BMI calculated (using height from screening)  
 Physical examination including components needed to calculate the  Charlson 
Comorbidity Index  
 Vital signs: systolic and diastolic blood pressure, pulse, temperature, and 
respirations 
 12-lead ECG (to be performed in triplicate at Day -1 of whichever period is 
conducted first [Day  -1 before the subject’s first day of dosing]) 
 Hematology, coagulation, and serum chemistry 
 Saliva drug screen 
 Alcohol breath test (only if subject is suspected of being under the influence 
of alcohol) 
 Serum pregnancy test (only for Day -1 of whichever period is conducted first) 


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9.5.2. 
Single-dose Administration of Minocin IV (Period 2, Day 1) 
The following assessments/procedures will be performed Pre-Dose on Day 1 (only 
required if Day-1 procedures are completed outside noted time windows): 
 Review of concomitant medications 
 Review of AEs 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature before dosing, and at the following hours post-dose: 1, and 4 
hours 
 12-lead ECG before dosing and at 4 hours post-dose 
 A pre-spent dialysate sample is collected prior to initiating HD 
 Complete HD therapy session using a non-reuse dialyzer 
 Transport subject from the clinical center to the dialysis center and back once 
HD is complete (if transportation to another unit is required) 
 The study drug IV infusion lock and PK sampling lock will be placed in the 
arm opposite of the HD access. The PK sampling lock will be placed distal to 
the IV infusion lock to prevent contamination of the PK samples. If a 
peripheral line is not an option and a central line is in place then this can be 
used, provided that an appropriate flush is used. Instances where the infusion 
and/or PK lock cannot be placed in this manner should be discussed with the 
Sponsor to ensure the infusion and sample collection is not compromised. 
 Once all pre-dose assessments/procedures and dialysis are completed the 
Minocin IV infusion can begin. All subjects will receive 200 mg Minocin IV 
infused over 1 hour. 
 The infusion should be scheduled so that infusion begins approximately 
2 hours AFTER dialysis is completed 
 Plasma samples will be collected for PK assessments at the following time 
points: pre-dose (0), 1 (end-of-infusion), 2, 4, 8, 12, and 18 hours after dosing  
9.5.3. 
Ongoing Clinical Assessment (Period 2, Day 2) 
The following assessments/procedures will be performed on Day 2, period 2: 
 Review of concomitant medications 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 24 hours post-dose 
 12-lead ECG at 24 hours post-dose 
 Plasma samples will be collected for PK assessments at 24 and 36 hours after 
dosing 
 Review of AEs 


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9.5.4. 
Ongoing Clinical Assessment (Period 2, Day 3) 
The following assessments/procedures will be performed on Day 3, period 2: 
 Review of concomitant medications 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 48 hours post-dose 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 48 hours after dosing 
 HD therapy can be completed on Day 3 or at Day 4, before or after other 
procedures, per the subject’s usual frequency of HD therapy. 
 Complete HD therapy session using a non-reuse dialyzer 
9.5.5. 
Ongoing Clinical Assessment (Period 2, Day 4) 
Subjects will remain confined until all assessments have been completed on Day 4, 
period 2.  
The following assessments/procedures will be performed on Day 4: 
 Review of concomitant medications 
 Physical examination 
 Vital signs: systolic and diastolic blood pressure, pulse, respiration rate, and 
temperature at 72 hours 
 Review of AEs 
 Plasma samples will be collected for PK assessments at 72 hours after dosing 
 HD therapy can be completed on Day 3 or at Day 4, before or after other 
procedures, per the subject’s usual frequency of HD therapy. 
 Complete HD therapy session using a non-reuse dialyzer 
 Release from clinical center 
Because Periods 1 and 2 do not have to occur in sequence, this visit may be a subject’s 
final in-patient clinical assessment visit. If this visit is the final in-patient clinical 
assessment visit for a subject, the following additional assessments should be conducted: 
 12-lead ECG at 72 hours post-dose 
 Hematology, coagulation, and serum chemistry 
 Serum pregnancy test 
9.6. 
Study Conduct for Group 5 HD Subjects – Follow-Up 
Telephone Call (last Period Day 6 + ≤ 2 days) 
Following the final in-patient clinical assessment visit (Day 4 of Period 1 or 2, whichever 
period occurs second), subjects will be contacted by telephone for study follow-up. On 


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Day 6 (plus a ≤ 2 day window), subjects will be contacted once by telephone to 
determine status of ongoing AEs and concomitant medications. Subject-reported data will 
be documented in the subject’s study-specific files and included in the clinical database, 
as appropriate. 
9.7. 
Early Termination 
An Early Termination Visit is required for any subject that discontinues the study prior to 
Day 4 (or the final period Day 4, for Group 5 HD subjects). All Day 4 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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10. 
PROTOCOL ASSESSMENTS 
10.1. 
Assessment of Safety  
10.1.1. 
Adverse Events  
Subjects will be carefully monitored for AEs by the Investigator during the designated 
study period (see Section 11 for details).   
10.1.2. 
Body Mass Index (BMI) 
BMI will be calculated using the following equation: 
BMI= Weight (kg)/Height (m2) 
10.1.3. 
Vital Signs  
Vital signs assessments will include systolic and diastolic blood pressure, pulse, body 
temperature, and respirations. 
Subjects should be resting in a semi-recumbent position for at least 5 minutes prior to and 
during vital signs measurements.  
10.1.4. 
Physical Exam and Charlson Comorbidity Index 
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. 
Presence or history of the components of the Charlson Comorbidity Index will also be 
collected at screening and Day -1. The Charlson Comorbidity Index involves recording 
specific medical conditions, (e.g., myocardial infarction, dementia, chronic obstructive 
pulmonary disease, etc.) against the index to provide an overall score and to estimate 
prognosis [Charlson, Mary E. et al., 1987]. 
Physical examination may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
10.1.5. 
ECG 
12-lead ECGs will be assessed. 
Triplicate 12-lead ECGs, each separated by at least 1 minute, will be taken at Day -1 (For 
Group 5: Day -1 of the first period conducted). ECGs will be taken following resting in 
the semi-recumbent position for 5 minutes. The average value for the triplicate will be 
utilized for assessing QTc 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): 
 QTc increase from baseline triplicate average > 30 msec 
 QRS duration > 130 msec 


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 PR interval > 240 msec 
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. 
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. 
10.1.6. 
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. Abnormal lab ranges must be documented as 
CS or NCS by a study Investigator and filed with the source documents. 
At a minimum, the following lab tests should be performed during the designated time 
points: 
10.1.6.1. Hematology 
Hemoglobin, Hematocrit, White blood cell count (with automated differential), Red 
blood cell count, Platelet count 
10.1.6.2. Coagulation 
Activated partial thromboplastin time (aPTT), international normalized ratio (INR) 
10.1.6.3. Chemistry 
Urea, 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, Phosphorus 
10.1.6.4. Urinalysis  
Midstream urine sample analyzed by dipstick (Note: microscopic examination of 
sediment will only occur if a strong positive result is observed). 
10.1.6.5. Human Chorionic Gonadotropin (Pregnancy Test) 
Pregnancy tests are required for women of childbearing potential only.  


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10.1.6.6. Testing for Drugs of Abuse  
Amphetamines, barbiturates (not in saliva test screen), benzodiazepines, cannabinoids, 
cocaine, methadone, and opiates will be tested in urine for Groups 1-4, in saliva for 
Group 5. 
10.1.6.7. Breath Alcohol Testing 
Breath alcohol test is only required for subjects suspected of being under the influence of 
alcohol. 
10.1.6.8. Creatinine Clearance 
Estimated glomerular filtration rate will be calculated at screening by CKD-EPI 2009 
equation (subjects with renal insufficiency) or Cockroft-Gault (subjects with normal renal 
function) equation, to assign subjects to group [Levey, A. S. et al, 2009]. 
For subjects in Groups 1, 2, 3, and 4, a 24 hour urine collection will be done on Day 1 to 
determine creatinine clearance for further analysis of data. 
10.1.7. 
Birth Control Measures 
Female subjects that are not postmenopausal are expected to use highly effective birth 
control measures as defined by the European Heads of Medicines Agencies Clinical Trial 
Facilitation Group (CTFG) between randomization and for 7 days after the completion of 
the study. Highly effective methods of birth control are [UK MHRA, 2014]: 
 combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
o  oral (in combination with male condom) 
o intravaginal  
o transdermal 
 progestogen-only hormonal contraception associated with inhibition of 
ovulation 
o oral (in combination with male condom) 
o injectable 
o implantable 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomized partner 
 sexual abstinence 
There is no evidence of a drug-drug interaction between tetracyclines and hormonal 
contraceptives [RCOG, 2012]. There is some possibility that antibiotics in general can 


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change the gut flora and potentially inhibit absorption of hormonal contraceptives, but 
there is no recommendation to practice additional barrier contraception with these agents. 
In consideration of CTFG guidance [UK MHRA, 2014] and in the absence of data from a 
clinical PK interaction study, subjects in this trial must only use oral hormonal 
contraceptives when in combination with male condom. 
10.2. 
Assessment of Efficacy  
Efficacy will not be assessed in this study. 
10.3. 
Assessment of Pharmacokinetics  
The PK sample collection times are all from the start of the study drug infusion. 
10.3.1. 
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 
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. 
 


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11. ADVERSE EVENTS  
11.1. 
Definitions 
11.1.1. 
Adverse Event 
Adverse Event (AE): Any untoward medical occurrence in a subject or clinical trial 
subject administered a medicinal product and which 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. 
The date and time of onset, duration, and outcome (resolved, improved, unchanged, 
worse, fatal, or unknown/lost to follow-up) of each event will be noted. All AEs will be 
reported in detail as indicated on the eCRF. 
 
11.1.1.1. 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 
Common Terminology Criteria for Adverse Events (CTCAE) as follows: 
Grade 1 = mild 
Grade 2 = moderate 
Grade 3 = severe 
Grade 4 = life-threatening or disabling 
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 
selfcare 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. 
11.1.1.2. 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 investigational medicinal product (IMP).  
No Reasonable possibility - There are few to no facts (evidence) or arguments to suggest 
a causal relationship between the event and the IMP.  
11.1.2. 
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 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 


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might not be immediately life threatening or result in death or 
hospitalization but might jeopardize the subject 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. 
o 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. 
11.1.3. 
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 subject (i.e., not administered to the intended subject) 
Medication Errors include occurrences of overdose and underdose of the study drug, and 
abuse and misuse. 
Overdose: Unintentional administration of a quantity of the study drug given per 
administration or per day that 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. 
Underdose: Unintentional administration of a quantity of the study drug given per 
administration or per day that 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 that 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. 


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11.1.4. 
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. 
11.1.5. 
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 Pregnancy/lactation exposures with or without any AEs related to the parent 
or child 
o Suspected transmission via a medicinal product of an infectious agent 
o Drug interactions 
o Occupational exposure 
o Unexpected benefit 
 
11.2. 
Procedure for Non-Serious Adverse Event Recording 
All non-serious AEs that occur from the first administration of IMP through the Follow-
Up Call (Day 6 [+ ≤ 2]), must be assessed and recorded on the source documents and 
eCRF regardless of causal relationship to the study drug. 
All AEs, occurring throughout the study or at the Final Visit, considered possibly or 
probably related to the study drug, will be followed until the subject is stable or the AE is 
resolved. 
11.3. 
Procedure for Serious Adverse Event Reporting 
Note: This procedure may need to be followed for reporting Special Situations. 
All SAEs that occur from the first administration of IMP through the Follow-Up Call 
(Day 6 [+ ≤ 2]), must be reported to the Sponsor’s Global Pharmacovigilance (GPV) 
Department or its designated representative 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. 


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The Investigator must assess the causality for each SAE/AESI. 
The Sponsor or its designated representative 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 or its designated representative on an updated 
SAE/AESI Report Form as soon as it becomes available. 
If the Investigator is notified of a SAE/AESI that occurs post-study period, that he or she 
wishes to report to the Sponsor or its designated representative (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 EC and/or national regulatory authority in addition to the 
Sponsor. 
11.4. 
Procedure for Medication error reporting for Study Drugs 
Medication errors with or without an associated AE as described in Section 11.1.3 need 
to be recorded as medication errors in the eCRF. 
Medication errors with an associated SAE need to be recorded as medication errors in the 
eCRF and reported to the Sponsor’s GPV Department or its designated representative as 
described in Section 11.1.2. 
A mis-dosing protocol deviation (refer to Section 15.3) would need to be reported as a 
medication error if it was an “unintended error” as defined in Section 11.1.3. 
11.5. 
Procedure For Reporting Adverse Events Of Special Interest 
There are no AESIs identified for the study drug, Minocin IV, in this protocol. 
11.6. 
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 SAE, the Serious 
Adverse Event Report 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 that 
occurs from the first administration until 30 days after last dose needs to be reported. 
11.7. 
Procedure For Reporting Special Situations 
If there is an occurrence of a Special Situation event, defined in Section 11.1.4, report 
this occurrence to the Sponsor as per Section 11.3, Procedure for Serious Adverse Event 
Reporting. Note: The Special Situations event does not need to be serious to be reported 
on the SAE/AESI Report form. 


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12. 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 Clinical Trials Center Cologne. All users 
will be trained on the technical features of the EDC as well as the content of the eCRF via 
an e-learning course prior to gaining access to the EDC. A UserID/Password will be 
granted after training. This ID 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 5 
days after the Day 4 visit (of each period for Group 5) and 3 days after the Day 5-7 
follow-up. 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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13. 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 the Institute of Medical Statistics, Informatics and Epidemiology 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. 
13.1. 
Sample Size 
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. It has been determined adequate to meet 
the study objectives. Eight subjects per group are planned, hence n = 40 subjects in total. 
13.2. 
Randomization 
This is an open-label, single-dose study, with only one active arm and no randomization. 
13.3. 
General Statistical Considerations and Definitions 
13.3.1. 
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 
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. An analysis of the PK and AEs will be performed based on gender. No 
interim analysis is planned. 
13.3.2. 
Analysis Population 
The following populations will be used for data analyses and/or presentation. 
13.3.2.1. Intent-to-Treat (ITT) Population  
All subjects enrolled into the trial. Classification will be based on the subject’s group 
(degree of renal function). 
13.3.2.2. Modified Intent-to-Treat (mITT) Population 
All ITT subjects who receive at least one dose of study drug. 


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13.3.2.3. PK Population 
All subjects who have any valid samples measured for study drug levels. This will be 
used for PK analysis. 
13.3.2.4. 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 data review before database lock. 
This will be the supportive population for the analyses. 
13.3.2.5. Safety Population 
The safety set will be the mITT population (for definition see Section 13.3.2.2). 
13.3.3. 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from 
the associated analysis. 
13.4. 
Statistical Analyses 
13.4.1. 
Demographic and Background Characteristics 
Subject demographics and baseline characteristics will be summarized descriptively by 
subject’s group (degree of renal function) using the ITT, mITT, PK, and PP. 
13.4.2. 
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 subject’s group (degree of renal 
function). Medications will be coded using the most updated version of the World Health 
Organization (WHO) Drug Dictionary available (e.g., version WHODDE 01 DEC 2015 
or later).  
13.4.2.1. Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for 
coding AEs. The current version will be used when coding is started. All AEs are listed 
by subject with severity, relationship to study drug, and subject’s group. 
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, and subject’s group. AE analysis is done for Safety Population. 
13.4.2.2. Laboratory Tests 
Laboratory values will be summarized descriptively by group, including changes and 
percent changes from baseline at each time point.  
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 


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be performed and separated by each of the laboratory parameters. A shift analysis by 
normal range will be done, which counts the number of subjects with a low, normal, or 
high value at baseline and a low, normal, or high value post-baseline. 
13.4.2.3. Vital Signs 
Change and percent change from baseline in vital signs will be summarized descriptively 
at each scheduled time point by treatment group. 
13.4.2.4. 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 NCS, and CS abnormality by group and time point 
of collection. 
13.4.2.5. Pharmacokinetic Parameters  
The plasma concentration-time data for minocycline will be analyzed by non-
compartmental methods. Groups 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. 
Detailed methods used and the results obtained will be included in a separate PK report. 


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14. RECORDS RETENTION 
Current EU Directives / Regulations and International Conference on Harmonization 
(ICH) guidelines collectively require that essential clinical trial documents (including 
case report forms) other than subject’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 CA, United States Food and Drug Administration 
(FDA), and/or other regulatory agencies. 
 


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15. QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Monitoring 
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 
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.   
15.2. 
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. 
15.3. 
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, 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. 
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 


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16. ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard 
operating procedures (SOPs) and/or guidelines, the FDA regulations, the ICH GCP 
guidelines, the Declaration of Helsinki, and other local regulations, as applicable. 
16.1. 
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. 
16.2. 
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 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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17. 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. 
Sponsor commits to comply with all applicable data protection laws and regulations and 
take all appropriate measures to ensure that subjects’ data is processed securely and 
appropriately. Sponsor adheres to the privacy principles of notice, choice, accountability 
for onward transfer, security, data integrity, purpose limitation, access, and enforcement 
regarding the collection, use, and retention of personal information from European 
Economic Area countries and Switzerland. In addition, Sponsor’s Global Commercial 
General Liability with Umbrella Liability and Global Products / Clinical Trial Liability 
policy includes coverage for the processing of subjects’ data. 


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18. 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 International Conference on Harmonization (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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19. REFERENCES 
 
Andreev, E. et al. A rise in plasma creatinine that is not a sign of renal failure: which 
drugs can be responsible? J Intern Med. 246(3):247-52 (1999) 
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). 
Charlson, Mary E. et al. A new method of classifying prognostic comorbidity in 
longitudinal studies: Development and validation. Journal of Chronic Diseases. 40 (5): 
373–83 (1987) 
Fagan, S. C. et al. Minocycline to improve neurologic outcome in stroke (MINOS): a 
dose-finding study. Stroke 41, 2283-2287 (2010). 
Generating Antibiotic Incentives Now (GAIN) Act, United States, 2012. 
Levey, A. S. et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern 
Med. 150(9): 604–612 (2009) 
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 [package insert] Parsippany, NJ: The Medicines Company; April 2015. 
Minocin IV Investigator’s Brochure, Edition 1, August 2015. 
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. 
RCOG Faculty of Sexual & Reproductive Healthcare. Clinical Guidance - Drug 
Interactions with Hormonal Contraception, Clinical Effectiveness Unit. 2012:1755-103X 
Shlaes DM, Sahm D, Opiela C et al. The FDA reboot of antibiotic development. 
Antimicrobial Agents and Chemotherapy. 2013;57:4605-07. 
UK MHRA. Recommendations related to contraception and pregnancy testing in clinical 
trials. Advisory non-binding guidance supported by national competent authorities 
represented at the CTFG-meeting in Rome 2014-09-15. 2014 
 


This is a representation of an electronic record that was signed electronically.
This page is a manifestation of the electronic signature(s).
Signature Page for MDCO-CLIN-002575 v1.0
Approval
David Sylvester
Clinical
30-Aug-2017 15:27:34 GMT+0000
Approval
Jeff Loutit
Medical
31-Aug-2017 01:33:52 GMT+0000
Approval
Liz Morgan
Clinical
06-Sep-2017 00:10:09 GMT+0000

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Minocin 702  
Statistical Analysis Plan 
Page 3 of 33 
SAP_Minocin_702_V04 
 
V04 
Content 
1 
Background ....................................................................................................................... 4 
1.1 
Trial objective ............................................................................................................. 4 
1.2 
Trial design ................................................................................................................ 4 
1.3 
Timing of Analyses ..................................................................................................... 9 
1.4 
Sample Size ............................................................................................................... 9 
2 
Analysis populations ......................................................................................................... 9 
2.1 
Definitions .................................................................................................................. 9 
2.2 
Application ................................................................................................................. 9 
2.3 
Major protocol violations / Withdrawals .................................................................... 10 
3 
Trial centres .................................................................................................................... 10 
4 
Analysis variables ........................................................................................................... 10 
4.1 
Demography and baseline characteristics ............................................................... 10 
4.2 
Variables for safety and tolerability analysis ............................................................ 13 
4.3 
PK Variables ............................................................................................................ 16 
5 
Handling of missing values and outliers .......................................................................... 17 
5.1 
Missing values ......................................................................................................... 17 
5.2 
Outliers ..................................................................................................................... 17 
6 
Statistical analyses / methods ......................................................................................... 17 
6.1 
Patient / Subject Disposition .................................................................................... 17 
6.2 
Demography and baseline characteristics ............................................................... 18 
6.3 
Prior or concomitant medication and diseases ........................................................ 18 
6.4 
Study drug administration ........................................................................................ 18 
6.5 
Exposition to treatment/Compliance ........................................................................ 18 
6.6 
Analysis of safety and tolerability ............................................................................. 19 
6.6.1 
Adverse events/Serious adverse events .......................................................... 19 
6.6.2 
Laboratory tests (Hematology, Chemistry, Urinalysis) ...................................... 20 
6.6.3 
Vital signs ......................................................................................................... 20 
6.6.4 
ECGs ................................................................................................................ 20 
6.6.5 
Physical Examination ........................................................................................ 20 
6.6.6 
Charlson Comorbidity Index ............................................................................. 21 
6.6.7 
Creatinine clearance ......................................................................................... 21 
6.6.8 
HD therapy and dialysate sampling .................................................................. 21 
6.6.9 
Medication error ................................................................................................ 21 
6.7 
Pharmacokinetic analyses ....................................................................................... 21 
6.8 
Planned subgroup analyses ..................................................................................... 21 
6.9 
Interim analyses ....................................................................................................... 21 
7 
Deviations from the protocol ........................................................................................... 21 
8 
Interpretation of results ................................................................................................... 21 
9 
Data problems ................................................................................................................. 22 
10  Software .......................................................................................................................... 22 
11  References ...................................................................................................................... 22 
12  Appendices ..................................................................................................................... 23 
12.1 
Reference ranges of laboratory parameters ......................................................... 23 
12.2 
Planned tables ...................................................................................................... 25 
12.3 
Planned listings .................................................................................................... 30 
12.4 
Planned graphics .................................................................................................. 32 
12.5 
List of abbreviations ............................................................................................. 33 
 
 
 


Minocin 702  
Statistical Analysis Plan 
Page 4 of 33 
SAP_Minocin_702_V04 
 
V04 
1 
Background 
This analysis plan details the analyses that will be performed for Minocin 702 Trial, a phase 1 
study. 
1.1 
Trial objective 
To evaluate the safety and tolerability of Minocin IV (Minocycline for Injection) in subjects 
with renal insufficiency and in subjects receiving hemodialysis (HD) therapy. 
To assess the pharmacokinetics (PK) of Minocin IV in subjects with renal insufficiency and in 
subjects receiving HD therapy. 
1.2 
Trial design 
This is a Phase 1, open label, single dose study to assess the safety, tolerability, and PK of 
intravenously administered Minocin IV in adults with varying degrees of renal insufficiency 
and in adult subjects receiving HD therapy as compared to subjects with normal renal 
function. 
There will be at least eight subjects assigned to each of the following groups based on 
estimated glomerular filtration rate (eGFR) calculated at screening, using CKD-EPI 2009 for 
Groups 1-3, and using Cockroft-Gault for Group 4 (normal renal function). Group 5 is instead 
assigned by the requirement for HD therapy. 
 
Group 1: Mild renal insufficiency (eGFR 60-89 mL/min/1.73m2) 
 
Group 2: Moderate renal insufficiency (eGFR 30 to < 60 mL/min/1.73m2) 
 
Group 3: Severe renal insufficiency (eGFR < 30 mL/min/1.73m2) not receiving HD 
therapy 
 
Group 4: Healthy subjects with normal renal function (eGFR ≥ 90 mL/min/1.73m2) 
 
Group 5: Subjects with end stage renal disease (ESRD) receiving HD therapy 3 times 
a week for at least 3 months prior to Day 1 
Subjects with mild, moderate, and severe renal insufficiency (Groups 1, 2, and 3, 
respectively) will be enrolled in the study concurrently. 
Once the mild, moderate, and severe renal insufficiency groups are fully enrolled, healthy 
subjects (Group 4) will be matched to the pooled mean values of age (± 10 years), body 
mass index (BMI; ± 20%), and gender. 
Group 5 will be enrolled after completion of Groups 1 - 4. It will include subjects who require 
HD therapy 3 times a week for at least 3 months prior to Day 1. Subjects in Group 5 will 
receive Minocin administered intravenously twice over the course of the study, once before 
HD therapy (Period 1) and once after (Period 2). Periods 1 and 2 do not have to occur in 
sequence for any given subject. A Washout Period will occur between the 2 Periods 


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regardless of the sequence of the Periods. The Washout Period will be scheduled to ensure 
that study drug administration is at least 6 days apart and no more than 14 days apart. 
The planned length of participation in the study for each subject with mild, moderate, or 
severe renal insufficiency and normal renal function (excluding screening) is approximately 5 
days from check-in on Day -1 (Day -1 procedures can also be completed pre-dose on Day 1 
at the site’s discretion) through completion of the Day 4 post-dose procedures. Subjects will 
remain within the clinic for the duration of the single dose period until completion of the post-
dose procedures on Day 4. Subjects will receive a follow-up phone call on Day 6 (with a 
window of + ≤2 days). The total duration of participation, excluding screening period and 
including follow-up call, for each subject will be approximately 7-9 days. 
Subjects with HD will participate in two 5 day periods; Periods 1 and 2, each from check-in 
on Day -1 (Day -1 procedures can also be completed pre-dose on Day 1 at the site’s 
discretion) through completion of the Day 4 post-dose procedures. During each period, 
subjects will be confined to the clinic during Day -1 through Day 4. To separate Periods 1 
and 2, a Washout Period will be scheduled to ensure that study drug administration is at 
least 6 days apart and no more than 14 days apart. Subjects will receive a follow-up phone 
call on Day 6 (with a window of + ≤ 2 days) after their second dosing. The total duration of 
participation, excluding screening period, for each subject will be approximately 12-23 days. 
Subjects that discontinue the study early are required to complete Early Termination 
procedures. 
Safety will be assessed throughout the study, and serial blood samples will be collected for 
the safety and PK assessment of Minocin IV. 
The schedule of events/assessments is given in Figure 1-1 and Figure 1-2 and a schematic 
diagram of trial design is shown in Figure 1-3.  
The study is planned to take place over approximately 24 weeks depending on rate of 
enrollment. 


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1.3 
Timing of Analyses 
After completion of the last visit of the last subject, when (at best) 40 subjects passed the 
complete trial, 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).  
1.4 
Sample Size 
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. It has been determined adequate to meet the study 
objectives. Eight subjects per group are planned, hence n = 40 subjects in total. 
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 enrolled into the trial.  
Modified Intent-to-Treat (mITT) Population 
All ITT subjects who receive at least one dose of study drug. 
Pharmacokinetics (PK) Population 
All subjects who have any valid samples measured for study drug levels. This will be used for 
PK analysis.  
Per-Protocol (PP) Population 
All mITT subjects who received their assigned study drug according to protocol. For 
Group 5, the time between dosing and HD therapy during Period 2 must not exceed 3h. 
The PP population will be the supportive population for the analyses. 
Safety Population 
The safety set will be the mITT population. 
2.2 
Application 
Decision on the analysis populations is made prior to data lock. 


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The safety population and the PP 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. Drop-outs will be listed with group, time and 
reason (see 12.3, 2.). 
3 
Trial centres 
This clinical trial will be carried out at a single German study site –  
University Hospital Cologne 
Department II for Internal Medicine 
Kerpener Str. 62 
50937 Koeln, Germany 
The planned sample size is 8 subjects per cohort for all 5 groups. 
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 (Period 1). 
The following demographic variables will be analyzed: 
 
Age [years] 
 
Sex [M, F] 
 
Race [White, Black, Asian, Hawaii, Indian, Other] 
 
Estimated glomerular filtration rate (eGFR) 
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] 


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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] 
 
Charlson Comorbidity Index 
o Myocardial infarct [Yes, No] 
o Congestive heart failure [Yes, No] 
o Peripheral vascular disease [Yes, No] 
o Dementia [Yes, No] 
o Chronic pulmonary disease [Yes, No] 
o Connective tissue disease [Yes, No] 
o Ulcer disease [Yes, No] 
o Mild liver disease [Yes, No] 
o Diabetes [Yes, No] 
o Hemiplegia [Yes, No] 
o Moderate or severe renal disease [Yes, No] 
o Diabetes with end organ damage [Yes, No] 
o Any tumor [Yes, No] 
o Leukemia [Yes, No] 
o Lymphoma [Yes, No] 
o Moderate or severe liver disease [Yes, No] 
o Metastatic solid tumor [Yes, No] 
o AIDS [Yes, No] 
o Sum of score 
 
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] 
 
12-lead-ECG 
o ECG result [normal, clinically insignificant abnormality, clinically significant 
abnormality, not assessable] 
     For each ECG measurement (1., 2. and 3. measurement): 
o ECG Mean Ventricular Rate [bpm] 
o PR Interval [msec] 


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o QRS Duration [msec] 
o QT Interval, uncorrected [msec] 
o QT Interval, corrected [msec] 
 
Laboratory Tests 
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 [%; clinical significant] 
 
Basophils [%; clinical significant] 
 
Monocytes [%; clinical significant] 
 
Lymphocytes [%; clinical significant] 
 
Red blood cell counts [x10^12/l; clinical significant] 
 
Platelet count [x10^12/l; clinical significant] 
 
Prothrombin Intl. Normalized Ratio (INR) [%; clinical significant] 
 
Activated partial thromboplastin time (aPTT) [sec; clinical significant] 
o Safety Lab: Chemistry 
 
Urea [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] 
 
Asparate 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] 
 
Phosphorus [mmol/L; clinical significant] 


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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 [negative, positive; clinical significant] 
 
Additional microscopic exam [yes, no; clinical significant] 
 
Alcohol and drug screening 
o Alcohol [negative, positive] 
o Drug [negative, positive] 
 
Pregnancy test 
o Pregnancy test not done [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: 
 
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] 
o Causality to Study Drug [reasonable possibility, no reasonable possibility, 
unclassified, unclassifiable] 
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] 


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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 4 Period 1, Day  4 Period 2 (only Group 5)) 
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 [%; clinical significant] 
 
Basophils [%; clinical significant] 
 
Monocytes [%; clinical significant] 
 
Lymphocytes [%; clinical significant] 
 
Red blood cell counts [x10^12/l; clinical significant] 
 
Platelet count [x10^12/l; clinical significant] 
 
Prothrombin Intl. Normalized Ratio (INR) [%; clinical significant] 
 
Activated partial thromboplastin time (aPTT) [sec; clinical significant] 
o Safety Lab: Chemistry 
 
Urea [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] 
 
Asparate 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] 


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 
Lactate dehydrogenase [U/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 [negative, positive; clinical significant] 
 
Additional microscopic exam [yes, no; clinical significant] 
 
Vital Signs (Day 1 (1h, 4h), Day 2 - 4, Period 1 and Period 2 (only Group 5)) 
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 (4h), Day 2, Day 4, Period 1 and Period 2 (only Group 5)) 
o ECG result [normal, clinically insignificant abnormality, clinically significant 
abnormality, not assessable] 
     For each ECG measurement (1., 2. and 3. measurement): 
o ECG Mean Ventricular Rate [bpm] 
o PR Interval [msec] 
o QRS Duration [msec] 
o QT Interval, uncorrected [msec] 
o QT Interval, corrected [msec] 
 
Physical Examination (Day 4, Period 1 and Period 2 (only Group 5)) 
o Height [cm] 
o Weight [kg] 
o BMI [kg/m2] 
o Skin [normal, abnormal, not done] 
o Head [normal, abnormal, not done] 
o Ears, eyes, nose and throat [normal, abnormal, not done] 
o Respiratory system [normal, abnormal, not done] 


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o Cardiovascular system [normal, abnormal, not done] 
o Gastrointestinal system [normal, abnormal, not done] 
o Neurological condition [normal, abnormal, not done] 
o Blood and lymphatic system [normal, abnormal, not done] 
o Musculoskeletal system [normal, abnormal, not done] 
o Other [normal, abnormal, not done] 
 
Charlson Comorbidity Index (Day 4, Period 1 and Period 2 (only Group 5)) 
o Sum of score 
 
Creatinine clearance (Day 1, Period 1 (only Group 1 - 4)) 
o Result [Unit] 
 
HD therapy and dialysate sampling (only Group 5: Day 1, Period 1 and 2) 
o Dialysis performed [yes, no] 
o Start date of dialysis [DD/MM/YYYY] 
o Start time of dialysis [HH:MM] 
o End of dialysis [HH:MM] 
o Planned time of sampling [HH:MM] 
o Time of sampling [HH:MM] 
o Sampling not done [yes, no] 
 
Medication error (Day 1, Period 1 and Period 2 (only Group 5)) 
o Are there any medication errors [yes, no] 
o Kind of medication error [wrong study drug, overdose, underdose, wrong route 
of administration, abuse of medicinal product, misuse, wrong patient, other] 
o Medication error associated with AE/SAE [yes, no] 
4.3 
PK Variables 
Plasma samples for PK analysis will be collected relative to dosing. The actual sampling 
times will be used in the parameter calculations and PK parameters will be derived using 
standard non-compartmental methods in Phoenix WinNonLin® version 6.2 or higher. 
The following Plasma PK parameters will be assessed from the plasma concentration of 
single dose of Minocin IV will be derived. 
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 
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If required then additional parameters will be derived and included in CSR. The maximum 
plasma concentration (Cmax), the time of maximum concentration (tmax) will be determined by 
inspection of the concentration-time profiles. The AUC0-t will be calculated using the linear 
trapezoidal rule. Where appropriate, the AUC0-t will be extrapolated to infinity using λz to 
obtain AUC0-inf. 
5 
 Handling of missing values and outliers 
5.1 
Missing values 
Missing values will not be imputed. Instead, subjects withdrawn for reasons other than drug 
related AEs with fewer than 4 PK samples within 24 hours of dosing (at either period for 
Group 5 subjects) will be replaced. Subjects who drop-out/are withdrawn before taking any 
study drug will be replaced. 
If subjects drop-out after dosing but before end of study all data collected up until the time of 
subject withdrawal is to be entered into the electronic case report form (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. 
5.2 
Outliers 
A special outlier handling is not done. 
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). 
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 and with 
given written informed consent). 


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Definition of mITT population: All ITT subjects with number of administered infusions ≥ 1. 
Definition of PP population: All mITT subjects with number of administered infusions = 1 
(Group 1 - 4) or 2 (Group 5), number of administered doses per protocol = 1 (Group 1 - 4) or 
2 (Group 5). For Group 5: Time between dose and HD therapy <= 3h and the time difference 
between the two doses is 6 and 14 days. 
Definition of PK population: All subjects with at least one administered infusion and any valid 
PK blood or urine sampling. 
Definition of safety population: All subjects of the mITT population. 
Absolute and relative frequencies of patients per group 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) will serve as the 
baseline value. For Group 5 the baseline for Period 2 will be updated after Washout Period 
with the last measurement before second dosing (Day -1 or Day 1 of Period 2). 
Demographic and baseline variables will be summarized descriptively by group (for Group 5 
both baselines, at period 1 and 2 will be described) for the safety and PP population. For 
demographics, the total of groups 1 to 5 at the baseline of Period 1 will be given. 
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 group and patients 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 group. 
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, 6.). 
6.5 
Exposition to treatment/Compliance 
Number of subjects in the ITT population with number of administered infusions = 0 (Group 1 
to 4) and = 0/1 (Group 5) will be calculated per group. 


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Listing of drop-outs will be given (see 2.3 and 12.3, 2.). 
6.6 
Analysis of safety and tolerability 
Variables for the analysis of safety and tolerability will be evaluated in the safety population 
as well as in the PP population. 
Tables and listings presented by group will always list ‘Group 5 dose before HD’ and ‘Group 
5 dose after HD’ separately. 
6.6.1 Adverse events/Serious adverse events 
All AEs occurring from the time when informed consent is obtained at screening up to the last 
follow-up visit (phone call on Day 6) are listed by subject with group, AE number, AE Term, 
preferred term (MedDRA dictionary), primary system-organ class, start date, start time, end 
date, end time, ongoing at study end, severity, causality, therapy, therapy specification, 
outcome and seriousness (see 12.3, 3.). 
Additionally, all SAEs will be listed by subject with 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, 4.). 
Listing of AE and SAE will be done separated by pre- and post-treatment. For Group 5 in 
Period 2 only Day -1 and Day 1 (before dosing) are considered as pre-treatment. 
In the following section a treatment emergent adverse event (TEAE) defines an AE that 
occurred or worsened after the start of the treatment. 
The total number (percentage) of TEAEs will be tabulated by 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 TEAEs will be tabulated by group 
and classified by: 
1. any TEAE, related TEAE, unrelated TEAE, 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 TEAEs or SAEs, related and not related to study drug, then the 
subject is counted as related (‘causality’ = yes). If a subject has multiple TEAEs/SAEs with 


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the same preferred term, it is counted only once. Likewise, if a subject has multiple TEAEs 
with the same preferred term but different severities, the maximal severity is used and the 
subject is counted only once. 
6.6.2 Laboratory tests (Hematology, Chemistry, Urinalysis) 
Laboratory variables will be summarized descriptively by group, including mean change and 
mean percent change 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 Day 4, of each parameter 
will be given by group. For Group 1 - 4 one table per variable is given for baseline vs. Day 4. 
For Group 5, comparisons of baseline vs. Day 4 for both periods, dose before and after HD 
therapy, are given (see Table 12-8). 
6.6.3 Vital signs 
Vital signs will be summarized descriptively by group, including mean change and mean 
percent change from (period-corresponding) 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 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 group for 
each scheduled time point. Additionally, a shift table (see Table 12-8) will be presented for 
ECGs results for each group (Group 1 - 4), comparing baseline to Day 4. For Group 5, 
comparisons of baseline vs. Day 4 for both periods, dose before and after HD therapy, are 
given. 
6.6.5 Physical Examination 
Physical examination variables will be summarized descriptively by group for each scheduled 
time point. 
Furthermore, for all variables assessed as normal/abnormal/not done, normal-abnormal shift 
tables (see Table 12-8) will be presented by group. For Group 1 - 4 one table per variable is 
given baseline vs. Day 4. For Group 5, comparisons of baseline vs. Day 4 for both periods, 
dose before and after HD therapy, are given. 


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6.6.6 Charlson Comorbidity Index 
Sum of score will be summarized descriptively by group for each scheduled time point with 
additional rows for mean change and mean percent change from (period-corresponding) 
baseline (see Table 12-7). 
6.6.7 Creatinine clearance 
Result of creatinine clearance will be summarized descriptively by group (only Group 1 - 4). 
6.6.8 HD therapy and dialysate sampling 
Number of performed dialysis and number of dialysate samples are summarized 
descriptively for Group 5. 
6.6.9 Medication error 
Occurrence of medication errors, kind of medication errors and associations with AE/SAE will 
be summarized descriptively. Additionally medication errors will be listed with kind of 
medication error, other error specification, medication error associated with AE/SAE and 
referring AE No (see 12.3, 5.). 
6.7 
Pharmacokinetic analyses 
Pharmacokinetic variables will be evaluated in the PK population. 
6.8 
Planned subgroup analyses 
Analysis of PK and analysis of AEs will be performed stratified by sex. 
6.9 
Interim analyses 
Not applicable. 
7 
Deviations from the protocol 
Additional to all pre-specified analyses in the study protocol this SAP contains further 
sections with specifications concerning the analysis of Physical Examination, Charlson 
Comorbidity Index, Creatinine Clearance, HD therapy and dialysate sampling and Medication 
error. 
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-16-03, Version 2.0, final 30-NOV-16. 
 
 


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12 Appendices 
12.1 Reference ranges of laboratory parameters 
 
Hemoglobin (male): 13.5 – 18 g/dl 
 
Hemoglobin (female): 12 – 16 g/dl 
 
Hematocrit (male): 42 – 50 % 
 
Hematocrit (female): 36 – 45 % 
 
White blood cell count: 4.4 – 11.3 x10^9/l 
 
Neutrophils abs.: 2 – 7.5 x10^9/l 
 
Neutrophils: 53 – 75 % 
 
Eosinophils: 2 – 4 % 
 
Basophils: 0 – 2 % 
 
Monocytes: 25 – 40 % 
 
Lymphocytes: 2 – 14 % 
 
Red blood cell count (male): 4.5 – 5.9 x10^12/l 
 
Red blood cell count (female): 4 – 5.2 x10^12/l 
 
Platelet count: 150 – 400 x10^9/l 
 
Prothrombin Intl. Normalized Ratio (INR): 2 – 4.5 
 
Activated partial thromboplastin time (aPTT): 22 – 36 sec 
 
Urea: 0 – 50 mg/dl 
 
Serum Creatinine (male): 0.5 – 1.1 mg/dl 
 
Serum Creatinine (female): 0.5 – 0.9 mg/dl 
 
Total Bilirubin: 0 – 1.2 mg/dl 
 
Direct Bilirubin: 0 – 0.3 μmol/L 
 
Alkaline phosphatase (male): 40 – 130 U/L 
 
Alkaline phosphatase (female): 35 – 105 U/L 
 
Asparate transaminase (male): 0 – 50 U/L 
 
Asparate transaminase (female): 0 – 35 U/L 
 
Alanine transaminase (male): 0 – 50 U/L 
 
Alanine transaminase (female): 0 – 35 U/L 
 
Albumin: 35 – 52 g/L 
 
Total protein: 66 – 87 g/L 
 
Glucose: 74 – 109 mg/dL 
 
Calcium (age: 18 – 60 years): 2.04 – 2.59 mmol/L 
 
Calcium (age: 60 – 90 years): 1.93 – 2.60 mmol/L 
 
Chloride: 97 – 108 mmol/L 


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 
Sodium: 135 – 145 mmol/L 
 
Magnesium: 0.7 – 1.1 mmol/L 
 
Potassium: 3.6 – 4.8 mmol/L 
 
Uric acid (male): 3.4 – 7.0 mg/dl 
 
Uric acid (female): 2.4 – 5.7 mg/dl 
 
Lactate dehydrogenase: 0 – 250 U/L 
 
Phosphorus: 0.81 – 1.45 mmol/L 
 
pH: 5 - 8 
 
Specific gravity: 1.010 - 1.025 g/L 
 
Physical examination results are assessed as normal/abnormal and (if abnormal) 
clinically significant yes/no in the eCRF.  
 
 


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12.2 Planned tables  
All tables with stratification by group follow the group order Group 4, 1, 2, 3, Group 5 dose 
before HD, Group 5 dose after HD. For simplification the following presentation contains 
example groups (‘X’, ‘Y’ and ‘Z’). 
 
Table 12-1 Table of quantitative variables. 
 
Group X 
(n = ) 
Group Y 
(n = ) 
Group Z 
(n = ) 
Total 
(n = ) 
Quantitative 
Variable 1 
n 
 
 
 
 
mean 
 
 
 
 
SD 
 
 
 
 
median 
 
 
 
 
Q1 
 
 
 
 
Q3 
 
 
 
 
min 
 
 
 
 
max 
 
 
 
 
Quantitative 
Variable 2 
n 
 
 
 
 
mean 
 
 
 
 
SD 
 
 
 
 
median 
 
 
 
 
Q1 
 
 
 
 
Q3 
 
 
 
 
min 
 
 
 
 
max 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


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Table 12-2 Table of qualitative variables. 
 
 
Group X 
(n = ) 
Group Y 
(n = ) 
Group Z 
(n = ) 
Total 
(n = ) 
Total 
n 
 
 
 
 
Qualitative Variable 1 
 
 
 
 
 
Expression 1 
n 
 
 
 
 
 
c% 
 
 
 
 
Expression 2 
n 
 
 
 
 
 
c% 
 
 
 
 
Qualitative Variable 2 
 
 
 
 
 
Expression 1 
n 
 
 
 
 
 
c% 
 
 
 
 
 
… 
 
 
 
 
 
Table 12-3 AE tabulation. 
 
Group X
Group Y 
Group Z 
Total 
System-
organ 
class 
SOC 1 
n (%) 
… 
 
 
SOC 2 
… 
 
 
 
… 
 
 
 
 
Preferred 
term 
Term 1 
 
 
 
 
Term 2 
 
 
 
 
… 
 
 
 
 
Severity 
Grade 1 
 
 
 
 
… 
 
 
 
 
Grade 5 
 
 
 
 
Causality 
Reasonable possibility 
 
 
 
 
No reasonable possibility 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 12-4 AE tabulation (version 1). 
 
Group X 
Group Y 
Group Z 
Total 
AE 
any 
n (%) 
… 
 
 
 
related 
… 
 
 
 
 
unrelated  
 
 
 
SAE 
any 
 
 
 
 
 
related 
 
 
 
 
 
unrelated  
 
 
 
 
Table 12-5 AE tabulation (version 2). 
 
 
Group X 
Group Y
Group Z 
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 
Group X 
Group Y 
Group Z 
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 Shift table for quantitative variables (mean (percent) change from (period-
corresponding) baseline). 
 
Group X 
(n = ) 
Group Y 
(n = ) 
Group Z 
(n = ) 
Total 
(n = ) 
Quantitative 
Variable 1 
n 
 
 
 
 
mean 
 
 
 
 
SD 
 
 
 
 
median 
 
 
 
 
Q1 
 
 
 
 
Q3 
 
 
 
 
min 
 
 
 
 
max 
 
 
 
 
mean 
change 
 
 
 
 
mean % 
change 
 
 
 
 
Quantitative 
Variable 2 
n 
 
 
 
 
mean 
 
 
 
 
SD 
 
 
 
 
median 
 
 
 
 
Q1 
 
 
 
 
Q3 
 
 
 
 
min 
 
 
 
 
max 
 
 
 
 
mean 
change 
 
 
 
 
mean % 
change 
 
 
 
 
… 
 
 
 
 
 
 
Table 12-8 Shift table for qualitative variables. 
 
Baseline, Period x 
Category 1 
Category 2 
… 
Total 
Day 4, 
Period x 
Category 1 
n (%) 
… 
 
 
Category 2 
… 
 
 
 
… 
 
 
 
 
Total 
 
 
 
 
 
 


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12.3 Planned listings 
1. 
Prior or concomitant medication by subject (see 6.3) 
Group ID 
Medication 
(tradename) 
WHO drug 
name 
Indication
Total daily 
dose 
Unit Route of 
administration
xx 
xx 
xxxxx 
xxxxx 
xxxxx 
xxx 
xx 
xxxxx 
 
Start date 
More than 2 weeks 
before dosing 
End date 
Ongoing at 
study end 
dd.mm.yyyy 
x 
dd.mm.yyyy 
x 
2. 
Drop-outs with group, time, reason (Day 1 - Day 6, Period 1/2) (see 2.3, 0) 
ID 
Group 
Date 
Time 
Reason 
xx 
xx 
dd.mm.yyyy 
hh:mm 
xxxxx 
3. 
All AEs 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 and group (see 
6.6.1) 
ID 
Group AE 
No. 
AE 
Term 
Preferred 
term 
(MedDRA)
System-organ 
class 
Start date 
Start 
time 
xx 
xx 
xx 
xxxxx xxxxx 
xxxxx 
dd.mm.yyyy hh:mm 
 
End date 
End time 
Ongoing at the 
end of study 
Severity
Causality
Therapy 
dd.mm.yyyy 
hh:mm 
x 
xx 
xx 
x 
 
 
 
4. 
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 and group (see 
6.6.1) 
ID Group SAE 
No. 
AE 
No. 
Preferred 
term 
(MedDRA) 
System-
organ class 
Date AE 
turned 
serious 
Time AE 
turned serious 
xx xx 
xx 
xx 
xxxxx 
xxxxx 
dd.mm.yyyy
hh:mm 
 
 
 
 
Therapy 
specification 
Outcome 
Seriousness 
CRF comment 
xxxxx 
xx 
x 
xxxxx 


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SAE 
diagnosis 
Results 
in death 
Life-
threatening
Results in significant 
damage 
Hospitalization 
xxxxx 
x 
x 
x 
x 
 
 
 
5. 
Medication error (see 6.6.9) 
ID 
Group Are there any 
medication 
errors 
Kind of 
medication 
error 
Other error 
specification
Medication 
error associated 
with AE/SAE? 
Referring 
AE No. 
xx 
xx 
x 
xxxxx 
xxxxx 
x 
xx 
 
6. 
Study Drug Administration (see 6.4) 
ID 
Infusion 
administered 
Start date 
Start 
time 
End date 
End 
time 
xx 
x 
dd.mm.yyyy
hh:mm
dd.mm.yyyy
hh:mm
 
 
Congenital anomaly 
or birth defect 
Another medically 
significant event 
Description 
of event 
CRF 
comment 
x 
x 
xxxxx 
xxxxx 
Reasons for not 
per protocol 
Residual 
volume (ml) 
xxxxx 
xx 


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12.4 Planned graphics 
 
 
Figure 12-1 Flow chart. 
 
 
 
Allocation
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= )
Analysis
Analysed for mITT (n= )
‐ Excluded from analysis (give reasons) (n= )
Analysed for mITT (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= )
Excluded (n= )
‐ Declined to participate (n= )
‐ Other reasons (n= )
Allocated to Group 1 (n= )
‐ Received allocated intervention (n= )
‐ Did not receive allocated intervention (give 
reasons) (n= )
Group 2, 3, 4
Analogous
Allocated to Group 5 (n= )
‐ Received allocated intervention (n= )
‐ Did not receive allocated intervention (give 
reasons) (n= )
Signed informed consent (n= )
Consent


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12.5 List of abbreviations 
AE 
Adverse Event 
BMI 
Body mass index 
BR 
Breathing rate 
c% 
Column percent 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CTCC 
Clinical Trial Centre Cologne 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiography 
HD 
Hemodialysis 
HR 
Heart rate 
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 
NCS 
Not clinically significant 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
Q1 
First quartile 
Q3 
Third quartile 
RR 
Blood pressure (Scipione Riva-Rocci) 
SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization