A Multi-Center, Randomized, Double-Blind, Parallel-Group, Controlled Study to Assess the Efficacy, Safety and Tolerability of Oral DFD-29 Extended Release Capsules for the Treatment of Inflammatory Lesions of Rosacea Over 16 Weeks
Phase: PHASE2
Conditions: Rosacea
Sponsor: Dr. Reddy's Laboratories Limited

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 1 of 107 
Version 01. Eff. Template date 21-Sep-2012 
 
Protocol title: A Multi-Center, Randomized, Double-Blind, Parallel-Group, Controlled 
Study to Assess the Efficacy, Safety and Tolerability of Oral DFD-29 Extended Release 
Capsules for the Treatment of Inflammatory Lesions of Rosacea over 16 weeks 
 
 
 
Protocol ID 
DFD-29-CD-002 
QPS study code 
160382 
Authors 
Dr. Jessica Prattner 
Dr. Martina Brandner 
 
Document type 
Clinical Study Protocol  
Study Phase 
2 
Document status/version 
final, Amendment IV 
Date 
02 October 2018 
EudraCT number 
2016-003197-41 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of this 
study, Dr. Reddy’s. It is therefore provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an Ethics Committee or Institutional Review Board. It is 
understood that this information will not be disclosed to others without written authorization from Dr. Reddy’s, 
except to the extent necessary to obtain informed consent from those persons to whom the study drug may be 
administered. 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 2 of 107 
Version 01. Eff. Template date 21-Sep-2012 
KEY STUDY FACILITIES 
 
CRO 
 
QPS Austria GmbH 
 
 
Parkring 12 
 
 
 
 
 
 
8074 Grambach, Austria 
 
CENTRAL LABORATORY: 
 
Labor Dr. Spranger & Partner 
 
 
 
 
 
 
Lindberghstr. 9-13 
 
 
 
 
 
 
85051 Ingolstadt, Germany 
 
 
 
 
 
 
Phone +49-841-973 920  
 
 
 
 
 
 
info@ingolab.de 
 
PHARMACY: 
 
ABF Pharmaceutical Services GmbH 
Gastgebgasse 5-13 
1230 Vienna, Austria  
Phone +43 1 890 12 00 20 
Email: Martin.Zeppetzauer@abf-pharma.com 
 
DATA MANAGEMENT: 
 
QPS Netherlands B.V. 
 
 
Clinical Research Europe 
 
 
Petrus Campersingel 123 
 
 
 
 
 
 
9713 AG Groningen, the Netherlands 
 
PHARMACOVIGILANCE  
 
Dr. Reddy’s Laboratories Ltd 
 
 
 
 
Clinical Pharmacovigilance 
 
 
 
 
Dr. Shahida Hasan, MD 
 
 
 
 
Associate Director 
 
 
 
 
107 College Road East 
 
 
 
 
Princeton, NJ 08540 USA 
 
 
 
 
Fax: +1 609-228-5402 
 
 
 
 
Email: sae@drreddys.com 
 
MEDICAL MONITOR: 
 
 
QPS: 
 
 
 
 
 
 
Antón Alvarez, MD, PhD 
Country and Clinical Research Director QPS 
Holdings, LLC 
Ronda de Nelle 22, E2 
15005 A Coruña, Spain  
Phone +34 981 236718| 
Fax +34 881 090633  
Email: anton.alvarez@qps.com 
 
 
 
 
 
 
 
Dr. Reddy’s: 
Dr. Usha Ranganathan, MD  
Associate Director Clinical Development 
Dr. Reddy’s Laboratories Ltd  
Princeton, NJ 08540 
United States of America 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 3 of 107 
Version 01. Eff. Template date 21-Sep-2012 
Phone: +1-609 4557 138 (Direct)  
uranganathan@drreddys.com 
 
SPONSOR:  
Dr. Reddy’s Laboratories Ltd., India  
8-2-337, Road No. 3, 
Banjara Hills, Hyderabad 
Telangana 500034, India 
Phone: +91-40-4900 2900 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 5 of 107 
Version 01. Eff. Template date 21-Sep-2012 
2 SIGNATURE PAGE FOR INVESTIGATOR 
 
Investigational product name 
DFD-29 (minocycline HCl) Extended Release Capsules 
 
Protocol number  
DFD-29-CD-002 
 
I agree to the terms and conditions relating to this study as defined in this Study Protocol, 
electronic Case Report Form (eCRF), and any other protocol-related documents. I fully 
understand that any changes instituted by the investigator(s) without previous agreement with 
the sponsor would constitute a violation of the study protocol, including any ancillary studies 
or procedures performed on study subjects (other than those procedures necessary for the 
well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki and its 
amendments, International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines and applicable regulations and laws. In particular, I will obtain approval by 
an Ethics Committee or Institutional Review Board (EC/IRB) prior to study start and signed 
informed consent from all subjects included in this study. In addition, I will allow direct 
access to source documents and agree to inspection by auditors from the sponsor and Health 
Authorities. I will ensure that the study drug(s) supplied by the sponsor are being used only 
as described in this protocol. Furthermore, I confirm herewith that the sponsor is allowed to 
enter and utilize my professional contact details and function in an electronic database for 
internal purposes and for submission to worldwide Health Authorities. 
 
 
 
 
 
 
 
Name (print) 
Principal Investigator 
 
Signature 
 
Date 
 
 
Name institution (print) 
 
 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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PROTOCOL CHANGES LOG  
Amendment IV, dated 02 October 2018, Amendment III, dated 26 February 2018, Amendment II, dated 01 August 2017, Amendment I issued 
29 May 2017. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20EC of the European 
Parliament and the Council of the European Union. 
An additional analysis set, the Full Analysis Set (FAS), was defined in the study protocol. In addition to the changes stated below, minor 
typographic errors have been corrected. 
 
Section Reference 
Old text 
Amended text 
Header and 
Title page 
Clinical Study Protocol 
26 February 2018, Amendment III 
Clinical Study Protocol 
26 February 2018, Amendment III 02 October 2018, Amendment 
IV 
Section 8.3.2  
Study Drug 
Supply and 
Packaging 
DFD-29 (minocycline HCl) Extended Release Capsules and 
placebo for DFD-29 will be supplied by Dr. Reddy´s 
Laboratories as 30 count in HDPE bottle. The study drug 
will be imported by QPS and further managed by ABF 
DFD-29 (minocycline HCl) Extended Release Capsules and 
placebo for DFD-29 will be supplied by Dr. Reddy´s 
Laboratories as 30 25 count in HDPE bottle. The study drug 
will be imported by QPS and further managed by ABF. 
Section 10.2 
Analysis 
Population 
Four different analysis sets are defined. Subjects who 
withdraw from the study, or who have missing data, will be 
included in the statistical analyses provided that they are 
eligible for inclusion in the analysis population as described 
below. 
 
Intention to treat population: This analysis population 
includes all subjects who have been randomized and 
dispensed the study drug. 
Four different analysis sets are defined. Subjects who 
withdraw from the study, or who have missing data, will be 
included in the statistical analyses provided that they are 
eligible for inclusion in the analysis population as described 
below. 
 
Full analysis set (FAS): This analysis population includes 
all subjects who have been randomized and had at least one 
post baseline efficacy assessment. The FAS population will 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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Safety population: This analysis population includes 
subjects who had at least one safety assessment post-
baseline. The safety population will be employed in the 
analysis of tolerability and safety variables.  
 
Per-protocol 
population: 
This 
analysis 
population 
comprises all subjects who did not violate the protocol in a 
way that might affect the evaluation of the effect of the study 
drug(s) on the primary endpoint, i.e., without major protocol 
violations or deviations. 
be the primary population for the efficacy analyses. 
 
Intention to treat population (ITT): This analysis 
population includes all subjects who have been randomized 
and dispensed the study drug. 
 
Safety population: This analysis population includes 
subjects who had at least one safety assessment post-
baseline. The safety population will be employed in the 
analysis of tolerability and safety variables.  
 
Per-protocol population (PP): This analysis population 
comprises all subjects who did not violate the protocol in a 
way that might affect the evaluation of the effect of the study 
drug(s) on the primary endpoint, i.e., without major protocol 
violations or deviations. 
 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
Page 8 of 107 
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Amendment III, dated 26 February 2018, Amendment II, dated 01 August 2017, Amendment I issued 29 May 2017, 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 2001/20EC of the European 
Parliament and the Council of the European Union. 
Some of the available study medication kits are expiring on July 31st 2018 and stratification of the randomization per site and IGA score resulted 
in a high number of kits to be stored at the individual study sites. In order to be able to use up the study medication kits with limited stability, the 
amount of kits on site needs to be reduced thus the stratification by IGA score is dropped. 
All changes made in the course of this amendment are stated in the table below. 
Section Reference 
Old text 
Amended text 
Header and 
Title page 
Clinical Study Protocol 
01 August 2017, Amendment II 
Clinical Study Protocol 
01 August 2017, Amendment II, 26 February 2018, Amendment III 
Key Study 
Facilities 
Dr. Srinivas Shenoy B., MBBS, MD, Principal Scientist- 
Clinical Studies 
Dr. Reddy’s Laboratories Ltd  
Innovation Plaza, Survey No.s 42, 45, 46 and 54,  
Bachupally, Qutbullapur Mandal, R.R. District,  
Telengana, 500 090 India 
Phone: +91-40-4434 6126 (Direct)  
srinivasshenoyb@drreddys.com 
Dr. Usha Ranganathan, MD, Associate Director Clinical Development 
Dr. Reddy’s Laboratories Ltd  
Princeton, NJ 08540 
United States of America 
Phone: +1-609 4557 138 (Direct)  
uranganathan@drreddys.com 
 
Signature page 
Dr. Srinivas Shenoy B., MD, Principal Scientist- Clinical 
Development, Proprietary Products R & D, Dr. Reddy’s 
Laboratories Ltd., India 
Denise Montagne, QPS – Statistician 
Dr. Usha Ranganathan, MD,Associate Director Clinical Development of 
Dr. Reddy’s Laboratories Ltd. 
 
John Chen, QPS – Statistician 
8.6.2 
Treatment 
Assignment 
Randomization will be stratified per site and per IGA 
score (score above or equal to 2) at Baseline. 
Randomization will be stratified per site. The first randomizations 
(approximately 40% of the patients) were also stratified per IGA score. 
This stratification resulted in a high amount of study medication kits to be 
stored at the site, limiting the overall availability of unexpired kits in the 
study. Therefore, stratification per IGA score is dropped and 
randomization is only stratified per site per IGA score (score above or 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
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equal to 2) at Baseline 
Section 
8.6.4: 
Emergency 
Procedure 
for 
Unblinding 
Documentation 
about 
any 
code 
break 
must 
be 
documented and attached to the eCRF. 
Documentation about any code break must be documented and attached to 
the eCRF. 
Every code break must be documented. 
 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
Page 10 of 107 
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Amendment II, dated 01 August 2017, Amendment I issued 29 May 2017, 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 2001/20EC of the European 
Parliament and the Council of the European Union. 
The Study medication label was updated with regard to the amount contained in a bottle, contact information, storage conditions and overall 
information content of the label. Instead of Annex 13 to the Current Edition of the Good Manufacturing Practices Guidelines Drugs Used in 
Clinical Trials (GUI-0036) GCP guideline is followed. 
In addition to the changes stated below (additions are underlined, removals are crossed out), minor typographic errors have been corrected. 
Section Reference 
Old text 
Amended text 
Header and 
Title page 
Clinical Study Protocol 
29 May 2017, Amendment I 
Study Phase II 
Clinical Study Protocol 
29 May 2017 01 August 2017, Amendment II 
Study Phase II2 
8.1.3.7: 
Laboratory 
Assessments 
As a rule, the blood samples will be taken from the 
subject by puncture of a vein in the cubital or the 
antebrachial region. Samples will be collect under 
fasted conditions (at least 8 hours). 
As a rule, the blood samples will be taken from the subject by 
puncture of a vein in the cubital or the antebrachial region. Samples 
will be collect under fasted conditions (at least 8 hours). 
8.3.2: Study Drug 
Supply 
and 
Packag ing 
… containing 30 capsules. The medication bottles will be 
labeled according to ABF’s procedure as stated in Section 
8.3.3 See sample label  
The clinical labelled study drug will be supplied to the 
investigational sites in HDPE bottle packs of 30 units for 
each strength of DFD-29 (minocycline HCl) Extended 
Release Capsules (20 mg and 40 mg), Oraycea® 
(doxycycline) Modified Release Hard Capsules and 
placebo. 
One reserve bottle with 30 units will be available for each 
subject. This bottle will be provided on Day 1. 
… containing 3025 capsules. The medication bottles will be labeled 
according to ABF’s procedure as stated in Section 8.3.3 See sample label, 
Figure 8-1. 
The clinical labelled study drug will be supplied to the investigational sites 
in HDPE bottle packs of 3025 units for. Boxes containing 6 bottles of each 
strength of DFD-29 (minocycline HCl) Extended Release Capsules (20 mg 
and 40 mg), Oraycea® (doxycycline) Modified Release Hard Capsules and 
placebo will be provided as individual subject kits. The six bottles in each 
individual subject kit are numbered consecutively. From the kit, two 
consecutively numbered bottles will be provided to the subjects during 
visits 2-5, starting with the lowest number available. Subjects will be 
instructed to always take the capsules from the bottle with the lowest 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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number, until the same is empty and then start with the other bottle. Both 
bottles received by subject during a visit, whether unused, partially used or 
empty, must be returned to the study staff at the successive visit, who will 
verify the accountability of the IMPs. Partially used bottles will be re-
dispensed at the successive visit, while emptied bottles will be replaced 
with the next bottle from the kit bearing the lowest available number. 
One reserve bottle with 30 units will be available for each subject. This 
bottle will be provided on Day 1. 
Figure 8-1: Flowchart for dispensing and returning study medication 
 
8.3.3: Study Drug 
Labeling 
…and regulations, especially Annex 13 to the Current 
Edition of the Good Manufacturing Practices Guidelines 
Drugs Used in Clinical Trials (GUI-0036). The labels… 
 
The labels will be in German and Dutch language. An 
English version will be available for review purposes. 
 Study number (DFD-29-CD-002) 
 Study drug (30x DFD-29 10 mg / 20 mg / 40 mg / 
placebo Capsules) 
 Visit number or ‘Reserve Bottle’ 
 Name of Investigator 
…and regulations, especially Annex 13 to the Current Edition of the Good 
Manufacturing Practices Guidelines Drugs Used in Clinical Trials (GUI-
0036). The labels… 
 
The labels will be in German and Dutch language. An English version will 
be available for review purposes. 
 Study number (DFD-29-CD-002) 
 Study drug (3025x DFD-29 20 mg / 40 mg / placebo / Oraycea® 
Capsules) 
 VisitBottle number or ‘Reserve Bottle’ 
 Name of Investigator 
Figure 
8-2: 
Sample Label 
Bottle Label 
 
Prüfplancode: DFD-29-CD-002 
EudraCT Nr.: 2016-003197-41 
Sponsor: Dr. Reddy’s Laboratories Ltd., India; 8-2-337, 
Road No. 3, Banjara Hills, Hyderabad; Telangana 
Bottle Label Text 
Figure 8-2: Sample Label 
 
Prüfplancode: DFD-29-CD-002 
EudraCT Nr.: 2016-003197-41 
Sponsor: Dr. Reddy’s Laboratories Ltd., India; 8-2-337, Road No. 3, 
Banjara Hills, Hyderabad; Telangana 500034, India; Tel: 00-91-40-4900 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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500034, India; Tel: +91-40-4900 2900 
CRO: QPS Austria GmbH; Parkring 12; 8074 Grambach, 
Austria; Tel.:+43 316 258 111  
Inhalt: 30 Kapseln 20 mg Minocyclin oder 40 mg 
Minocyclin oder 40 mg Oraceya oder Placebo zur oralen 
Anwendung 
Nach Anweisung des Prüfarztes anwenden. 
Lagerung bei 15°C -25°C. 
Für Kinder unzugänglich aufbewahren. 
Nur zur klinischen Prüfung bestimmt.  
Nicht verbrauchte Kapseln und leere Flaschen sind 
spätestens beim letzten Studienbesuch zurückzugeben. 
Ch.-B.: XXXXX 
Verwendbar bis: MM/YYYY 
Kitnr.: XXXX 
Flasche [X] X = 1 oder 2 oder 3 oder 4 oder Reserve 
 
Patientennr.: _________ 
 
Box Label 
 
29004434-6126 
CRO: QPS Austria GmbH; Parkring 12; 8074 Grambach, Austria; Tel.:+43 
316 258 111 
Inhalt: 3025 Kapseln 20 mg Minocyclin oder 40 mg Minocyclin oder 40 
mg Oraceya oder Placebo zur oralen Anwendung 
Nach Anweisung des Prüfarztes anwenden. 
Lagerung bei 15°C -25°25°C. Temperaturabweichungen zwischen 15°C -
30°C sind erlaubt. 
Für Kinder unzugänglich aufbewahren. 
Nur zur klinischen Prüfung bestimmt.  
Geöffnete Flaschen sind innerhalb von 30 Tagen zu verbrauchen. 
Nicht verbrauchte Kapseln und leere Flaschen sind spätestens beim letzten 
Studienbesuch zurückzugeben. 
Ch.-B.: XXXXX 
Verwendbar bis: MM/YYYY 
Kitnr.: XXXX 
Flasche [X] X = 1 oder 2 oder 3 oder 4 oder Reserve5 oder 6 
 
Patientennr.: _________ 
 
Box Label Text 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
Page 13 of 107 
Version 01. Eff. Template date 21-Sep-2012 
Prüfplancode: DFD-29-CD-002 
EudraCT Nr.: 2016-003197-41 
Sponsor: Dr. Reddy’s Laboratories Ltd., India; 8-2-337, 
Road No. 3, Banjara Hills, Hyderabad; Telangana 
500034, India; Tel: +91-40-4900 2900 
CRO: QPS Austria GmbH; Parkring 12; 8074 Grambach, 
Austria; Tel.:+43 316 258 111 340 
Inhalt: 5 Flaschen zu je 30 Kapseln 20 mg Minocyclin 
oder 40 mg Minocyclin oder 40 mg Oraycea® oder 
Placebo zur oralen Anwendung 
Nach Anweisung des Prüfarztes anwenden. 
Lagerung bei 15°C -25°C. 
Für Kinder unzugänglich aufbewahren. 
Nur zur klinischen Prüfung bestimmt.  
Nicht verbrauchte Kapseln und leere Flaschen sind 
spätestens beim letzten Studienbesuch zurückzugeben. 
Ch.-B.: XXXXX 
Verwendbar bis: MM/YYYY 
Kitnr.: XXXX 
Patientennr.: _________ 
 
Figure 8-1: Sample Label 
 
Prüfplancode: DFD-29-CD-002 
EudraCT Nr.: 2016-003197-41 
Sponsor: Dr. Reddy’s Laboratories Ltd., India; 8-2-337, Road No. 3, 
Banjara Hills, Hyderabad; Telangana 500034, India; Tel: +Tel: 00-91-40-
4900 29004434-6126 
CRO: QPS Austria GmbH; Parkring 12; 8074 Grambach, Austria; Tel.:+43 
316 258 111 340 
Inhalt: 56 Flaschen zu je 3025 Kapseln 20 mg Minocyclin oder 40 mg 
Minocyclin oder 40 mg Oraycea® oder Placebo zur oralen Anwendung 
Nach Anweisung des Prüfarztes anwenden. 
Lagerung bei 25°C. Temperaturabweichungen zwischen 15°C -2530°C 
sind erlaubt. 
Für Kinder unzugänglich aufbewahren. 
Nur zur klinischen Prüfung bestimmt.  
Geöffnete Flaschen sind innerhalb von 30 Tagen zu verbrauchen. 
Nicht verbrauchte Kapseln und leere Flaschen sind spätestens beim 
letztenbei jedem Studienbesuch zurückzugeben. 
Ch.-B.: XXXXX 
Verwendbar bis: MM/YYYY 
Kitnr.: XXXX 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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Patientennr.: _________ 
Figure 8-1: Sample Label 
 
 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential  
 
 
 
 
 
 
 
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Amendment I, dated 29 May 2017, original Protocol issued 21 November 2016 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20EC of the European 
Parliament and the Council of the European Union. 
The 4 treatment arms in the study were changed from 10 mg, 20 mg, 40 mg DFD-29 (minocycline HCL) and placebo to 20 mg and 40 mg DFD-
29 (minocycline HCl), 40 mg Oraycea® (doxycycline) and placebo. In addition to the changes stated below, minor typographic errors have been 
corrected. 
Section Reference 
Old text 
Amended text 
Header 
Clinical Study Protocol 
21 November 2016, Version 2 
Clinical Study Protocol 
29 May 2017, Amendment I 
Title page 
Protocol title:  A Multi-Center, Randomized, Double-
Blind, Parallel-Group, Placebo-Controlled Study to 
Assess the Efficacy, Safety and Tolerability of Oral DFD-
29 (minocycline HCl) Extended Release Capsules 
Compared to Placebo for the Treatment of Inflammatory 
Lesions of Rosacea over 16 weeks 
Protocol title: A Multi-Center, Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability 
of Oral DFD-29 (minocycline HCl) Extended Release Capsules Compared 
to Placebo for the Treatment of Inflammatory Lesions of Rosacea over 16 
weeks 
Title page 
Clinical Study Protocol 
21 November 2016, Version 2 
Clinical Study Protocol 
29 May 2017, Amendment I 
Key 
Study 
Facilities 
CRO 
QPS Netherlands B.V. 
Clinical Research Europe 
Petrus Campersingel 123 
9713 AG Groningen, the Netherlands 
QPS Austria 
Parkring 12 
8074 Grambach, Austria 
Key 
Study 
Facilities 
Pharmacy 
QPS Netherlands B.V. 
Clinical Research Europe 
Petrus Campersingel 123 
9713 AG Groningen, the Netherlands 
ABF Pharmaceutical Services GmbH 
Gastgebgasse 5-13 
1230 Vienna, Austria  
Phone +43 1 890 12 00 20 
Email: Martin.Zeppetzauer@abf-pharma.com 
Section 
1: 
Signature Page 
CRO 
Jan Bart Hak, PhD,  
QPS, Director of Clinical Research Europe 
CRO 
Robert Wronski, Ph.D., MBA 
QPS – Director Clinical Research Services 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
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Section 4: List of 
Abbreviations 
 
updated 
Section 
5: 
Synopsis, Centers 
/ Countries 
15 centers:  
The Netherlands, Germany 
At least 15 centers in Germany 
Section 
5: 
Synopsis, 
Investigational 
Product 
and 
Dosage Forms 
DFD-29 (minocycline HCl) Extended Release Capsules 
containing minocycline hydrochloride equivalent to 10 
mg, 20 mg and 40 mg of minocycline. 
DFD-29 (minocycline HCl) Extended Release Capsules containing 
minocycline hydrochloride equivalent to 20 mg and 40 mg of minocycline. 
Section 
5: 
Synopsis, 
Comparative 
Product 
and 
Dosage Forms 
Placebo capsules 
Placebo capsules 
Oraycea® modified release hard capsules containing 40 mg of anhydrous 
doxycycline 
Section 
5: 
Synopsis, 
Objectives 
To evaluate the efficacy of multiple strengths of oral 
DFD-29 (minocycline 10 mg, 20 mg and 40 mg capsules) 
in comparison to placebo in the treatment of inflammatory 
lesions of rosacea for 16 weeks. 
To evaluate the safety and tolerability of multiple 
strengths of oral DFD-29 in comparison to placebo in the 
treatment of inflammatory lesions of rosacea for 16 
weeks. 
Primary Objectives: 
• 
To evaluate the efficacy of multiple strengths of oral DFD-29 
(minocycline 10 mg, 20 mg andHCl 40 mg capsules) in comparison to 
placebo in the treatment of inflammatory lesions of rosacea for 16 
weeks 
• 
To evaluate the safety and tolerability of multiple strengths of oral 
DFD-29 (minocycline HCl 40 mg capsules) in comparison to placebo 
in the treatment of inflammatory lesions of rosacea for 16 weeks. 
Secondary Objectives: 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 20 mg 
capsules) in comparison to placebo in the treatment of inflammatory 
lesions of rosacea for 16 weeks 
• 
To evaluate the efficacy of the two dosage strengths of oral DFD-29 
(minocycline HCl 20 mg and 40 mg capsules) in comparison to 
Oraycea® (doxycycline 40 mg capsules) in the treatment of 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
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inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of oral DFD-29 (minocycline 
HCl 20 mg capsules) in comparison to placebo in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of the two dosage strengths of 
oral DFD-29 (minocycline HCl 20 mg and 40 mg capsules) in 
comparison to Oraycea® (doxycycline 40 mg capsules) in the treatment 
of inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 mg 
capsules) in comparison to oral DFD-29 (minocycline HCl 20 mg 
capsules)  in the treatment of inflammatory lesions of rosacea for 16 
weeks. 
• 
To evaluate the safety and tolerability of oral DFD-29 (minocycline 
HCl 40 mg capsules) in comparison to DFD-29 (minocycline HCl 20 
mg capsules) in the treatment of inflammatory lesions of rosacea for 16 
weeks 
Section 
5: 
Synopsis, Design 
This is a 16-week, multicenter, placebo-controlled, 
randomized, parallel group, double-blind study. Subjects, 
who are at least 18 years old, diagnosed with 
papulopustular rosacea will be randomized to 4 different 
treatment groups. 
This is a 16-week, multicenter, placebo-controlled, randomized, parallel 
group, double-blind study. Subjects, who are at least 18 years old, 
diagnosed with papulopustular rosacea will be randomized to 4 different 
treatment groups. 
Section 
5: 
Synopsis, 
Treatments 
1. 
DFD-29 (minocycline HCl) Extended Release 
Capsules (10 mg) once daily for 16 weeks 
2. 
DFD-29 (minocycline HCl) Extended Release 
Capsules (20 mg) once daily for 16 weeks 
3. 
DFD-29 (minocycline HCl) Extended Release 
Capsules (40 mg) once daily for 16 weeks 
4. 
Placebo for DFD-29 Capsules once daily for 16 
weeks 
Each subject will be allocated to one of the following treatment groups, 
receiving 1 capsule once daily in the morning for 16 weeks: 
1. DFD-29 (minocycline HCl) Extended Release Capsules (40 mg) 
2. DFD-29 (minocycline HCl) Extended Release Capsules (20 mg) 
3. Oraycea® (doxycycline) Modified Release Hard Capsules (40 mg) 
4. Placebo Capsules 

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Section 
5: 
Synopsis, 
Summary 
of 
Study Design 
…and collection of adverse event data.  
…and collection of adverse event data.  
Impact of the treatment on the Quality of Life (QOL) of the subjects will 
be done using a rosacea specific tool RosaQol at Baseline, and at weeks 4, 
8, 12 and 16. 
Section 
5: 
Synopsis, 
Inclusion criteria 
3. Subjects, any gender or ethnicity (Fitzpatrick skin type 
I – III), must be in good general health as determined 
by the Investigator. 
3. Subjects, any gender or ethnicity (and of Fitzpatrick skin type I – III), 
must be in good general health as determined by the Investigator. 
Section 
5: 
Synopsis, 
Concomitant 
Medication Table 
 
Other systemic drugs used for 
treatment of rosacea 
30 days 
Prohibited 
Antacids containing calcium, 
magnesium or aluminum, Iron 
preparations, bismuth 
subsalicylate 
Not 
applicable 
Restricted for 
1.5 hours 
before to 3.0 
hours after 
ingestion of 
IP 
Others 
Facial procedures such as 
chemical peel, photodynamic 
therapy, acne surgery, 
cryodestruction or 
chemodestruction, x-ray 
therapy, intralesional steroids, 
dermabrasion, or depilation 
(except eyebrow shaping) 
45 days 
Prohibited 
Laser therapy or Intense Pulse 
Light Treatment 
45 days 
Prohibited 
Other procedures on face 
(Thermage® etc) 
45 days 
Prohibited 
Other investigational product 
or device 
90 days 
Prohibited 
 
 
Systemic retinoid (including high dose 
vitamin A >10,000 units per day) 
180 days 
Prohibited 
Other systemic drugs used for treatment of 
rosacea 
30 days 
Prohibited 
Antacids containing calcium, magnesium or 
aluminum, Iron preparations, bismuth 
subsalicylate 
Not 
applicable 
Restricted for 1.5 
hours before to 
3.0 hours after 
ingestion of IP 
Others 
Facial procedures such as chemical peel, 
photodynamic therapy, acne surgery, 
cryodestruction or chemodestruction, x-ray 
therapy, intralesional steroids, dermabrasion, 
or depilation (except eyebrow shaping) 
45 days 
Prohibited 
Laser therapy or Intense Pulse Light 
Treatment 
45 days 
Prohibited 
Other procedures on face (Thermage® etc) 
45 days 
Prohibited 
Other investigational product or device 
90 days 
Prohibited 
 
Other systemic drugs used for treatment of rosacea 
30 days 
Prohibited 
Barbiturates 
30 days 
Prohibited 
Rifampicin 
30 days 
Prohibited 
Carbamazepine 
30 days 
Prohibited 
Phenytoin (Diphenylhydantoin) 
30 days 
Prohibited 

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Primidone 
30 days 
Prohibited 
Cyclosporin 
30 days 
Prohibited 
Methoxyflurane 
30 days 
Prohibited 
Section 
5: 
Synopsis, Primary 
Efficacy 
Endpoints 
Co-Primary endpoints: 
 
Proportion of subjects with IGA (modified scale 
without erythema) success – Grade 0 or 1 at the end 
of study with at least 2 grade reduction from Baseline 
to Week 16. 
 
Total inflammatory lesion count (sum of papules, 
pustules, and nodules) reduction from Baseline to 
Week 16. 
Co-Primary endpoints: 
 
Proportion of subjects with IGA (modified scale without erythema) 
success‘treatment success’ – Grade 0 or 1 at the end of study with at 
least 2 grade reduction from Baseline to Week 16. 
 
Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Week 16. 
Section 
5: 
Synopsis, 
Secondary 
Efficacy 
Endpoints 
 
Proportion of subjects with at least a two grade 
improvement of IGA (modified scale without 
erythema) grade from Baseline to Week 16. 
 
Change in clinician’s erythema assessment (CEA) 
score from Baseline to Week 16. 
 
Total inflammatory lesion count reduction from 
Baseline compared to Weeks 4, 8 and 12. 
 
Percentage reduction in total inflammatory lesion 
count from Baseline to Week 16. 
 
Change in Telangiectasia score from Baseline to 
Week 16. 
 
Proportion of subjects with at least a two 2 grade improvement 
reduction 
in 
of 
IGA 
(modified 
scale 
without 
erythema) 
grade‘treatment success’ score from Baseline to Week 16. 
 
Change in clinician’s erythema assessment (CEA) score from Baseline 
to Week 16. 
 
Total inflammatory lesion count reduction from Baseline compared to 
Weeks 4, 8 and 12. 
 
Percentage reduction Median change in total inflammatory lesion 
count from Baseline to Week 16. 
 
Change in Telangiectasia RosaQol score from Baseline to Week 16. 
Section 
5: 
Synopsis, 
Exploratory 
Efficacy 
Endpoints 
 
Mean change in high sensitivity C-reactive protein 
(hs-CRP) levels from Baseline compared to Week 16. 
 
Proportion of subjects meeting CEA treatment 
success criteria (i.e. a two grade improvement in the 
CEA scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting IGA treatment success 
criteria (i.e. a two grade improvement in the IGA 
scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting the CEA treatment 
success criteria at the end of the study will be 
 
Proportion of subjects with IGA (modified scale without erythema) 
‘treatment success’ from Baseline to Weeks 4, 8 and 12. 
 
Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Weeks 4, 8 and 12. 
 
Proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from baseline to week 4,8 
and 12. 
 
Median change in total RosaQol score from Baseline to Weeks 4, 8 
and 12. 
 
Mean change in high sensitivity C-reactive protein (hs-CRP) levels 

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compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
 
Proportion of subjects meeting the IGA treatment 
success criteria at the end of the study will be 
compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
 
Comparison 
of 
the 
above-mentioned 
efficacy 
parameters between two dose levels (i.e. 40 mg vs 20 
mg, 40 mg vs 10 mg, and 20 mg vs 10 mg) of DFD-
29. 
from Baseline compared to Week 16. 
 
Change in Telangiectasia score from Baseline compared to Week 16. 
 
Proportion of subjects meeting CEA ‘treatment success’ criteria (i.e. a 
two grade improvement in the CEA scale) at weeks 4, 8, 12 and 16. 
 
Proportion of subjects meeting IGA treatment success criteria (i.e. a 
two grade improvement in the IGA scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting the CEA treatment success criteria at 
the end of the study will be compared between placebo, the 10 mg, 20 
mg, and 40 mg dose levels of DFD-29. 
 
Proportion of subjects meeting the IGA treatment success criteria at 
the end of the study will be compared between placebo, the 10 mg, 20 
mg, and 40 mg dose levels of DFD-29. 
 
Comparison of the above-mentioned efficacy parameters between two 
dose levels (i.e. 40 mg vs 20 mg, 40 mg vs 10 mg, and 20 mg vs 10 
mg) of DFD-29. 
Synopsis, 
Statistical 
Methodology 
Safety and tolerability data will be listed individually and 
summarized using descriptive statistics and frequency 
tables. Shifts in mean clinical laboratory parameters and 
vital sign parameters at Week 16 as compared to Baseline, 
will be computed and analyzed. 
 
 
 
 
 
 
 
 
Safety and tolerability data will be listed individually and summarized 
using descriptive statistics and frequency tables. Shifts in mean clinical 
laboratory parameters and vital sign parameters at Week 16 as compared to 
Baseline, will be computed and analyzed. Change from Baseline will be 
analyzed for the following parameters: 
 
Change from baseline to each scheduled time point up to EOS for vital 
signs compared between DFD-29, Oraycea® and placebo. 
 
Change from Screening up to EOS for physical examination compared 
between DFD-29, placebo and Oraycea®. 
 
Change from Screening up to EOS for clinical laboratory tests 
compared between DFD-29 Oraycea® and placebo. 
 
Treatment-emergent AEs up to EOS compared between DFD-29, 
Oraycea® and placebo. 
 
Treatment-emergent AEs leading to premature discontinuation of study 
drug compared between DFD-29, Oraycea® and placebo. 
 
Treatment-emergent SAEs up to EOS compared between DFD-29, 

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Efficacy 
Co-Primary endpoints: 
 
The proportion of subjects with IGA (modified scale 
without erythema) success – will be investigated with 
a Chi-square test for placebo versus active treatment. 
Success is described as having at least 2 grade 
reduction from baseline with grade 0 or 1 at the end 
of the study. 
 
The difference between placebo and active treatment 
will be tested for the total inflammatory lesion count 
reduction from baseline at week 16 with a MIXED 
Model, with the investigator as a random factor. 
 
 
Secondary endpoints: 
 
Proportion of subjects with at least a two grade 
improvement of IGA (modified scale without 
erythema) grade from Baseline to Week 16 will be 
investigated with a Chi-square test comparing 
placebo with active treatment. 
 
Change in clinician’s erythema assessment (CEA) 
score from Baseline to Week 16 will be investigated 
with an ANOVA comparing placebo with active 
treatment. 
 
The difference between placebo and active treatment 
will be tested for the total inflammatory lesion count 
reduction from Baseline, at Weeks 4, 8 and 12 using 
MIXED Model with the investigator as a random 
factor. 
Oraycea® and placebo. 
 
Efficacy 
For all endpoints, the comparison of oral DFD-29 (40 mg capsule) versus 
placebo will be the primary objective of the study. All other comparisons 
viz, between oral DFD-29 (20 mg capsule) and placebo, between oral 
DFD-29 (40 and 20 mg capsules) and Oraycea® and between oral DFD-29 
40 mg capsules and DFD-29 20 mg capsules, will be treated as secondary. 
 
Co-Primary endpointsEndpoints: 
 
The proportion of subjects with IGA (modified scale without 
erythema) treatment success – will be investigated with a Chi-square 
test for placeboversus active treatment. Treatment Success is described 
as having at least 2 grade reduction from baseline with grade 0 or 1 at 
the end of the study Week 16. 
 
The difference between placebo and active treatment will be tested for 
the treatments in terms of the change from baseline in the total 
inflammatory lesion count reduction from baseline at Week 16with a 
will be tested using MIXED Model, with the investigator as a random 
factor. 
 
Secondary endpointsEndpoints: 
 
The proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from baseline to week 16, will 
be investigated with a Chi-square test. 
 
Median change in total RosaQol score from Baseline to Week 16 will 
be analyzed using ANOVA. 
 
Exploratory Endpoints 
 
Proportion of subjects with at least a two grade improvement of IGA 
(modified scale without erythema) grade from Baseline to Week 16 

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 
Percentage reduction in total inflammatory lesion 
count from Baseline to Week 16 will be investigated. 
 
Change in Telangiectasia score from Baseline to 
Week 16 will be investigated with an ANOVA 
comparing placebo with active treatment. 
 
Exploratory endpoints: 
 
The difference between placebo and active treatment 
will be tested for the mean change in high sensitivity 
C-reactive protein (hs-CRP) levels from Baseline to 
Week 16 using ANOVA. 
 
The proportion of subjects meeting the CEA 
treatment success criteria at Weeks 4, 8, and 12 for 
placebo versus active treatment will be tested using a 
Chi-square test. 
 
The proportion of subjects meeting the IGA treatment 
success criteria at Weeks 4, 8, and 12 for placebo 
versus active treatment will be tested using a Chi-
square test. 
 
The proportion of subjects meeting the treatment 
success criteria in terms of CEA at the end of the 
study will be compared between the 10 mg, 20 mg, 
and 40 mg dose levels of DFD-29 using a Chi-square 
test. 
 
The proportion of subjects meeting the treatment 
success criteria in terms of IGA at the end of the 
study will be compared between the 10 mg, 20 mg, 
and 40 mg dose levels of DFD-29 using a Chi-square 
test. 
 
Comparison of the above-mentioned exploratory 
efficacy parameters of the differences between two 
dose levels (i.e. 40 mg vs 20 mg, 40 mg vs 10 mg, 
Weeks 4, 8 12 will be investigated with a Chi-square test comparing 
placebo with active treatment. 
 
Change in clinician’s erythema assessment (CEA) score from Baseline 
to Week 16 will be investigated with an ANOVA comparing placebo 
with active treatment. 
 
The difference between placebo and active treatment will be tested for 
treatments in terms of the change from baseline in the total 
inflammatory lesion count reduction from Baseline, at Weeks 4, 8 and 
12 will be tested using MIXED Model with the investigator as a 
random factor. 
 
Percentage reduction The proportion of subjects with at least a 2 grade 
reduction in IGA (modified scale without erythema) score from 
baseline to week 4, 8 and 12, will be investigated with a Chi-square 
test. 
 
Median change in total inflammatory lesion count RosaQol score from 
Baseline to Weeks 4, 8 and 12 will be investigated using ANOVA. 
 
Change in Telangiectasia score from Baseline to Week 16 will be 
investigated with an ANOVA comparing placebo with active 
treatment.  
 
Exploratory endpoints: 
 
The difference between placebo and active treatmenttreatments will be 
tested for the mean change in high sensitivity C-reactive protein (hs-
CRP) levels from Baseline to Week 16 using ANOVA 
 
The proportionChange in Telangiectasia score from Baseline to Week 
16 will be investigated using ANOVA. 
 
Proportion of subjects meeting the CEA ‘treatment success’ criteria 
(i.e. a two grade improvement in the CEA scale) in the treatment 
groups at Weeks 4, 8, 12 and 12 for placebo versus active treatment 
will be tested using a Chi-square test. 
 
The proportion of subjects meeting the IGA treatment success criteria 
at Weeks 4, 8, and 12 for placebo versus active treatment16 will be 

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and 20 mg vs 10 mg) of DFD-29 using ANOVA. 
testedinvestigated using a Chi-square testANOVA. 
 
The proportion of subjects meeting the treatment success criteria in 
terms of CEA at the end of the study will be compared between the 10 
mg, 20 mg, and 40 mg dose levels of DFD-29 using a Chi-square test. 
 
The proportion of subjects meeting the treatment success criteria in 
terms of IGA at the end of the study will be compared between the 10 
mg, 20 mg, and 40 mg dose levels of DFD-29 using a Chi-square test. 
 
Comparison of the above-mentioned exploratory efficacy parameters 
of the differences between two dose levels (i.e. 40 mg vs 20 mg, 40 mg 
vs 10 mg, and 20 mg vs 10 mg) of DFD-29 using ANOVA. 
Exploratory analyses for the following subgroups will be performed: 
 
Male versus female. 
 
Mild (score 2), moderate (score 3) and severe (score 4) IGA score. 
 
Normal hs-CRP versus abnormal hs-CRP at baseline. 
Table 1: Visit and 
Assessment 
schedule 
Demographic data 
 
… 
Demographic data including Fitzpatrick Skin Type 
 
RosaQoL Score (added at Day -30 to Day -3, Day 1, Day 29, Day 57, Day 
85 and Day 113). 
Section 6.2: Study 
Rational 
This is a multi-center, randomized, double-blind, parallel-
group, placebo-controlled study to assess the efficacy, 
safety and tolerability of multiple strengths of oral DFD-
29 (minocycline HCl) Extended Release Capsules 
compared to placebo for the treatment of inflammatory 
lesions of rosacea for 16 weeks. 
This is a multi-center, randomized, double-blind, parallel-group, placebo- 
controlled study to assess the efficacy, safety and tolerability of 
multipletwo dosage strengths of oral DFD-29 (minocycline HCl) Extended 
Release Capsules compared to placebo and Oraycea® Modified Release 
Hard Capsules for the treatment of inflammatory lesions of rosacea for 16 
weeks. 
Section 
6.2.1: 
Dose Selection 
…dose strengths of DFD-29 to be evaluated in this study 
are 10 mg, 20 mg and 40 mg 
…dose strengths of DFD-29 to be evaluated in this study are 10 mg, 20 mg 
and 40 mg 
Section 7: Study 
Objectives 
Objectives 
To evaluate the efficacy of multiple strengths of oral 
DFD-29 (minocycline 10 mg, 20 mg and 40 mg capsules) 
in comparison to placebo in the treatment of inflammatory 
lesions of rosacea for 16 weeks. 
To evaluate the safety and tolerability of multiple 
Primary Objectives: 
• 
To evaluate the efficacy of multiple strengths of oral DFD-29 
(minocycline 10 mg, 20 mg andHCl 40 mg capsules) in comparison to 
placebo in the treatment of inflammatory lesions of rosacea for 16 
weeks 
• 
To evaluate the safety and tolerability of oral DFD-29 (minocycline 

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strengths of oral DFD-29 in comparison to placebo in the 
treatment of inflammatory lesions of rosacea for 16 
weeks. 
HCl 40 mg capsules) in comparison to placebo in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
Secondary Objectives: 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 20 mg 
capsules) in comparison to placebo in the treatment of inflammatory 
lesions of rosacea for 16 weeks. 
• 
To evaluate the efficacy of the two dosage strengths of oral DFD-29 
(minocycline HCl 20 mg and 40 mg capsules) in comparison to 
Oraycea® (doxycycline 40 mg capsules) in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of oral DFD-29 (minocycline 
HCl 20 mg capsules) in comparison to placebo in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of the two dosage strengths of 
oral DFD-29 (minocycline HCl 20 mg and 40 mg capsules) in 
comparison to Oraycea® (doxycycline 40 mg capsules) in the treatment 
of inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 mg 
capsules) in comparison to oral DFD-29 (minocycline HCl 20 mg 
capsules) in the treatment of inflammatory lesions of rosacea for 16 
weeks. 
• 
To evaluate the safety and tolerability of oral DFD-29 (minocycline 
HCl 40 mg capsules) in comparison to DFD-29 (minocycline HCl 20 
mg capsules) in the treatment of inflammatory lesions of rosacea for 16 
weeks. 
Section 7.1: Study 
Endpoints 
Co-Primary endpoints: 
 
Proportion of subjects with IGA (modified scale 
without erythema) success – Grade 0 or 1 at the end 
of study with at least 2 grade reduction from Baseline 
Endpoints were moved to the Section 8.7: study parameters 

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to Week 16. 
 
Total inflammatory lesion count (sum of papules, 
pustules, and nodules) reduction from Baseline to 
Week 16. 
 
Secondary Endpoints 
 
Proportion of subjects with at least a two grade 
improvement of IGA (modified scale without 
erythema) grade from Baseline to Week 16. 
 
Change in clinician’s erythema assessment (CEA) 
score from Baseline to Week 16. 
 
Total inflammatory lesion count reduction from 
Baseline compared to Weeks 4, 8 and 12. 
 
Percentage reduction in total inflammatory lesion 
count from Baseline to Week 16. 
 
Change in Telangiectasia score from Baseline to 
Week 16. 
 
Exploratory Endpoints 
 
Mean change in high sensitivity C-reactive protein 
(hs-CRP) levels from Baseline compared to Week 16. 
 
Proportion of subjects meeting CEA treatment 
success criteria (i.e. a two grade improvement in the 
CEA scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting IGA treatment success 
criteria (i.e. a two grade improvement in the IGA 
scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting the CEA treatment 
success criteria at the end of the study will be 
compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
 
Proportion of subjects meeting the IGA treatment 

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success criteria at the end of the study will be 
compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
 
Comparison 
of 
the 
above-mentioned 
efficacy 
parameters between two dose levels (i.e. 40 mg vs 20 
mg, 40 mg vs 10 mg, and 20 mg vs 10 mg) of DFD-
29. 
Section 
8.1: 
Overall 
Study 
Design 
This is a 16-week, multicenter, placebo-controlled, 
randomized, parallel group, double-blind study. Subjects, 
who are at least 18 years old, diagnosed with 
papulopustular rosacea will be randomized to one of the 
following treatments: 
1. DFD-29 
(minocycline 
HCl) 
Extended 
Release 
Capsules (10 mg) once daily for 16 weeks 
2. DFD-29 
(minocycline 
HCl) 
Extended 
Release 
Capsules (20 mg) once daily for 16 weeks 
3. DFD-29 
(minocycline 
HCl) 
Extended 
Release 
Capsules (40 mg) once daily for 16 weeks 
4. DFD-29 placebo capsules once daily for 16 weeks 
 
… 
This is a 16-week, multicenter, placebo-controlled, randomized, parallel 
group, double-blind study. Subjects, who are at least 18 years old and 
diagnosed with papulopustular rosacea will be randomized to one of the 
following treatments: 
1. DFD-29 (minocycline HCl) Extended Release Capsules (1040 mg) once 
daily for 16 weeks 
2. DFD-29 (minocycline HCl) Extended Release Capsules (20 mg) once 
daily for 16 weeks 
3. DFD-29 (minocycline HCl) Extended Oraycea® (doxycycline) Modified 
Release Hard Capsules (40 mg) once daily for 16 weeks 
4. Placebo capsules once daily for 16 weeks 
 
… Impact of the treatment on the Quality of Life (QoL) of the subjects will 
be done using a rosacea specific tool RosaQol at Baseline, and at weeks 4, 
8, 12 and 16. 
Section 
8.1.2.1: 
Screening 
(Visit 
1) 
 Evaluation of vital sign parameters (refer to Section 
8.1.3.4) 
 Physical examination (refer to Section 8.1.3.5) 
 … 
  
 Inclusion and Exclusion Criteria 
 
Evaluation of vital sign parameters (refer to section Section 
8.1.3.4) 
 
Physical examination (refer to section Section 8.1.3.5) 
 
… 
 
RosaQoL (Section 8.1.4.4) 
 
 
 
Inclusion and Exclusion Criteria (Sections 8.2.1 and 8.2.2) 
 
Week 2 (Phone call) 
 
Eligibility confirmation (based on inclusion (Section 8.2.1) and 

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exclusion criteria (Section 8.2.2)) 
 
Review of AEs… 
 
RosaQoL Score (Section 8.1.4.4) was added to Visit 2, Visit 3, Visit 4, 
Visit 5 and Visit 6 
 
In Section 8.1.2.2 Hs CRP was deleted 
Section 
8.1.4.4: 
Rosacea 
Quality 
of Life (RosaQoL) 
… 
The RosaQoL assessment is carried out by the Investigator by asking 
questions as per the validated RosaQoL questionnaire instrument, at every 
study visit from Screening up to Week 16 (or at early termination). The 
patients will have to rate on a 5 grade scale their perception of the impact 
that Rosacea has on various dimensions influencing their quality of life. 
Section 
8.2.3.1:  
Concomitant 
Medications 
Drugs that influence the inflammatory lesions in acne and 
rosacea must be avoided… 
…Furthermore, drugs interacting with minocycline or 
 
 
Other systemic drugs used for 
treatment of rosacea 
30 days 
Prohibited 
Antacids containing calcium, 
magnesium or aluminum, Iron 
preparations, bismuth 
subsalicylate 
Not 
applicable 
Restricted for 
1.5 hours 
before to 3.0 
hours after 
ingestion of 
IP 
Others 
Facial procedures such as 
chemical peel, photodynamic 
therapy, acne surgery, 
cryodestruction or 
chemodestruction, x-ray 
therapy, intralesional steroids, 
dermabrasion, or depilation 
45 days 
Prohibited 
Drugs that influence the inflammatory lesions in acne and rosacea must be 
avoided. Facial procedures, influencing acne and rosacea [such as chemical 
peel, 
photodynamic 
therapy, 
acne 
surgery, 
cryodestruction 
or 
chemodestruction, x-ray therapy, intralesional steroids, dermabrasion, or 
depilation (except eyebrow shaping), laser therapy or Intense Pulse Light 
Treatment as well as other procedures on face (Thermage® etc.)] are 
prohibited from 45 days prior to the intake of study medication throughout 
the whole study period.  
Systemic retinoids (including high dose vitamin A >10,000 units per day) 
must be avoided from 180 days prior to the intake of study medication 
throughout the whole study period 
Furthermore, drugs interacting with minocycline and Oraycea® or 
 
Systemic retinoid (including high dose 
vitamin A >10,000 units per day) 
180 days 
Prohibited 
Other systemic drugs used for treatment of 
rosacea 
30 days 
Prohibited 
Antacids containing calcium, magnesium or 
aluminum, Iron preparations, bismuth 
subsalicylate 
Not 
applicable 
Restricted for 1.5 
hours before to 
3.0 hours after 
ingestion of IP 

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(except eyebrow shaping) 
Laser therapy or Intense Pulse 
Light Treatment 
45 days 
Prohibited 
Other procedures on face 
(Thermage® etc) 
45 days 
Prohibited 
Other investigational product 
or device 
90 days 
Prohibited 
 
 
Others 
Facial procedures such as chemical peel, 
photodynamic therapy, acne surgery, 
cryodestruction or chemodestruction, x-ray 
therapy, intralesional steroids, dermabrasion, 
or depilation (except eyebrow shaping) 
45 days 
Prohibited 
Laser therapy or Intense Pulse Light 
Treatment 
45 days 
Prohibited 
Other procedures on face (Thermage® etc) 
45 days 
Prohibited 
Other investigational product or device 
90 days 
Prohibited 
 
Other systemic drugs used for treatment of rosacea 
30 days 
Prohibited 
Barbiturates 
30 days 
Prohibited 
Rifampicin 
30 days 
Prohibited 
Carbamazepine 
30 days 
Prohibited 
PhenytoinTDiphenylhydantoin 
30 days 
Prohibited 
Primidone 
30 days 
Prohibited 
Cyclosporin 
30 days 
Prohibited 
Methoxyflurane 
30 days 
Prohibited 
Section 
8.2.3.2: 
Dietary Aspects 
Substances 
which 
can 
potentially 
interfere 
with 
absorption of minocycline like antacids containing 
aluminum 
Substances which can potentially interfere with absorption of minocycline 
like antacids, multivitamins or other products containing aluminum 
Section 8.3: Study 
Drugs 
Study drugs include the investigational product DFD-29 
(minocycline HCl) Extended Release Capsules (10 mg, 20 
mg, and 40 mg) and matching placebo administered 
during the study. 
 
Study drugs include the investigational products DFD-29 (minocycline 
HCl) Extended Release Capsules (10 mg, 20 mg and 40 mg) and matching 
placebo and Oraycea® (doxycycline) Modified Release Hard Capsules 
administered during the study. 
Section 
8.3.1: 
Investigational 
Product 
and 
matching Placebo 
Dr. Reddy´s will provide DFD-29 (minocycline HCl) 
Extended Release Capsules (10 mg, 20 mg, and 40 mg) 
and matching placebo. 
…..capsules matching DFD-29, formulated with the same 
Dr. Reddy´s will provide DFD-29 (minocycline HCl) Extended Release 
Capsules (10 mg, 20 mg, and 40 mg) and matching placebo. 
 
…..capsules matching DFD-29, formulated with the same excipients, but 

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excipients, but without minocycline hydrochloride. The 
identity of the study drug is given in Table 4. The identity 
of the placebo is given in Table 5. 
without minocycline hydrochloride. The identity of the study drug is given 
in Table 4. The identity of the placebo is given in Table 5 Oraycea® 
capsules are commercially available and will be purchased by ABF. In 
order to maintain double blinding of all treatments, ‘over-encapsulation’ 
(enclosing the original capsule within a second larger capsule shell) will be 
performed. The identity of the study drug is given in Table 4. The identity 
of the placebo is given in Table 5, the identity of Oraycea® is given in 
Table 6. 
Section 
8.3.1: 
Investigational 
Product 
and 
matching Placebo 
Table 4: Identity of Investigational Medicinal Product 
Dose strength: 10 mg, 20 mg or 40 mg minocycline 
Table 4: Identity of Investigational Medicinal Product 
Dose strength: 10 mg 20 mg or40 mg minocycline 
Section 
8.3.1: 
Investigational 
Product 
and 
matching Placebo 
No information 
Table 6: Identity of Oraycea® 
 
Test treatment 
Name: 
Oraycea® 
Active ingredient: 
Doxycycline 
Formulation: 
Capsule with 30 mg immediate release 
and 10 mg delayed release beads 
Dose strength: 
40 mg doxycycline 
Dose: 
1 capsule 
Posology: 
1-0-0 (once daily, in the morning) 
Mode of administration: 
Oral administration with approx. 240 
mL water 
Administration condition: 
Fasting 
state 
preferred, 
but 
not 
mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
Section 
8.3.2: 
Study 
Drug 
Supply 
and 
Packaging 
DFD-29 (minocycline HCl) Extended Release Capsules 
and placebo for DFD-29 will be supplied by Dr. Reddy´s 
Laboratories as 30 count in HDPE bottle, and the IMPs 
will be imported and managed by QPS. The qualified 
DFD-29 (minocycline HCl) Extended Release Capsules and placebo for 
DFD-29 will be supplied by Dr. Reddy´s Laboratories as 30 count in 
HDPE bottle. ..and the IMPs will be imported and managed by QPS. The 
qualified person of QPS will certify that the manufacturing and the 

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person of QPS will certify that the manufacturing and the 
packaging is carried out in accordance with EU cGMP-
guidelines and the IMPD. 
The study drug will be supplied to QPS where the clinical 
labeling will be performed. The medication bottles will be 
labeled according to QPS’s procedure 
 
… Extended Release Capsules (10 mg, 20 mg and 40 mg) 
and placebo 
packaging is carried out in accordance with EU cGMP-guidelines and the 
IMPD. 
 The study drug will be imported by QPS and further managed by ABF.  
 
The study drugs will be supplied to QPSABF where the over-
encapsulation, re-packaging and the clinical labeling will be 
performed. Over-encapsulation will be performed with DFD-29, 
placebo and Oraycea® capsules in order to achieve double blinding 
of formulations. Subsequently, the capsules will be re-packed into 
new HDPE bottles (of specifications identical to the one in which 
stability of DFD-29 capsules has been evaluated) containing 30 capsules. 
The medication bottles will be labeled according to QPS’sABF’s 
procedure as stated in Section 8.3.3. A See sample label will be filed 
in the Investigator File.  
 
… Extended Release Capsules (10 mg 20 mg and 40 mg), Oraycea® 
(doxycycline) Modified Release Hard Capsules and placebo 
Section 
8.3.3: 
Study 
Drug 
Labeling 
The labels will be in German and Dutch language. An 
English version will be available for review purposes. 
 Study number (DFD-29-CD-002) 
 Study drug (30x DFD-29 10 mg / 20 mg / 40 mg / 
placebo Capsules) 
The labels will be in German and Dutch language. An English version will 
be available for review purposes. 
 Study number (DFD-29-CD-002) 
 Study drug (30x DFD-29 20 mg / 40 mg / placebo / Oraycea® Capsules) 
Section 
8.3.3: 
Study 
Drug 
Labeling 
Any relabeling activities will be coordinated by QPS 
Netherlands. 
Any relabeling activities will be coordinated by QPS. 
Section 
8.3.3: 
Study 
Drug 
Labeling 
No sample label 
Bottle Label 
 

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Prüfplancode: DFD-29-CD-002 
EudraCT Nr.: 2016-003197-41 
Sponsor: Dr. Reddy’s Laboratories Ltd., India; 8-2-337, Road No. 3, 
Banjara Hills, Hyderabad; Telangana 500034, India; Tel: +91-40-4900 
2900 
CRO: QPS Austria GmbH; Parkring 12; 8074 Grambach, Austria; 
Tel.:+43 316 258 111 
Inhalt: 30 Kapseln 20 mg Minocyclin oder 40 mg Minocyclin oder 40 
mg Oraceya oder Placebo zur oralen Anwendung 
Nach Anweisung des Prüfarztes anwenden. 
Lagerung bei 15°C -25°C. 
Für Kinder unzugänglich aufbewahren. 
Nur zur klinischen Prüfung bestimmt.  
Nicht verbrauchte Kapseln und leere Flaschen sind spätestens beim 
letzten Studienbesuch zurückzugeben. 
Ch.-B.: XXXXX 
Verwendbar bis: MM/YYYY 
Kitnr.: XXXX 
Flasche [X] X = 1 oder 2 oder 3 oder 4 oder Reserve 
 
Patientennr.: _________ 
 
Figure 2-1: Sample Label 

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Section 
8.3.6: 
Storage 
and 
Return of Study 
Drug 
All unused investigational material (drugs and packaging) 
must be returned to QPS. 
All unused investigational material (drugs and packaging) must be returned 
to ABF. 
Section 
8.6.1: 
Assignment 
of 
Subject Numbers 
Subjects will receive a number on Day 1 before start of 
procedures/assessments. The assignment of number and 
code for subject identification is based on the obligation 
for anonymity. The number will consist of a 2-digit site 
number followed by a 2-digit number. Example: Subject 6 
at site 3 will receive subject number 0306. 
 
Subjects 
will 
receive 
a 
number 
on 
Day 
1 
before 
start 
of 
procedures/assessments. The assignment of number and code for subject 
identification is based on the obligation for anonymity. The number will 
consist of a 2-digit site number followed by a 2-digit number. Example: 
Subject 6 at site 3 will receive subject number 0306. 
During Screening, the sites will assign three-digit sequential subject 
numbers preceded by a site number. Upon inclusion into the study, the 
subjects will receive a four-digit randomization number (kit code) which 
does not contain site identification. 
 
Section 
8.6.2: 
Treatment 
Assignment 
Subjects will be randomized to any of the treatments 
assigned in a 1:1:1:1 fashion. Block size will be 
determined by the statistician of QPS Netherlands. 
Randomization will be stratified per site. 
Subjects will be randomized to any of the treatments assigned in a 1:1:1:1 
fashion. Block size will be determined by the statistician of QPS 
Netherlands. Randomization will be stratified per site and per IGA score 
(score above or equal to 2) at Baseline. In order to achieve a patient 
population in the study with adequate representation of patients with 
moderate to severe illness (IGA score above 2) not more than 20 % of 
enrollments in the study will be of IGA grade 2 at Baseline. 
 
Section 
8.6.3: 
Double-blinding 
The investigational product and its matching placebo are 
indistinguishable 
The investigational product and its matching placebo and active 
comparator (Oraycea® ) are indistinguishable after over-encapsulation  
Section 
8.6.4: 
Emergency 
Procedure 
for 
Unblinding 
…access to digital emergency envelopes. 
 
Investigators are immediately notified by the Sealed 
Envelope™ in case of unblinding. Documentation about 
any code break must be documented and attached to the 
eCRF. 
…access to digital emergency envelopes. 
 
Investigators are immediately notified by the Sealed Envelope™ in case of 
unblinding. Documentation about any code break must be documented and 
attached to the eCRF. 

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Section 
8.7.1: 
Efficacy 
Parameters 
Endpoints 
Co-Primary endpoints: 
 
Proportion of subjects with IGA (modified scale 
without erythema) success – Grade 0 or 1 at the end 
of study with at least 2 grade reduction from Baseline 
to Week 16. 
Total inflammatory lesion count (sum of papules, 
pustules, and nodules) reduction from Baseline to Week 
16. 
 
Secondary endpoints 
 
Proportion of subjects with at least a two grade 
improvement of IGA (modified scale without 
erythema) grade from Baseline to Week 16. 
 
Change in clinician’s erythema assessment (CEA) 
score from Baseline to Week 16. 
 
Total inflammatory lesion count reduction from 
Baseline compared to Weeks 4, 8 and 12. 
 
Percentage reduction in total inflammatory lesion 
count from Baseline to Week 16. 
Change in Telangiectasia score from Baseline to Week 
16. 
 
Exploratory Endpoints 
 
Mean change in high sensitivity C-reactive protein 
(hs-CRP) levels from Baseline compared to Week 16. 
 
Proportion of subjects meeting CEA treatment 
success criteria (i.e. a two grade improvement in the 
CEA scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting IGA treatment success 
criteria (i.e. a two grade improvement in the IGA 
scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting the CEA treatment 
Co-Primary Endpoints: 
 
Proportion of subjects with IGA (modified scale without erythema) 
success‘treatment success’ – Grade 0 or 1 at the end of study with at 
least 2 grade reduction from Baseline to Week 16. 
 
Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Week 16. 
 
Secondary Endpoints 
 
Proportion of subjects with at least a two 2 grade improvement 
reduction 
in 
of 
IGA 
(modified 
scale 
without 
erythema) 
grade‘treatment success’ score from Baseline to Week 16. 
 
Change in clinician’s erythema assessment (CEA) score from Baseline 
to Week 16. 
 
Total inflammatory lesion count reduction from Baseline compared to 
Weeks 4, 8 and 12. 
 
Percentage reduction Median change in total inflammatory lesion 
count from Baseline to Week 16. 
Change in Telangiectasia RosaQol score from Baseline to Week 16 
 
Exploratory Endpoints 
 
Proportion of subjects with IGA (modified scale without erythema) 
‘treatment success’ from Baseline to Weeks 4, 8 and 12. 
 
Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Weeks 4, 8 and 12. 
 
Proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from baseline to week 4, 8 
and 12. 
 
Median change in total RosaQol score from Baseline to Weeks 4, 8 
and 12. 
 
Mean change in high sensitivity C-reactive protein (hs-CRP) levels 
from Baseline compared to Week 16. 
 
Change in Telangiectasia score from Baseline compared to Week 16. 

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success criteria at the end of the study will be 
compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
 
Proportion of subjects meeting the IGA treatment 
success criteria at the end of the study will be 
compared between placebo, the 10 mg, 20 mg, and 
40 mg dose levels of DFD-29. 
Comparison of the above-mentioned efficacy parameters 
between two dose levels (i.e. 40 mg vs 20 mg, 40 mg vs 
10 mg, and 20 mg vs 10 mg) of DFD-29. 
 
Proportion of subjects meeting CEA ‘treatment success’ criteria (i.e. a 
two grade improvement in the CEA scale) at weeks 4, 8, 12 and 16. 
 
Proportion of subjects meeting IGA treatment success criteria (i.e. a 
two grade improvement in the IGA scale) at weeks 4, 8, and 12. 
 
Proportion of subjects meeting the CEA treatment success criteria at 
the end of the study will be compared between placebo, the 10 mg, 20 
mg, and 40 mg dose levels of DFD-29. 
 
Proportion of subjects meeting the IGA treatment success criteria at 
the end of the study will be compared between placebo, the 10 mg, 20 
mg, and 40 mg dose levels of DFD-29. 
 
Comparison of the above-mentioned efficacy parameters between two 
dose levels (i.e. 40 mg vs 20 mg, 40 mg vs 10 mg, and 20 mg vs 10 
mg) of DFD-29. 
Section 
8.7.2: 
Safety 
and 
Tolerability 
Parameters 
Endpoints 
 
Change from baseline to each scheduled time point up 
to EOS for vital signs compared between DFD-29 and 
placebo. 
 
Change from Screening up to EOS for physical 
examination compared between DFD-29 and placebo. 
 
Change from Screening up to EOS for clinical 
laboratory tests compared between DFD-29 and 
placebo. 
 
Treatment-emergent AEs up to EOS compared 
between DFD-29 and placebo. 
 
Treatment-emergent AEs leading to premature 
discontinuation of study drug compared between 
DFD-29 and placebo. 
 
Treatment-emergent SAEs up to EOS compared 
between DFD-29 and placebo. 
 
Change from Baseline to each scheduled time point up to EOS for vital 
signs compared between DFD-29 and placebo. 
 
Change from Screening up to EOS for physical examination compared 
between DFD-29 and placebo. 
 
Change from Screening up to EOS for clinical laboratory tests 
compared between DFD-29 and placebo. 
 
Treatment-emergent AEs up to EOS compared between DFD-29 and 
placebo. 
 
Treatment-emergent AEs leading to premature discontinuation of 
study drug compared between DFD-29 and placebo. 
 
Treatment-emergent SAEs up to EOS compared between DFD-29 and 
placebo. 
 
Section 
9.1.3: 
Relationship 
to 
Study Drug 
…causal relationship to the study drug and reported as 
either definite, probable, possible, unlikely, not related, 
not assessable as defined in Table 6:. 
…causal relationship to the study drug and reported as either definite, 
probable, possible, unlikely, not related, not assessable as defined in Table 
6:.below: 

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Table 6: Causality Categories 
Causality Term Assessment definition 
DEFINITE 
 
Definite temporal relationship 
with drug treatment.  
 
Known or suspected reaction to 
the administered investigational 
study medication.  
 
Improvement on stopping of 
dosage, 
reappearance 
of 
reaction on re-exposure.  
 
Event cannot be explained by 
subject's clinical state or other 
factors. 
PROBABLE 
 
Reasonable temporal sequence 
with drug administration.  
 
Likely to be known reaction to 
the administered investigational 
study medication.  
 
Event 
cannot 
easily 
be 
explained by subject's clinical 
state or other factors. 
POSSIBLE 
 
Reasonable 
temporal 
relationship 
with 
drug 
treatment.  
 
Event could have also been 
caused by subject's clinical 
state. 
UNLIKELY 
 
Poor 
or 
no 
temporal 
relationship 
with 
drug 
treatment. 
Table 6: Causality Categories 
Causality Term Assessment definition 
DEFINITE 
 
Definite 
temporal 
relationship 
with 
drug 
treatment.  
 
Known or suspected reaction to the administered 
investigational study medication.  
 
Improvement 
on 
stopping 
of 
dosage, 
reappearance of reaction on re-exposure.  
 
Event cannot be explained by subject's clinical 
state or other factors. 
PROBABLE 
 
Reasonable 
temporal 
sequence 
with 
drug 
administration.  
 
Likely to be known reaction to the administered 
investigational study medication.  
 
Event cannot easily be explained by subject's 
clinical state or other factors. 
POSSIBLE 
 
Reasonable temporal relationship with drug 
treatment.  
 
Event could have also been caused by subject's 
clinical state. 
UNLIKELY 
 
Poor or no temporal relationship with drug 
treatment. 
 
Event can easily also be explained by subject's 
clinical state or other factors. 
NOT 
RELATED 
 
No temporal relationship with study drug 
administration (e.g. Event occurred before 
dosing). 
 
Event is clearly related to other factors than drug 
treatment, such as clinical state, concomitant 
medication or therapeutic intervention. 

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 
Event 
can 
easily 
also 
be 
explained by subject's clinical 
state or other factors. 
NOT 
RELATED 
 
No temporal relationship with 
study drug administration (e.g. 
Event occurred before dosing). 
 
Event is clearly related to other 
factors than drug treatment, 
such 
as 
clinical 
state, 
concomitant 
medication 
or 
therapeutic intervention. 
NOT 
ASSESSABLE 
 
There is not enough data 
available for an evaluation. 
 
Should only be chosen when all 
measures have been taken and 
all attempts have been made 
without 
success 
to 
obtain 
enough data for an evaluation. 
It is not available for the final 
assessment. 
 
NOT 
ASSESSABLE 
 
There is not enough data available for an 
evaluation. 
 
Should only be chosen when all measures have 
been taken and all attempts have been made 
without success to obtain enough data for an 
evaluation. It is not available for the final 
assessment. 
 
1. Not Related: The event is clearly due to extraneous causes (e.g., 
diseases, environment, etc.). Specify if known. Or, the event is 
most probably produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant therapy and 
does not follow a known response pattern to the study product. 
 
2. Possibly Related: The event is temporally related to study product 
use but can be explained by another etiology. Information on the 
effect of study product withdrawal may be lacking. 
 
3. Probably Related: The event is temporally related to study product 
use and is consistent with known effects of the study product 
and/or improves upon withdrawal of the study product.  
 
4. Definitely Related: The event follows a reasonable temporal 
sequence from the time of study product administration and/or 
follows a known response pattern to the study product, and could 
not have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention, or concomitant therapy, and 
either occurs immediately following study product administration 
or improves on stopping the product, or there is a positive reaction 
at the application site. 
 

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10.2: 
Analysis 
SetsPopulations 
… analysis population as described below. 
 
All-treated set: This analysis set includes all randomized 
subjects who received study drug (at least one dose). 
 
Intention to treat set: This analysis set includes all 
subjects who have received one or more doses and have 
undergone at least one post-baseline efficacy evaluation. 
 
Safety set: This analysis set includes subjects from the 
all-treated set who had at least one safety assessment 
post-baseline. The safety set will be employed in the 
analysis of tolerability and safety variables.  
 
Per-protocol set: This analysis set comprises all subjects 
included in the All-treated set who did not violate the 
protocol in a way that might affect the evaluation of the 
effect of the study drug(s) on the primary endpoint, i.e., 
without major protocol violations or deviations. 
 
… analysis population as described below. 
 
All-treated set: This analysis set includes all randomized subjects who 
received study drug (at least one dose). 
 
Intention to treat setpopulation: This analysis setpopulation includes all 
subjects who have received one or more doses been randomized and have 
undergone at least one post-baseline efficacy evaluationdispensed the study 
drug. 
 
Safety setpopulation: This analysis setpopulation includes subjects from 
the all-treated set who had at least one safety assessment post-baseline. The 
safety setpopulation will be employed in the analysis of tolerability and 
safety variables.  
 
Per-protocol setpopulation: This analysis setpopulation comprises all 
subjects included in the All-treated set who did not violate the protocol in a 
way that might affect the evaluation of the effect of the study drug(s) on 
the primary endpoint, i.e., without major protocol violations or deviations. 
 
10.2.1: 
Sample 
Size 
missing 
 
 
The above determined sample size of 44 subjects per treatment 
group was also seen to ensure an adequately powered analysis (87%) 
for demonstrating non-inferiority of DFD-29 40 mg and DFD-29 20 
mg treatments against the active comparator Oraycea® while 
assuming the lower limit of the 90% CI for concluding non-
inferiority to be ≤3 for the absolute change in total inflammatory 
lesion count from baseline at Week 16 for the individual DFD-29 
treatment arms versus Oraycea® arm, a common standard deviation 
of 5 lesion counts, the expected difference of treatment means to be 
0 and alpha of 0.05 (one sided). Similarly, this sample size will also 

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achieve 91% power to detect a non-inferiority margin difference of 
0.5 points on the RosaQoL, assuming a common standard deviation 
of 0.77 points. 
 
Section 
10.3.1: 
Statistical 
Analysis 
of 
Efficacy 
Parameters 
Efficacy 
Co-Primary endpoints: 
 
The proportion of subjects with IGA (modified scale 
without erythema) success – will be investigated with 
a Chi-square test for placebo versus active treatment. 
Success is described as having at least 2 grade 
reduction from baseline with grade 0 or 1 at the end 
of the study. 
 
The difference between placebo and active treatment 
will be tested for the total inflammatory lesion count 
reduction from baseline at week 16 with a MIXED 
Model, with the investigator as a random factor. 
 
Secondary endpoints: 
 
Proportion of subjects with at least a two grade 
improvement of IGA (modified scale without 
erythema) grade from Baseline to Week 16 will be 
investigated with a Chi-square test comparing 
placebo with active treatment. 
 
Change in clinician’s erythema assessment (CEA) 
score from Baseline to Week 16 will be investigated 
with an ANOVA comparing placebo with active 
treatment. 
 
The difference between placebo and active treatment 
will be tested for the total inflammatory lesion count 
reduction from Baseline, at Weeks 4, 8 and 12 using 
MIXED Model with the investigator as a random 
factor. 
Efficacy 
For all endpoints, the comparison of oral DFD-29 (40 mg capsule) versus 
placebo will be the primary objective of the study. All other comparisons 
viz , between oral DFD-29 (20 mg capsule) and placebo, between oral 
DFD-29 (40 and 20 mg capsules) and Oraycea® and between oral DFD-29 
40 mg capsules and DFD-29 20 mg capsules, will be treated as secondary. 
 
Co-Primary endpointsEndpoints: 
 
The proportion of subjects with IGA (modified scale without 
erythema) treatment success – will be investigated with a Chi-square 
test for placeboversus active treatment. Treatment Success is described 
as having at least 2 grade reduction from baseline with grade 0 or 1 at 
the end of the study Week 16. 
 
The difference between placebo and active treatment will be tested for 
the treatments in terms of the change from baseline in the total 
inflammatory lesion count reduction from baseline at Week 16with a 
will be tested using MIXED Model, with the investigator as a random 
factor. 
 
Secondary endpointsEndpoints: 
 
The proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from baseline to week 16, will 
be investigated with a Chi-square test. 
 
Median change in total RosaQol score from Baseline to Week 16 will 
be analyzed using ANOVA. 
 
For secondary and exploratory endpoints we assume that non-
inferiority would be established if the mean change in inflammatory 

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 
Percentage reduction in total inflammatory lesion 
count from Baseline to Week 16 will be investigated. 
 
Change in Telangiectasia score from Baseline to 
Week 16 will be investigated with an ANOVA 
comparing placebo with active treatment. 
lesion count reduction from Baseline, at Weeks 4, 8 and 12 using 
MIXED Model with the investigator as a random factor. 
 
Percentage reduction in total inflammatory lesion count from Baseline 
to Week 16 will be investigated. 
 
Change in Telangiectasia score from Baseline to Week 16 will be 
investigated with an ANOVA comparing placebo with active 
treatment. 
 
 
Exploratory endpoints: 
 
The difference between placebo and active treatment will be tested for 
the mean change in high sensitivity C-reactive protein (hs-CRP) levels 
from Baseline to Week 16 using ANOVA. 
 
The proportion of subjects meeting the CEA treatment success criteria 
at Weeks 4, 8, and 12 for placebo versus active treatment will be tested 
using a Chi-square test. 
 
The proportion of subjects meeting in the IGA treatment success 
criteria at Weeks 4, 8, and 12 for placebo versus active treatment will 
be tested using a Chi-square test. 
 
The proportion of subjects meetingDFD-29 (40 mg capsule) group 
would be within 3 less than in the treatment success criteria in terms of 
CEA at Oraycea® group for the endlower limit of the study will be 
compared between the 10 mg, 20 mg, and 40 mg dose levels of DFD-
29 using a Chi-square test. 
 
The proportion of subjects meeting the treatment success criteria in 
terms of IGA at the end of the study will be compared between the 10 
mg, 20 mg, and 40 mg dose levels of DFD-29 using a Chi-square test. 
 
Comparison of the above-mentioned exploratory efficacy parameters 
of the differences between two dose levels (i.e. 40 mg vs 20 mg, 40 mg 
vs 10 mg, and 20 mg vs 10 mg) of DFD-29 using ANOVA90% 
Confidence Intervals 
10.4 
Safety set is used to perform all safety analyses.  
most recent MedDRA version 
Safety setpopulation is used to perform all safety analyses.  
…most recent MedDRA version at the study start. 

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…observations, and change from screening or baseline. 
Individual subject listings of vital signs data and 
laboratory measurements will be provided. 
 
 
 
…observations, and change from screening or baseline for the following 
parameters:  
 
Change from Baseline to each scheduled time point up to EOS for 
vital signs compared between DFD-29, Oraycea® and placebo. 
 
Change from Screening up to EOS for physical examination 
compared between DFD-29, Oraycea®.and placebo.  
 
Change from Screening up to EOS for clinical laboratory tests 
compared between DFD-29 Oraycea® and placebo. 
 
Treatment-emergent AEs up to EOS compared between DFD-29, 
Oraycea® and placebo. 
 
Treatment-emergent AEs leading to premature discontinuation of 
study drug compared between DFD-29, Oraycea® and placebo. 
 
Treatment-emergent SAEs up to EOS compared between DFD-29, 
Oraycea® and placebo. 
Section 
10.7: 
Exploratory 
Analysis 
Exploratory analyses for the following subgroups 
will be performed: 
• 
Male versus female. 
• 
Moderate (score 2) and severe (score 3 and 4) 
IGA score. 
• 
Normal hs-CRP versus abnormal hs-CRP at 
baseline. 
 
Exploratory Endpoints: 
 The difference between placebo and active 
treatment will be tested for the mean change in 
high sensitivity C-reactive protein (hs-CRP) 
levels from baseline at Weeks 8 and 16 using 
ANOVA. 
 The proportion 
of subjects 
meeting 
the 
Exploratory analyses for the following subgroups will be performed: 
• 
Male versus female. 
• 
Moderate (score 2) and severe (score 3 and 4) IGA score. 
• 
Normal hs-CRP versus abnormal hs-CRP at baseline. 
 
Exploratory Endpoints: 
 The difference between placebo and active treatment Proportion 
of subjects with at least a two grade improvement of IGA 
(modified scale without erythema) grade from Baseline to Weeks 
4, 8 and 12 will be investigated with a Chi-square test. 
 The difference between treatments in terms of the change from 
baseline in the total inflammatory lesion count at Weeks 4, 8 and 
12 will be tested using MIXED Model with the investigator as a 
random factor. 
 The proportion of subjects with at least a 2 grade reduction in 

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Treatment success criteria (in terms of IGA and 
CEA) at weeks 4, 8, 12 and 16 for each active 
treatment versus placebo will be tested using a 
Chi-square test. 
 The proportion 
of subjects 
meeting the 
Treatment success criteria (in terms of IGA and 
CEA) at the end of the study will be compared 
between the 10 mg, 20 mg, and 40 mg dose 
levels of DFD-29.. 
IGA (modified scale without erythema) score from baseline to 
week 4, 8 and 12, will be investigated with a Chi-square test. 
 Median change in total RosaQol score from baseline to Weeks 4, 
8 and 12 will be investigated using ANOVA. 
 The difference between treatments will be tested for the mean 
change in high sensitivity C-reactive protein (hs-CRP) levels 
from baseline at Weeks 8 and Baseline to Week 16 using 
ANOVA 
 The proportionChange in Telangiectasia score from Baseline to 
Week 16 will be investigated using ANOVA. 
 Proportion of subjects meeting the Treatment successCEA 
‘treatment success’ criteria (in terms of IGA and CEA) at weeks 
4, 8, 12 and 16 for each active i.e. a two grade improvement in 
the CEA scale) in the treatment versus placebogroups at Weeks 
4, 8, 12 and 16 will be testedinvestigated using a Chi-square 
testANOVA. 
The proportion of subjects meeting the Treatment success 
criteria (in terms of 
Exploratory analyses for the following subgroups will be performed: 
 Male versus female. 
• 
 IGA and CEA) at the end of the study will be compared 
between the 10 mg, 20 mg, and 40 mg dose levels of DFD-
29. 
 Mild (score 2), moderate (score 3) and severe (score 4) 
IGA score. 
 
Normal hs-CRP versus abnormal hs-CRP at baseline 
Section 
11.1.6: 
Handling of Study 
Drug 
QPS will supply all study drug… 
ABF will supply all study drug… 

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Appendix: 
Section 13.1: IGA 
Table 1: IGA Scale 
Score 
Definition 
Guideline 
0 = Clear 
No signs or 
symptoms 
present 
Completely clear of 
inflammatory 
lesions 
1 = Near 
clear 
1 or 2 papules 
1-2 
small 
noninflammatory 
papules 
2 = Mild 
Some papules 
and pustules 
3-10 papules and 
pustules 
3 
= 
Moderate 
Moderate 
number 
of 
papules 
and 
pustules 
11-19 papules and 
pustules 
4 = Severe Numerous 
papules 
and 
pustules, 
nodules 
≥20 
papules 
and 
pustules, nodules 
Table 1: IGA Scale 
Score 
Definition 
Guideline 
0 = Clear 
No signs or symptoms 
present 
Completely 
clear 
of 
inflammatory lesions 
1 
= 
Near 
clear 
1 or 2 papules 
1-2 
small 
noninflammatory papules 
2 = Mild 
Some 
papules 
and 
pustules 
3-10 papules and pustules 
3 
= 
Moderate 
Moderate number of 
papules and pustules 
11-19 
papules 
and 
pustules 
4 = Severe 
Numerous papules and 
pustules, nodules 
≥20 papules and pustules, 
nodules 
 
 
 
 
2.5 
Example of the Rosacea Quality of Life Instrument 
 
 

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3 TABLE OF CONTENTS 
1 
Signature Page ................................................................................................................... 4 
2 
Signature Page for Investigator .......................................................................................... 5 
PROTOCOL CHANGES LOG .............................................................................................. 6 
2.5 
Example of the Rosacea Quality of Life Instrument ................................................. 42 
3 
Table of Contents ............................................................................................................. 43 
4 
List of Abbreviations ....................................................................................................... 47 
5 
Protocol Synopsis ............................................................................................................ 49 
6 
Introduction and Rationale ............................................................................................... 58 
6.1 
Introduction ............................................................................................................... 58 
6.2 
Study Rationale ......................................................................................................... 59 
6.2.1 
Dose Selection ................................................................................................... 60 
6.2.2 
Ethical Conduct of the Study ............................................................................. 60 
7 
Study Objectives .............................................................................................................. 61 
8 
Study Design .................................................................................................................... 62 
8.1 
Overall Study Design ................................................................................................ 62 
8.1.1 
Informed Consent............................................................................................... 62 
8.1.2 
Baseline Parameters and Concomitant Medications .......................................... 63 
8.1.2.1 
Screening (Visit 1) ...................................................................................... 63 
8.1.2.2 
Baseline (Visit 2) ........................................................................................ 63 
8.1.2.3 
Prior and Concomitant Medications ........................................................... 63 
8.1.3 
Safety and Tolerability Assessments ................................................................. 64 
8.1.3.1 
Activities scheduled at Individual Study Visits .......................................... 64 
8.1.3.2 
Adverse Events ........................................................................................... 66 
8.1.3.3 
Telephonic Enquiry .................................................................................... 66 
8.1.3.4 
Vital Signs .................................................................................................. 66 
8.1.3.5 
Physical Examination ................................................................................. 66 
8.1.3.6 
Weight and Height ...................................................................................... 66 
8.1.3.7 
Laboratory Assessments ............................................................................. 67 
8.1.4 
Efficacy Assessments......................................................................................... 67 
8.1.4.1 
Investigator´s Global Assessment (IGA) .................................................... 67 
8.1.4.2 
Total Inflammatory Lesion Count .............................................................. 67 
8.1.4.3 
Clinician´s Erythema Assessment (CEA)................................................... 67 
8.1.4.4 
Rosacea Quality of Life (RosaQoL) ........................................................... 68 
8.1.4.5 
High sensitive C-reactive Protein (hs-CRP) ............................................... 68 
8.1.4.6 
Telangiectasia Score ................................................................................... 68 
8.1.5 
Pregnancy test .................................................................................................... 68 
8.2 
Study Population ....................................................................................................... 68 
8.2.1 
Inclusion Criteria ............................................................................................... 68 
8.2.2 
Exclusion Criteria .............................................................................................. 69 
8.2.3 
Diet, Activities, and Other Restrictions ............................................................. 71 

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8.2.3.1 
Concomitant Medication ............................................................................ 71 
8.2.3.2 
Dietary Aspects........................................................................................... 72 
8.2.3.3 
Sun Exposure .............................................................................................. 72 
8.2.3.4 
Contraceptives ............................................................................................ 72 
8.3 
Study Drugs ............................................................................................................... 72 
8.3.1 
Investigational Product and Matching Comparators.......................................... 72 
8.3.2 
Study Drug Supply and Packaging .................................................................... 74 
8.3.3 
Study Drug Labeling .......................................................................................... 76 
8.3.4 
Study Drug Administration ................................................................................ 78 
8.3.5 
Drug Accountability........................................................................................... 78 
8.3.6 
Storage and Return of Study Drug ..................................................................... 78 
8.4 
Study Drug Discontinuation and Study Withdrawal ................................................. 78 
8.4.1 
Study Drug Interruption or Discontinuation ...................................................... 78 
8.4.2 
Study Discontinuation ........................................................................................ 79 
8.4.3 
Subject’s Follow-up after Study Discontinuation .............................................. 80 
8.5 
Treatment Exposure and Compliance ....................................................................... 80 
8.6 
Treatment Assignment and Blinding......................................................................... 81 
8.6.1 
Assignment of Subject Numbers ....................................................................... 81 
8.6.2 
Treatment Assignment ....................................................................................... 81 
8.6.3 
Double-blinding ................................................................................................. 81 
8.6.4 
Emergency Procedure for Unblinding ............................................................... 82 
8.7 
Study Parameters ....................................................................................................... 82 
8.7.1 
Efficacy Endpoints ............................................................................................. 82 
8.7.2 
Safety and Tolerability Endpoints ..................................................................... 83 
9 
Safety Definitions and Reporting Requirements ............................................................. 84 
9.1 
Adverse Events .......................................................................................................... 84 
9.1.1 
Definitions of Adverse Events ........................................................................... 84 
9.1.2 
Intensity of Adverse Events ............................................................................... 85 
9.1.3 
Relationship to Study Drug ................................................................................ 85 
9.1.4 
Reporting of Adverse Events ............................................................................. 86 
9.1.5 
Follow-up of Adverse Events ............................................................................ 86 
9.2 
Serious Adverse Events ............................................................................................. 86 
9.2.1 
Definitions.......................................................................................................... 86 
9.2.1.1 
Serious Adverse Events .............................................................................. 86 
9.2.1.2 
Hospitalization - Prolongation of Existing Hospitalization ........................ 87 
9.2.1.3 
Serious Adverse Events Related to Study-mandated Procedures ............... 87 
9.2.2 
Reporting of Serious Adverse Events ................................................................ 87 
9.2.2.1 
Before Study Drug Initiation ...................................................................... 87 
9.2.2.2 
During Study Drug Administration ............................................................ 87 
9.2.2.3 
After Study Drug Discontinuation .............................................................. 88 
9.2.2.4 
Reporting Procedures ................................................................................. 88 
9.2.1 
Follow-up of Serious Adverse Events ............................................................... 89 
9.3 
Pregnancies................................................................................................................ 90 
10 
Statistical Methodology and Analyses ............................................................................. 91 

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10.1 Statistical Analysis Plan ............................................................................................ 91 
10.2 Analysis Populations ................................................................................................. 91 
10.2.1 Sample Size ........................................................................................................ 91 
10.2.2 Handling of Missing Data .................................................................................. 92 
10.3 Efficacy Parameters................................................................................................... 92 
10.3.1 Statistical Analysis of Efficacy Parameters ....................................................... 92 
10.4 Safety and Tolerability Parameters ........................................................................... 93 
10.5 Exposure to Study Drugs........................................................................................... 94 
10.6 Baseline Parameters and Concomitant Medications ................................................. 94 
10.7 Exploratory Analyses ................................................................................................ 94 
10.8 Clinical Study Report ................................................................................................ 95 
11 
Procedures and Good Clinical Practice............................................................................ 96 
11.1 Procedures ................................................................................................................. 96 
11.1.1 Protocol Amendments ........................................................................................ 96 
11.1.1.1 
Non-substantial Amendment ...................................................................... 96 
11.1.1.2 
Substantial Amendment .............................................................................. 96 
11.1.1.3 
Urgent Amendment .................................................................................... 96 
11.1.2 Monitoring ......................................................................................................... 97 
11.1.3 Data management............................................................................................... 97 
11.1.3.1 
Data Collection ........................................................................................... 97 
11.1.3.2 
Database Management and Quality Control ............................................... 98 
11.1.4 Recording of Data and Retention of Documents ............................................... 98 
11.1.5 Audit .................................................................................................................. 98 
11.1.6 Handling of Study Drugs ................................................................................... 99 
11.1.7 Publication of Study Results .............................................................................. 99 
11.1.8 Disclosure and Confidentiality .......................................................................... 99 
11.1.9 Premature Termination or Suspension of the Study .......................................... 99 
11.2 Good Clinical Practice ............................................................................................ 100 
11.2.1 Ethics and Good Clinical Practice ................................................................... 100 
11.2.2 Ethics Committee / Institutional Review Board .............................................. 100 
11.2.3 Informed Consent............................................................................................. 100 
11.2.4 Compensation to Subjects and Investigators ................................................... 100 
12 
Structured Risk Analysis ............................................................................................... 101 
13 
References ...................................................................................................................... 102 
14 
Appendices ..................................................................................................................... 105 
14.1 IGA .......................................................................................................................... 105 
14.2 CEA ......................................................................................................................... 105 
14.3 Telangiectasia Score ................................................................................................ 105 
14.4 Diagram of the Face ................................................................................................ 106 
14.5 Example of the Rosacea Quality of Life Instrument ............................................... 107 
 

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List of figures 
Figure 8-1: Flowchart for dispensing and returning of study medication ............................... 75 
Figure 8-2:Sample Label.......................................................................................................... 77 
Figure 13-1: Diagram of the Face .......................................................................................... 106 
Figure 13-2: Example of the Rosacea Quality of Life Instrument......................................... 107 
 
List of tables 
Table 1: Visit and Assessment Schedule ................................................................................. 57 
Table 2: Summary of Clinical Laboratory Tests...................................................................... 67 
Table 3: Prohibited Topical Drugs, Systemic Drugs, and Other Treatments .......................... 71 
Table 4: Identity of Investigational Medical Products ............................................................. 73 
Table 5: Identity of Placebo ..................................................................................................... 73 
Table 6: Identity of Oraycea® .................................................................................................. 73 
Table 7: Efficacy of Oracea®* 40 mg/day as shown in two phase 3 trials ............................... 92 
Table 8: IGA Scale................................................................................................................. 105 
Table 9: CEA Scale ................................................................................................................ 105 
Table 10: Telangiectasia Score .............................................................................................. 105 

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4 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical (ATC) Classification System 
BP 
Blood Pressure 
bpm 
Beats per minute 
BPO 
Benzoyl Peroxide 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CEA 
Clinician’s Erythema Assessment 
cGMP 
Current Good Manufacturing Practice 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CRS 
Clinical Research Services 
DFD-29 
Minocycline HCl (formulated as Extended Release Capsules) 
eCRF 
Electronic Case Report Form 
EC 
Ethic Committee 
EDC 
Electronic Data Capture 
EOS 
End of Study 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HbsAG 
Hepatitis B surface antigen 
HCl 
Hydrochloride 
HCV 
Hepatitis C Virus 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
hCG 
Human chorionic gonadotropin 
hs-CRP 
high sensitivity C-reactive protein 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment modified scale without erythema 
ITT 
Intention to treat 
IRB 
Institutional Review Board 
IUD 
Intra-Uterine Device 
IUS 
Intra-Uterine Hormone Releasing System 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mg 
Milligram 
MI 
Multiple Imputation 
mIU 
Milli International Units 
mL 
Milliliter 

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OTC 
Over The Counter 
PHY 
Phymatous rosacea 
PP 
Per protocol 
PPR 
Papulopustular rosacea 
QA 
Quality Assurance 
QP 
Qualified Person 
QoL 
Quality of Life 
RosaQoL 
Rosacea Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
TLR 
Toll-like receptors 
TMF 
Trial Master File 
UV 
Ultraviolet 
USFDA 
United States Food and Drug Administration  
WHO 
World Health Organization 
 
 

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5 PROTOCOL SYNOPSIS 
TITLE 
A Multi-Center, Randomized, Double-Blind, Parallel-Group, 
Controlled Study to Assess the Efficacy, Safety and Tolerability of 
Oral DFD-29 Extended Release Capsules for the Treatment of 
Inflammatory Lesions of Rosacea over 16 weeks 
PHASE 
2 
CENTERS 
/ COUNTRIES  
At least 15 centers in Germany 
INVESTIGATIONAL 
PRODUCT and 
DOSAGE FORMS 
DFD-29 (minocycline HCl) Extended Release Capsules containing 
minocycline hydrochloride equivalent to 20 mg, and 40 mg of 
minocycline. 
COMPARATIVE 
PRODUCT and 
DOSAGE FORMS 
Placebo capsules 
Oraycea® modified release hard capsules containing 40 mg of 
anhydrous doxycycline 
ROUTE OF 
ADMINISTRATION 
Oral administration 
OBJECTIVES 
Primary Objectives: 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 
mg capsules) in comparison to placebo in the treatment of 
inflammatory lesions of rosacea for 16 weeks 
• 
To evaluate the safety and tolerability of oral DFD-29 
(minocycline HCl 40 mg capsules) in comparison to placebo in 
the treatment of inflammatory lesions of rosacea for 16 weeks. 
Secondary Objectives: 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 20 
mg capsules) in comparison to placebo in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the efficacy of the two dosage strengths of oral 
DFD-29 (minocycline HCl 20 mg and 40 mg capsules) in 
comparison to Oraycea® (doxycycline 40 mg capsules) in the 
treatment of inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of oral DFD-29 
(minocycline HCl 20 mg capsules) in comparison to placebo in 
the treatment of inflammatory lesions of rosacea for 16 weeks. 
• 
To evaluate the safety and tolerability of the two dosage 
strengths of oral DFD-29 (minocycline HCl 20 mg and 40 mg 
capsules) in comparison to Oraycea® (doxycycline 40 mg 
capsules) in the treatment of inflammatory lesions of rosacea 
for 16 weeks. 
• 
To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 
mg capsules) in comparison to oral DFD-29 (minocycline HCl 
20 mg capsules) in the treatment of inflammatory lesions of 
rosacea for 16 weeks. 

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• 
To evaluate the safety and tolerability of oral DFD-29 
(minocycline HCl 40 mg capsules) in comparison to DFD-29 
(minocycline HCl 20 mg capsules) in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
DESIGN  
This is a 16-week, multicenter, controlled, randomized, parallel 
group, double-blind study. Subjects, who are at least 18 years old, 
diagnosed with papulopustular rosacea will be randomized to 4 
different treatment groups. 
TREATMENTS 
Each subject will be allocated to one of the following treatment 
groups, receiving 1 capsule once daily in the morning for 16 
weeks: 
1. DFD-29 (minocycline HCl) Extended Release Capsules (40 mg) 
2. DFD-29 (minocycline HCl) Extended Release Capsules (20 mg) 
3. Oraycea® (doxycycline) Modified Release Hard Capsules (40 
mg) 
4. Placebo Capsules 
SUMMARY OF 
STUDY DESIGN 
After assessing eligibility during an up to 28 days screening 
period, 200 subjects will be enrolled in the study (fifty subjects 
each in groups 1 to 4). Subject visits are scheduled at Screening, 
Baseline (Day 1), and Weeks 4, 8, 12 and 16. 
Clinical assessments of efficacy will be conducted based on 
Investigator’s Global Assessment (IGA, modified scale without 
erythema), Clinician’s Erythema Assessment (CEA), and on 
inflammatory lesion counts at Weeks 4, 8, 12 and 16 in 
comparison to Baseline. Additionally, high sensitivity C-reactive 
protein (hs-CRP) in the blood will be assessed at Baseline, and at 
Week 16 to explore any impact of the treatment on the 
inflammatory pathology. 
Laboratory assessments on blood (hematology and biochemistry) 
and urine (routine tests) will be conducted at Screening, Week 4 
and Week 16 (End of the study) to assess for any changes in the 
safety parameters. Other safety assessments include vital signs, 
physical examination, urine pregnancy tests (only for females with 
child bearing potential), and collection of adverse event data.  
Impact of the treatment on the Quality of Life (QoL) of the 
subjects will be done using the rosacea specific tool RosaQoL at 
Baseline, and at Weeks 4, 8, 12 and 16. 
STUDY 
POPULATION 
Two 
hundred 
(200) 
male 
and 
female 
subjects 
with 
papulopustular rosacea will be enrolled to get 176 completed 
subjects (forty-four (44) completers each in groups 1 to 4). 
INCLUSION 
CRITERIA 
The criteria for inclusion are: 
1. Subjects must be able to understand the requirements of the 
study and be willing to give written informed consent.  
2. Male and female subjects aged 18 years and above.  
3. Subjects, any gender or ethnicity (and of Fitzpatrick skin type I 
– III), must be in good general health as determined by the 

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Investigator. 
4. Subjects must have a clinical diagnosis of papulopustular 
rosacea, IGA grade 2 - 4. 
5. Subjects must have 10 - 40 (both inclusive) inflammatory 
lesions (papules and pustules) of rosacea over the face. 
6. Subjects must have not more than 2 nodules. 
7. Subjects with moderate to severe erythema with a total score 
of 5 - 20 on the CEA scale. 
8. Subjects must agree to only use the study products and to not 
use any other treatment for rosacea (prescription or Over The 
Counter (OTC)) during the course of the study. 
9. Subjects must be free of any systemic or dermatologic 
disorder, which in the opinion of the Investigator, will interfere 
with the study results, and especially free of any skin diseases 
(for example peri-oral dermatitis, facial keratosis pilaris, 
seborrheic dermatitis, and acne vulgaris) that may confound the 
evaluation of rosacea. 
10. Females must have a negative urine pregnancy test at the 
Screening and Baseline Visit. Sensitivity of such a test should 
at least be 25 mIU/mL or lower for hCG. 
11. Females must either be postmenopausal with no menses for at 
least 12 months or surgically sterile (hysterectomy or tubal 
ligation) or agree to use a highly effective method of 
contraception with a pearl index of <1% up to 1 month after 
last dose. Contraception methods with low user dependency 
should preferably be used, in particular when contraception is 
introduced as a result of participation in this clinical study. 
 ‘Highly effective’ methods of birth control include: 
 combined (estrogen and progesterone containing) hormonal 
contraception associated with inhibition of ovulation*: 
o oral 
o intravaginal 
o transdermal 
 progesterone-only hormonal contraception associated with 
inhibition of ovulation*: 
o oral 
o injectable 
o implantable† 
 intra-uterine device (IUD) † 
 intra-uterine hormone releasing system (IUS) † 
 bilateral tubular occlusion† 
 vasectomy of sexual partner that was performed at least 90 
days prior to Baseline, and has been medically assessed as 
successful† 
 sexual abstinence 
o Note: Sexually inactive female subjects may be enrolled 
at the investigator’s discretion provided that they are 
counseled to refrain from heterosexual intercourse for the 

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duration of the study and for one month after the last 
dose, and understand the possible risks involved in getting 
pregnant during the study. 
 
* Hormonal methods: If on hormonal contraceptives, must 
have been on the same hormonal contraceptive product 
for 3 months (90 days) prior to Baseline and continued on 
same method and dose throughout the duration of the 
study. If subject had used hormonal birth control and had 
stopped, this should have occurred more than 6 months 
prior to Baseline. Female subjects on low dose oral 
contraceptives (containing ≤35 µg of ethinyl estradiol or 
equivalent dose of other estrogens) must use a second 
form of contraceptive during the study. 
† Contraception methods that are considered to have low 
user dependency. 
12. Subjects must be in good general health as determined by 
the investigator and supported by the medical history and 
normal or not clinically significant abnormal vital signs 
(blood pressure and pulse). Subjects are eligible at screening 
if: 
a. 
Systolic BP ≤140 and ≥90 
b. Diastolic BP ≤100 and ≥50 
c. 
Pulse 50 – 100 bpm inclusive 
EXCLUSION 
CRITERIA 
Criteria for exclusion are: 
1. Females who are pregnant or nursing or planning to become 
pregnant during the study.  
2. Male whose female partner is planning to conceive a child. 
3. Subjects who have been treated for rosacea within the 30 days 
prior to the Baseline Visit (e.g. metronidazole, azelaic acid, 
doxycycline or brimonidine). 
4. Subjects who have been treated with systemic retinoids within 6 
months prior to the Baseline visit. 
5. Subjects who have participated in a trial involving any 
investigational product in the 90 days prior to the Baseline Visit. 
6. Subjects with any disease or medical condition that would 
interfere with the study outcome or place the subject at undue 
risk. 
7. Subjects who use or have used systemic steroids within the 30 
days prior to the Baseline Visit or any other immunosuppressive 
medication. 
8. Subjects who are on anti-coagulants or those who are likely to 
require anti-coagulants during the study period. 
9. Subjects who have used methoxyflurane or other nephrotoxic 
drugs (as judged by the investigator) within the past 30 days. 
10. Subjects with known hypersensitivity to minocycline or 
doxycycline or any component of the study products or against 
other kinds of tetracyclines. 

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11. Subjects with clinically significant abnormal laboratory test that, 
in the opinion of the investigator, would compromise the 
subject’s safety or ability to participate in the trial. 
12. Subjects who are unable to comply with study requirements. 
13. History of organ transplant requiring immunosuppression, HIV, 
or other immune compromised state. 
14. Subjects who in the opinion of the investigator or physician 
performing the initial examination, should not participate in the 
trial, e.g. due to probable noncompliance or inability to 
understand the trial and give adequately informed consent. 
15. Subjects with close affiliation with the investigator (e.g. a close 
relative) or persons working at the respective trial sites or 
subjects who are an employee of the sponsor. 
16. Subjects institutionalized because of legal or regulatory order. 
17. History of drug or alcohol abuse in the last year. 
CONCOMITANT 
MEDICATION 
Product 
Washout 
period before 
Baseline 
During Study 
Topical treatments on the face 
Benzoyl Peroxide (BPO) 
14 days 
Prohibited 
Antibiotics (e.g. Macrolides, 
Clindamycin) 
14 days 
Prohibited 
Anti-rosacea drugs (e.g. 
Metronidazole, azelaic acid, 
Brimonidine, Ivermectin) 
30 days 
Prohibited 
Immunomodulators (including 
topical calcineurin inhibitors) 
30 days 
Prohibited 
Corticosteroids 
30 days 
Prohibited 
Retinoids 
14 days 
Prohibited 
Astringents or abrasives (OTC 
scrubs, exfoliating cleansers and 
products containing salicylic acid and 
alcohol) 
7 days 
Prohibited 
Anti-microbial soaps and face wash 
Not 
applicable 
Prohibited 
Systemic Treatments 
Oral antibiotics (eg Minocycline, 
Doxycycline, Metronidazole or 
Macrolides) 
30 days 
Prohibited 
Corticosteroids 
30 days 
Prohibited 
Immunomodulators 
30 days 
Prohibited 
Oral Ivermectin 
30 days 
Prohibited 
Non-steroidal anti-inflammatory 
drugs 
(except aspirin at subanalgesic doses 
(i.e. <325 mg once daily) for subjects 
requiring platelet aggregation 
inhibition) 
7 days 
Chronic use of 
NSAIDs (>14 days) 
other than aspirin is 
prohibited 
Niacin at doses >500 mg /day 
7 days 
Prohibited 
Other systemic drugs used for 
30 days 
Prohibited 

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treatment of rosacea 
Barbiturates 
30 days 
Prohibited 
Rifampicin 
30 days 
Prohibited 
Carbamazepine 
30 days 
Prohibited 
Phenytoin (Diphenylhydantoin) 
30 days 
Prohibited 
Primidone 
30 days 
Prohibited 
Cyclosporin 
30 days 
Prohibited 
Methoxyflurane 
30 days 
Prohibited 
SAFETY / 
TOLERABILITY 
ENDPOINTS 
The following parameters have been defined as parameters 
regarding safety and tolerability: 
 Change from Baseline to each scheduled time point up to 
EOS for vital signs. 
 Change from Screening up to EOS for physical 
examination. 
 Change from Screening up to EOS for clinical laboratory 
tests. 
 Treatment-emergent AEs up to EOS. 
 Treatment-emergent 
AEs 
leading 
to 
premature 
discontinuation of study drug. 
 Treatment-emergent SAEs up to EOS. 
For pre-existing conditions, any event that worsens during 
treatment will be considered treatment-emergent. 
PRIMARY EFFICACY 
ENDPOINTS 
Co-Primary endpoints: 
 Proportion of subjects with IGA (modified scale without 
erythema) ‘treatment success’ – Grade 0 or 1 at the end of 
study with at least 2 grade reduction from Baseline to Week 
16. 
 Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Week 16. 
SECONDARY 
EFFICACY 
ENDPOINTS 
 Proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from Baseline to 
Week 16 
 Median change in total RosaQoL score from Baseline to Week 
16. 
EXPLORATORY 
EFFICACY 
ENDPOINTS 
 Proportion of subjects with IGA (modified scale without 
erythema) ‘treatment success’ from Baseline to Weeks 4, 8 and 
12. 
 Total inflammatory lesion count (sum of papules, pustules, and 
nodules) reduction from Baseline to Weeks 4, 8 and 12. 
 Proportion of subjects with at least a 2 grade reduction in IGA 
(modified scale without erythema) score from Baseline to 
Week 4,8 and 12. 
 Median change in total RosaQoL score from Baseline to 
Weeks 4, 8 and 12. 
 Mean change in high sensitivity C-reactive protein (hs-CRP) 
levels from Baseline compared to Week 16. 
 Change in Telangiectasia score from Baseline compared to 

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Week 16. 
 Proportion of subjects meeting CEA ‘treatment success’ 
criteria (i.e. a two grade improvement in the CEA scale) at 
Weeks 4, 8, 12 and 16 
STATISTICAL 
METHODOLOGY  
Safety and tolerability 
Safety and tolerability data will be listed individually and 
summarized using descriptive statistics and frequency tables. 
Change from Baseline will be analyzed for the following 
parameters: 
 Change from Baseline to each scheduled time point up to EOS 
for vital signs compared between DFD-29, Oraycea® and 
placebo. 
 Change from Screening up to EOS for physical examination 
compared between DFD-29, Oraycea®and placebo.  
 Change from Screening up to EOS for clinical laboratory tests 
compared between DFD-29, Oraycea® and placebo. 
 Treatment-emergent AEs up to EOS compared between DFD-
29, Oraycea® and placebo. 
 Treatment-emergent AEs leading to premature discontinuation 
of study drug compared between DFD-29, Oraycea® and 
placebo. 
 Treatment-emergent SAEs up to EOS compared between DFD-
29, Oraycea® and placebo. 
 
Efficacy 
For all endpoints, the comparison of oral DFD-29 (40 mg capsule) 
versus placebo will be the primary objective of the study. All other 
comparisons viz, between oral DFD-29 (20 mg capsule) and 
placebo, between oral DFD-29 (40 and 20 mg capsules) and 
Oraycea® and between oral DFD-29 40 mg capsules and DFD-29 
20 mg capsules, will be treated as secondary.  
 
Co-Primary Endpoints 
 The proportion of subjects with IGA (modified scale without 
erythema) ‘treatment success’ – will be investigated with a 
Chi-square test. ‘Treatment Success’ is described as having at 
least 2 grade reduction from Baseline with grade 0 or 1 at 
Week 16. 
 The difference between the treatments in terms of the change 
from Baseline in the total inflammatory lesion count at Week 
16 will be tested using MIXED Model, with the investigator as 
a random factor. 
 
Secondary Endpoints: 
  The proportion of subjects with at least a 2 grade reduction in 
IGA (modified scale without erythema) score from Baseline to 
Week 16, will be investigated with a Chi-square test. 

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 Median change in total RosaQoL score from Baseline to Week 
16 will be analyzed using ANOVA. 
 
Exploratory Endpoints: 
 Proportion of subjects with at least a two grade improvement of 
IGA (modified scale without erythema) grade from Baseline to 
Weeks 4, 8 and 12 will be investigated with a Chi-square test. 
 The difference between treatments in terms of the change from 
Baseline in the total inflammatory lesion count at Weeks 4, 8 
and 12 will be tested using MIXED Model with the 
investigator as a random factor. 
 The proportion of subjects with at least a 2 grade reduction in 
IGA (modified scale without erythema) score from Baseline to 
Week 4, 8 and 12 will be investigated with a Chi-square test. 
 Median change in total RosaQoL score from Baseline to 
Weeks 4, 8 and 12 will be investigated using ANOVA. 
 The difference between treatments will be tested for the mean 
change in high sensitivity C-reactive protein (hs-CRP) levels 
from Baseline to Week 16 using ANOVA 
 Change in Telangiectasia score from Baseline to Week 16 will 
be investigated using ANOVA. 
 Proportion of subjects meeting CEA ‘treatment success’ 
criteria (i.e. a two grade improvement in the CEA scale) in the 
treatment groups at Weeks 4, 8, 12 and 16 will be investigated 
using ANOVA. 
 
Exploratory analyses for the following subgroups will be 
performed: 
 
Male versus female. 
 
Mild (score 2), moderate (score 3) and severe (score 4) IGA 
score. 
 
Normal hs-CRP versus abnormal hs-CRP at Baseline. 
 

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Table 1: Visit and Assessment Schedule 
 
Visit 1 
Visit 2 
Phone 
call 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Screening 
Baseline Week 2 Week 4 
Week 8 Week 12 
Week 16 
Early 
termination 
Study Day 
Day -30 to 
Day -3 
Day 1 
Day 15 
(+/- 2 
days) 
Day 29 
(+/- 5 
days) 
Day 57 
(+/- 5 
days) 
Day 85 
(+/- 5 
days) 
Day 113 (+/- 5 
days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographic Data 
including Fitzpatrick Skin 
Type 
X 
 
 
 
 
 
 
Inclusion 
and 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
Eligibility Conclusion 
 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Medical History/ Prior 
Medications 
X 
X 
 
 
 
 
 
Vital Signs (BP, Pulse rate) 
X 
X 
 
X 
X 
X 
X 
Urine Pregnancy Test (for 
females 
of 
childbearing 
potential) 
X 
X 
 
X 
X 
X 
X 
IGA 
X 
X 
 
X 
X 
X 
X 
CEA 
X 
X 
 
X 
X 
X 
X 
Lesion count 
X 
X 
 
X 
X 
X 
X 
Telangiectasia 
X 
X 
 
X 
X 
X 
X 
RosaQoL Score 
X 
X 
 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
X 
Laboratory assessments 
(Blood & Urine) 
X 
 
 
X 
 
 
X 
hs-CRP 
 
X 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
X 
X 
X 
 
Dispense/Review/Collect  
Study Diary 
 
X 
 
X 
X 
X 
X 
Discussion of Subject 
Instructions 
 
X 
 
X 
X 
X 
 
Collect Study Drug 
 
 
 
X 
X 
X 
X 
Evaluate Study Drug 
Compliance 
 
 
X 
X 
X 
X 
X 
Adverse Event 
(Assessment/Collection) 
 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
 
 
X 
X 
X 
X 
X 
End of Study 
 
 
 
 
 
 
X 
Telephonic enquiry of well-
being 
and 
medication 
compliance  
 
 
X 
 
 
 
 

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6 INTRODUCTION AND RATIONALE 
6.1 
Introduction 
Rosacea is a chronic relapsing inflammatory cutaneous disorder, primarily of the convexities 
of the central face (cheeks, chin, nose, and central forehead). The main clinical forms of the 
disease are erythematotelangiectatic rosacea (ETR; subtype 1), papulopustular rosacea (PPR; 
subtype 2), phymatous rosacea (PHY; subtype 3), and ocular rosacea (subtype 4) (Wilkin 
et al, 2002). In addition to the classification system, the National Rosacea Society Expert 
Committee on the Classification and Staging of Rosacea devised a standard method for 
assessing gradations of the severity of rosacea (Wilkin et al, 2004). This standard grading 
system is essential to perform research, analyze results, and compare data; provides a 
common reference for diagnosis, treatment, and assessment of results in clinical practice; and 
is the basis for the Investigator’s Global Assessment (IGA) in rosacea. 
 
Rosacea is a common disorder with a prevalence of 12,3% in the general population of 
Germany according to a recent population-based epidemiological study (Tan et al, 2016). 
The prevalence of rosacea is highest in subjects of northern European or Celtic heritage 
and shows a South to North increase in Europe, ranging from 2% to more than 10% and 
20% in general and working populations, respectively (Abram et al, 2010; Tan et al, 2016). 
An overall incidence rate of 1.65 per 1000 person-years was reported for diagnosed rosacea 
(Spoendlin et al, 2012). However, the RISE study showed that over 80% of the cases were 
not previously diagnosed (Tan et al, 2016). Although subjects with fair skin (Fitzpatrick skin 
phenotypes I–III) are more likely to be affected, it can be diagnosed in subjects with skin of 
any color. Rosacea occurs in both men and women at any age, but is more common among 
female subjects and its incidence peaks between the ages of 30 and 50 years. 
 
The pathogenesis of rosacea is poorly understood. Contributing factors may include immune 
and inflammatory abnormalities, vascular alterations, neurogenic dysregulation, presence of 
cutaneous microorganisms, ultraviolet (UV) damage, and skin barrier dysfunction (Feldman 
et al, 2014; Holmes and Steinhoff, 2016; Steinhoff et al, 2011; Vemuri et al, 2015; Wollina, 
2014). Clinical features and trigger factors of rosacea indicate a complex dysregulation of 
inflammatory, vascular, and neuronal systems at an early stage. Elevated levels of 
antimicrobial peptides (Cathelicidins), processing enzymes (epidermal serine protease 
kallikrein 5), pro-inflammatory cytokines, C reactive protein, and toll-like receptors (TLR) 
seem to play a role in maintaining chronic inflammation in rosacea, which may induce 
modification of dermal structures mediated by vascular changes and collagen degeneration. 
Complex vascular mechanisms contribute to local vasodilation, angiogenesis and tissue 
fibrosis in rosacea. The involvement of the nervous system is supported by the fact that 
symptoms of rosacea are triggered when subjects are under emotional stress. 
 
Consistent with its immuno-inflammatory and neurovascular pathophysiology, rosacea was 
found to be associated with several autoimmune diseases (Egeberg et al, 2016a), with 
cardiovascular disease risk factors and cardiovascular diseases (Duman et al, 2014; Hua et al, 
2015), with migraine (Spoendlin et al, 2013), and with a 2- to 5-fold increased risk of 
depression and anxiety disorders (Gupta et al, 2005; Egeberg et al, 2016b). In addition, 

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almost half of the rosacea subjects report a significant impairment in their quality of life 
(Bewley et al, 2016; Tan et al, 2016). Taken into consideration these findings and that about 
50% of the subjects receive no rosacea care, effective treatment might contribute not only to 
symptomatic relief, but also to reduce cardiovascular risk and to improve the emotional 
health and the quality of life of subjects with rosacea. 
 
Oral tetracyclines, especially doxycyline and minocycline, have been a cornerstone of 
systemic treatment in rosacea. Independently of their antibacterial properties, tetracyclines 
at low doses exert anti-inflammatory effects, decrease matrix metalloproteinase activity 
involved in kallikrein activation, act as oxygen scavengers, and improve epidermal 
barrier function. All these biological activities could contribute to the effectiveness of 
low-dose tetracyclines in rosacea treatment. The use of tetracyclines was also found to be 
associated with a decreased incidence of vascular disease in veterans with rosacea (Dosal et 
al, 2014). 
6.2 
Study Rationale 
This is a multi-center, randomized, double-blind, parallel-group, controlled study to assess 
the efficacy, safety and tolerability of two dosage strengths of oral DFD-29 (minocycline 
HCl) Extended Release Capsules compared to placebo and Oraycea® Modified Release Hard 
Capsules for the treatment of inflammatory lesions of rosacea for 16 weeks. 
 
Papulopustular rosacea is the second most common form of the disease and represents a more 
inflammatory subtype, characterized by persistent central facial erythema with transient 
papules or pustules or both in a central facial distribution, but it can also present with 
telangiectases (usually masked by its typical manifestations) and occur concomitantly with 
acne vulgaris (Wilkin et al, 2002; Wollina, 2014). In northern European countries, the 
papulopustular subtype represents one fourth to one third of the rosacea cases (Abram et al, 
2010; Tan et al, 2016). Although there are multiple therapeutic options available for the 
treatment of papulopustular rosacea, the most widely used systemic agents are oral 
tetracycline derivatives, particularly doxycycline and minocycline. 
 
The main concern with the long-term use of tetracyclines in rosacea has been antibacterial 
resistance. However, the recent findings that tetracyclines exert anti-inflammatory effects and 
seem to be effective in papulopustular rosacea at low sub-antimicrobial doses opens new 
options for its clinical use in this indication that warrant further investigation (Feldman et al, 
2014; Garrido-Mesa et al, 2013; Griffin et al, 2010; van Zuuren et al, 2015). Doxycycline 
and minocycline show a variety of biological actions independent of their antibiotic activity, 
including scavenging of oxygen radicals, anti-inflammatory and anti-apoptotic actions, and 
inhibition of proteolysis, angiogenesis and tumor growth. Tetracyclines may reduce the 
inflammation associated with rosacea by downregulating proinflammatory cytokines and 
inhibiting matrix metalloproteinases involved in kallikrein activation (Feldman et al, 2014; 
Garrido-Mesa et al, 2013; Griffin et al, 2010). 
 
Minocycline modulates glutamate-induced excitotoxicity and has anti-apoptotic, antioxidant, 
anti-inflammatory and neuroprotective effects that proved beneficial in experimental models 
of various diseases with an inflammatory basis, including dermatological, autoimmune, 
vascular, psychiatric and neurological conditions, for which it has been postulated as an 

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adjunctive therapy (Garrido-Mesa et al, 2013; Griffin et al, 2010; Dean et al, 2014). The lack 
of photosensitivity represents a potential advantage of minocycline for the treatment of 
papulopustular rosacea because doxycycline exhibits a dose-related phototoxicity (Del Rosso, 
2015). Minocycline demonstrated benefit in the treatment of inflammatory lesions in subjects 
with rosacea (Jackson et al, 2014; van Zuuren et al, 2015) and proved remarkably effective in 
decreasing serum C-reactive protein (CRP) levels in other conditions (Kanai et al, 2009). 
However, the dose-related efficacy of minocycline at sub-antimicrobial doses in improving 
the clinical symptoms and reducing serum CRP in papulopustular rosacea has not been 
investigated. 
6.2.1 Dose Selection  
The proposed dose strengths of DFD-29 to be evaluated in this study are 20 mg and 40 mg. 
Currently there is no data available on the safety and efficacy of any of DFD-29 dose 
strengths, when used in patients of rosacea. Minocycline, along with doxycycline and 
tetracycline, has found a place in dermatologists’ therapeutic armamentarium, for treatment 
of inflammatory lesions (papules and pustules) in patients with moderate to severe rosacea; 
however, only sub-antimicrobial dose doxycycline has been approved in the US and EU for 
the above-mentioned indication. 
The rationale of selecting DFD-29 doses lower than the approved minocycline dose on mg/kg 
body weight basis, is based on the lower protein binding and higher lipophilicity of 
minocycline, as compared to doxycycline, which is expected to lead to higher tissue 
penetration and exposures of minocycline than those achieved for doxycycline with the 40 
mg oral dose used for rosacea. Assuming comparable anti-inflammatory effects, similar or 
higher exposure of minocycline achieved using the proposed DFD-29 doses are postulated to 
translate into efficacy at least similar to doxycycline 40 mg that is approved for rosacea. 
6.2.2 Ethical Conduct of the Study 
The study will be performed in accordance with the protocol, ICH Harmonized Tripartite 
Guidelines for Good Clinical Practice (GCP), the principles of the “Declaration of Helsinki” 
(as amended in Tokyo, Venice, Hong Kong, Somerset-West, Edinburgh, Washington DC, 
Tokyo, Seoul and Fortaleza), and applicable local regulations. Please refer to Section 11.2 
(Good Clinical Practice) for further ethical considerations. 

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7 STUDY OBJECTIVES 
 
Primary Objectives: 
 
 To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 mg capsules) in 
comparison to placebo in the treatment of inflammatory lesions of rosacea for 16 weeks. 
 
To evaluate the safety and tolerability of oral DFD-29 (minocycline HCl 40 mg capsules) 
in comparison to placebo in the treatment of inflammatory lesions of rosacea for 16 
weeks. 
 
Secondary Objectives: 
 
 To evaluate the efficacy of oral DFD-29 (minocycline HCl 20 mg capsules) in 
comparison to placebo in the treatment of inflammatory lesions of rosacea for 16 weeks. 
 To evaluate the efficacy of the two dosage strengths of oral DFD-29 (minocycline HCl 20 
mg and 40 mg capsules) in comparison to Oraycea® (doxycycline 40 mg capsules) in the 
treatment of inflammatory lesions of rosacea for 16 weeks. 
 
To evaluate the safety and tolerability of oral DFD-29 (minocycline HCl 20 mg capsules) 
in comparison to placebo in the treatment of inflammatory lesions of rosacea for 16 
weeks. 
 To evaluate the safety and tolerability of the two dosage strengths of oral DFD-29 
(minocycline HCl 20 mg and 40 mg capsules) in comparison to Oraycea® (doxycycline 
40 mg capsules) in the treatment of inflammatory lesions of rosacea for 16 weeks. 
 To evaluate the efficacy of oral DFD-29 (minocycline HCl 40 mg capsules) in 
comparison to oral DFD-29 (minocycline HCl 20 mg capsules)  in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
 To evaluate the safety and tolerability of oral DFD-29 (minocycline HCl 40 mg capsules) 
in comparison to DFD-29 (minocycline HCl 20 mg capsules) in the treatment of 
inflammatory lesions of rosacea for 16 weeks. 
 

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8 STUDY DESIGN 
8.1 
Overall Study Design 
This is a 16-week, multicenter, controlled, randomized, parallel group, double-blind study. 
Subjects, who are at least 18 years old and diagnosed with papulopustular rosacea will be 
randomized to one of the following treatments: 
1. DFD-29 (minocycline HCl) Extended Release Capsules (40 mg) once daily for 16 weeks 
2. DFD-29 (minocycline HCl) Extended Release Capsules (20 mg) once daily for 16 weeks 
3. Oraycea® (doxycycline) Modified Release Hard Capsules (40 mg) once daily for 16 
weeks 
4. Placebo capsules once daily for 16 weeks 
 
After assessing eligibility during an up to 28-days screening period, 200 subjects will be 
enrolled in the study (fifty (50) subjects each in groups 1 to 4) in order to get 176 completed 
subjects (forty four (44) completers each in group). 
The investigational products will be taken orally. Subject visits are scheduled at Screening, 
Baseline (Day 1), and Weeks 4, 8, 12 and 16. Clinical assessments of efficacy will be 
conducted based on Investigator’s Global Assessment (IGA, modified scale without 
erythema), Clinician’s Erythema Assessment (CEA), RosaQoL Score and on inflammatory 
lesion counts at Weeks 4, 8, 12 and 16 in comparison to Baseline. Additionally, high 
sensitivity C-reactive protein (hs-CRP) in the blood will be assessed at Baseline, and at Week 
16 to explore any impact of the treatment on the inflammatory pathology. 
Laboratory assessments on blood (hematology and biochemistry) and urine (routine tests) 
will be conducted at Screening, Week 4 and Week 16 (End of the study) to assess for any 
changes in the safety parameters. Other safety assessments include vital signs, physical 
examination, urine pregnancy tests (only for females with child bearing potential), and 
collection of adverse event data. Impact of the treatment on the Quality of Life (QoL) of the 
subjects will be done using a rosacea specific tool RosaQoL at Baseline, and at Weeks 4, 8, 
12 and 16. 
8.1.1 Informed Consent 
After adequate explanation of the aims, methods, objectives of the study and potential 
hazards of the study drug, a written informed consent from each individual participating in 
this study will be obtained. Informed consent must be obtained before a subject can 
participate in the study, prior to performing any study related procedures and before 
withdrawal of any therapies prohibited during the study. The consent form must be signed 
and dated by the subject and by the Investigator who obtained the subject’s informed consent. 
A copy of the signed and dated consent form must be given to the subject and the date of the 
consent process and the name of the study personnel who conducted the consent process must 
be documented in the source document. Please refer to Section 11.2.3 for further ethical 
considerations. 
The Investigator may need to inform a potential subject well in advance of the actual date of 
Screening that he/she needs to avoid certain drugs/therapies to comply with the Washout. 

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8.1.2 Baseline Parameters and Concomitant Medications 
8.1.2.1 Screening (Visit 1) 
The following Baseline and subject characteristics are collected as part of the Screening: 
 Informed Consent for participation in the study 
 Medical History (all relevant medical history including medication will be 
documented, including the previous therapy for the study indication) 
 Baseline demographics including sex, date of birth, ethnicity, weight, height, and 
Fitzpatrick Skin Type 
 Laboratory assessments on blood (hematology, serology and clinical chemistry) and 
urine (routine tests) (Section 8.1.3.7) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 Physical examination (Section 8.1.3.5) 
 Urine pregnancy test (Section 8.1.5) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count Section (8.1.4.2) 
 Telangiectasia score evaluation (Section 8.1.4.6) 
 Inclusion and Exclusion Criteria (Sections 8.2.1 and 8.2.2) 
8.1.2.2 Baseline (Visit 2) 
The following assessments are being conducted at Baseline: 
 Eligibility conclusion (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Confirmation of Medical History (all relevant medical history including medication 
will be documented) 
 Weight 
 Review of AEs (Section 8.1.3.2) 
 Blood sampling for hs-CRP assessment (Section 8.1.4.5) 
 Urine pregnancy test (Section 8.1.5) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count (Section 8.1.4.2) 
 Telangiectasia score evaluation (Section 8.1.4.6) 
 Randomization 
 Dispensing of study drug 
 Dispensing of study diary 
 Discussion of subject instructions 
8.1.2.3 Prior and Concomitant Medications 
All medications taken within 3 months before Screening should be recorded on the Prior 
Medications page. 

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All medications that are stopped to provide the required washout should be recorded on the 
Prior Medications page. 
All medications previously used for the study indication will be recorded on the Prior 
Medications page. 
All medications taken during the study or started during the course of the study should be 
recorded on the Concomitant Medications Page. 
Concomitant medications initiated, stopped, up-titrated or down-titrated for an AE (Adverse 
Event) will be recorded on a specific Concomitant Medications page. 
8.1.3 Safety and Tolerability Assessments 
Laboratory assessments on blood (hematology and biochemistry) and urine (routine tests) 
will be conducted at Screening, Week 4 and Week 16 (End of the study). A physical 
examination will be conducted at Screening and Week 16 (End of the study) to assess for any 
changes in the safety parameters. Other safety assessments include vital signs (blood 
pressure, pulse rate), urine pregnancy tests for women of child bearing potential and 
collection of adverse event data which will be conducted at every visit. A study diary will be 
dispensed and collected at every visit starting at the Baseline Visit. AE data, concomitant 
medication, and compliance data from the diary will be entered in the eCRF. 
The definitions, reporting, and Follow-up of AEs and SAEs are described in Section 9. 
Table 1 provides an overview of all time points on which safety assessments will be 
performed. 
A detailed description of the scheduled tasks at each visit can be found in Table 1 and 
Sections 8.1.2 and 8.1.3. Enough time should be reserved for all assessments to be performed. 
8.1.3.1 Activities scheduled at Individual Study Visits 
Week 2 (Phone call) 
 Eligibility confirmation (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Review of AEs (Section 8.1.3.2) 
 Use of Concomitant Medication (Section 8.2.3.1) 
 Evaluation of study drug compliance 
 Telephonic enquiry of well-being and medication compliance 
 
Week 4 (Visit 3) 
 Eligibility confirmation (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Review of AEs (Section 8.1.3.2) 
 Use of Concomitant Medication (Section 8.2.3.1) 
 Urine pregnancy test (Section 8.1.5) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count (Section 8.1.4.2) 

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 Telangiectasia score evaluation (Section 8.1.4.6) 
 Laboratory assessments on blood (hematology and clinical chemistry) and urine 
(routine tests) (Section 8.1.3.7) 
 Collection of study drug 
 Evaluate study drug compliance 
 Dispensing of study drug 
 Collection, review and dispensing of study diary 
 Discussion of subject instructions 
 
Week 8 (Visit 4) 
 Eligibility confirmation (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Review of AEs (Section 8.1.3.2) 
 Use of Concomitant Medication (Section 8.2.3.1) 
 Urine pregnancy test (Section 8.1.5) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count (Section 8.1.4.2) 
 Telangiectasia score evaluation (Section 8.1.4.6) 
 Collection of study drug 
 Evaluate study drug compliance 
 Dispensing of study drug 
 Collection, review and dispensing of study diary 
 Discussion of subject instructions 
 
Week 12 (Visit 5) 
 Eligibility confirmation (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Review of AEs (Section 8.1.3.2) 
 Use of Concomitant Medication (Section 8.2.3.1) 
 Urine pregnancy test (Section 8.1.5) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count (Section 8.1.4.2) 
 Telangiectasia score evaluation (Section 8.1.4.6) 
 Collection of study drug 
 Evaluate study drug compliance 
 Dispensing of study drug 
 Collection, review and dispensing of study diary 
 Discussion of subject instructions 
 
Week 16/End of Study or early termination (Visit 6) 

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 Eligibility confirmation (based on inclusion (Section 8.2.1) and exclusion criteria 
(Section 8.2.2)) 
 Review of AEs (Section 8.1.3.2) 
 Use of Concomitant Medication (Section 8.2.3.1) 
 Weight (Section 8.1.3.6) 
 Physical examination (Section 8.1.3.5) 
 Blood sampling for hs-CRP assessment (Section 8.1.4.5) 
 Laboratory assessments on blood (hematology and clinical chemistry) and urine 
(routine tests) (Section 8.1.3.7) 
 Urine pregnancy test (Section 8.1.5) 
 Evaluation of vital sign parameters (Section 8.1.3.4) 
 IGA (Section 8.1.4.1) 
 CEA (Section 8.1.4.3) 
 RosaQoL (Section 8.1.4.4) 
 Total inflammatory lesion count (Section 8.1.4.2) 
 Telangiectasia score evaluation (Section 8.1.4.6) 
 Collection of study drug 
 Evaluate study drug compliance 
 Collection, and review of study diary 
8.1.3.2 Adverse Events 
Adverse events will be recorded according to GCP requirements. For the safety analysis, only 
treatment-emergent adverse events will be analyzed. Treatment-emergent adverse events will 
include any AE occurring during the treatment period (from the first administration of the 
study drug until the end of study). For pre-existing conditions, any event that worsens during 
treatment will be considered treatment-emergent. 
8.1.3.3 Telephonic Enquiry 
At Week 2, a telephonic enquiry will be scheduled to assess the well-being of the subjects 
and study drug compliance. 
8.1.3.4 Vital Signs 
Blood pressure (systolic and diastolic) will be measured in sitting position, at least 5 minutes 
after assuming a sitting position and having rested. Pulse rate will be measured at the time of 
vital sign assessment. 
8.1.3.5 Physical Examination 
The physical examination will include general appearance, skin, eyes, ear/nose/throat, head 
and neck, heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, 
neurological, and other body systems, if applicable, for describing the status of the subject’s 
health. 
8.1.3.6 Weight and Height 
The subject’s body weight will be measured using an accurate balance. The balance should 
have a precision of at least 0.5 kg. Body weight will be recorded with 1 decimal. The 
subject's height and weight is measured without wearing shoes.  

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8.1.3.7 Laboratory Assessments 
Clinically significant laboratory abnormalities after screening must be reported by the 
investigator as an AE or SAE, as appropriate (see Section 9). 
As a rule, the blood samples will be taken from the subject by puncture of a vein in the 
cubital or the antebrachial region. The samples will be sent to the central laboratory for 
analysis. Details regarding overall blood volume collected, sample handling and shipment 
will be provided in a separate Laboratory manual. A summary of the routine tests conducted 
in this study (see Table 1) can be found in Table 2, any other investigation (including anti-
nuclear antibody and hepatic transaminases for suspected drug-induced lupus or auto-immune 
hepatitis in symptomatic subjects) will have to be symptom-driven or on Investigator 
judgment on a case to case basis. 
Additional safety samples may be taken at investigator discretion in consultation with the 
sponsor. 
Table 2: Summary of Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Others 
Complete Blood Count 
(CBC) 
Glucose 
Uric acid 
Calcium 
Sodium 
Potassium 
Chloride 
Alkaline phosphatase 
Total bilirubin 
Creatinine 
BUN 
AST (SGOT) 
ALT(SGPT) 
LDH 
Total protein 
Albumin 
Urobilinogena 
Nitritesa 
pHa 
Glucosea 
Proteina 
Blooda 
Ketonesa 
Pregnancyb 
hs-CRP 
Serology (for anti-HIV I, 
anti-HIV 2, HBsAG, and 
anti-HCV antibodies) 
a Dip stick. 
b Only required for women of child bearing potential 
 
8.1.4 Efficacy Assessments 
8.1.4.1 Investigator´s Global Assessment (IGA) 
The IGA (see Appendix 13.1) is carried out by visual inspection by the Investigator at every 
study visit from Screening up to Week 16 (or at early termination). 
8.1.4.2 Total Inflammatory Lesion Count 
The total inflammatory lesion count is carried out by visual inspection by the Investigator at 
every study visit from Screening up to Week 16 (or at early termination). Inflammatory 
lesions will be recorded on a diagram of a human face, divided in 4 quadrants. 
8.1.4.3 Clinician´s Erythema Assessment (CEA) 
The CEA is carried out by visual inspection by the Investigator at every study visit from 
Screening up to Week 16 (or at early termination). The erythema assessment will be carried 
out separately at 5 locations on the face- forehead, nose, chin, right cheek and left cheek. The 
scores from all 5 locations will be totaled to yield the final CEA grade. 

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8.1.4.4 Rosacea Quality of Life (RosaQoL) 
The RosaQoL assessment is carried out by the Investigator by asking questions as per the 
validated RosaQoL questionnaire instrument, at every study visit from Screening up to Week 
16 (or at early termination). The subjects will have to rate on a 5 grade scale their perception of 
the impact that Rosacea has on various dimensions influencing their quality of life. 
8.1.4.5 High sensitive C-reactive Protein (hs-CRP) 
Blood will be drawn for the analysis of hs-CRP at Baseline and Week 16. 
8.1.4.6 Telangiectasia Score 
Telangiectasia will be graded by visual inspection by the Investigator at every study visit 
from Screening up to Week 16 (or at early termination). 
8.1.5 Pregnancy test 
A urine pregnancy test will be performed for women of child bearing potential at every study 
visit from Screening up to Week 16 (or at early termination if previous pregnancy testing was 
performed more than 28 days prior).  
8.2 
Study Population 
The subject population will include human subjects, who are at least 18 years old, diagnosed 
with papulopustular rosacea and satisfy all entry criteria. 
8.2.1 Inclusion Criteria 
The following criteria must be met by all subjects considered for study participation: 
 
1. Subjects must be able to understand the requirements of the study and be willing to give 
written informed consent. 
2. Male and female subjects aged 18 years and above. 
3. Subjects, any gender or ethnicity (and of Fitzpatrick skin type I – III), must be in good 
general health as determined by the Investigator 
4. Subjects must have a clinical diagnosis of papulopustular rosacea, IGA grade 2 - 4. 
5. Subjects must have 10 - 40 (both inclusive) inflammatory lesions (papules and pustules) 
of rosacea over the face. 
6. Subjects must have not more than 2 nodules. 
7. Subjects with moderate to severe erythema with a total score of 5 - 20 on the CEA scale. 
8. Subjects must agree to only use the study products and to not use any other treatment for 
rosacea (prescription or Over The Counter (OTC)) during the course of the study. 
9. Subjects must be free of any systemic or dermatologic disorder, which in the opinion of 
the Investigator, will interfere with the study results, and especially free of any skin 
diseases (for example peri-oral dermatitis, facial keratosis pilaris, seborrheic dermatitis, and 
acne vulgaris) that may confound the evaluation of rosacea. 
10. Females must have a negative urine pregnancy test at the Screening and Baseline Visit. 
Sensitivity of such a test should at least be 25 mIU/mL or lower for hCG. 
11. Females must either be postmenopausal with no menses for at least 12 months or 
surgically sterile (hysterectomy or tubal ligation) or agree to use a highly effective 
method of contraception with a pearl index of <1% up to 1 month after last dose1. 

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Contraception methods with low user dependency should preferably be used, in particular 
when contraception is introduced as a result of participation in this clinical study. 
 ‘Highly effective’ methods of birth control include: 
 combined (estrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation*: 
o oral 
o intravaginal 
o transdermal 
 progesterone-only hormonal contraception associated with inhibition of ovulation*: 
o oral 
o injectable 
o implantable† 
 intra-uterine device (IUD) † 
 intra-uterine hormone releasing system (IUS) † 
 bilateral tubular occlusion† 
 vasectomy of sexual partner that was performed at least 90 days prior to Baseline, 
and has been medically assessed as successful† 
 sexual abstinence 
o Note: Sexually inactive female subjects may be enrolled at the investigator’s 
discretion provided that they are counseled to refrain from heterosexual 
intercourse for the duration of the study and for one month after the last dose, and 
understand the possible risks involved in getting pregnant during the study. 
 
* Hormonal methods: If on hormonal contraceptives, must have been on the same 
hormonal contraceptive product for 3 months (90 days) prior to Baseline and 
continued on same method and dose throughout the duration of the study. If subject 
had used hormonal birth control and had stopped, this should have occurred more 
than 6 months prior to Baseline. Female subjects on low dose oral contraceptives 
(containing ≤35 µg of ethinyl estradiol or equivalent dose of other estrogens) must 
use a second form of contraceptive during the study. 
† Contraception methods that are considered to have low user dependency. 
12. Subjects must be in good general health as determined by the investigator and 
supported by the medical history and normal or not clinically significant abnormal 
vital signs (blood pressure and pulse). Subjects are eligible at screening if: 
a. 
Systolic BP ≤140 and ≥90 
b. Diastolic BP ≤100 and ≥50 
c. Pulse 50 – 100 bpm inclusive 
8.2.2 Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria: 
1. Females who are pregnant or nursing or planning to become pregnant during the study.  
2. Male whose female partner is planning to conceive a child. 
3. Subjects who have been treated for rosacea within the 30 days prior to the Baseline Visit 
(e.g. metronidazole, azelaic acid, doxycycline or brimonidine). 
4. Subjects who have been treated with systemic retinoids within 6 months prior to the 
Baseline visit. 

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5. Subjects who have participated in a trial involving any investigational product in the 90 
days prior to the Baseline Visit. 
6. Subjects with any disease or medical condition that would interfere with the study outcome 
or place the subject at undue risk. 
7. Subjects who use or have used systemic steroids within the 30 days prior to the Baseline 
Visit or any other immunosuppressive medication. 
8. Subjects who are on anti-coagulants or those who are likely to require anti-coagulants 
during the study period. 
9. Subjects who have used methoxyflurane or other nephrotoxic drugs (as judged by the 
investigator) within the past 30 days. 
10. Subjects with known hypersensitivity to minocycline or doxycycline or any component of 
the study products or against other kinds of tetracyclines. 
11. Subjects with clinically significant abnormal laboratory test that, in the opinion of the 
investigator, would compromise the subject’s safety or ability to participate in the trial. 
12. Subjects who are unable to comply with study requirements. 
13. History of organ transplant requiring immunosuppression, HIV, or other immune 
compromised state. 
14. Subjects who in the opinion of the investigator or physician performing the initial 
examination, should not participate in the trial, e.g. due to probable noncompliance or 
inability to understand the trial and give adequately informed consent. 
15. Subjects with close affiliation with the investigator (e.g. a close relative) or persons 
working at the respective trial sites or subjects who are an employee of the sponsor. 
16. Subjects institutionalized because of legal or regulatory order. 
17. History of drug or alcohol abuse in the last year. 

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8.2.3 Diet, Activities, and Other Restrictions 
8.2.3.1 Concomitant Medication 
Drugs that influence the inflammatory lesions in acne and rosacea must be avoided. Facial 
procedures, influencing acne and rosacea [such as chemical peel, photodynamic therapy, acne 
surgery, cryodestruction or chemodestruction, x-ray therapy, intralesional steroids, 
dermabrasion, or depilation (except eyebrow shaping), laser therapy or Intense Pulse Light 
Treatment as well as other procedures on face (Thermage® etc.)] are prohibited from 45 days 
prior to the intake of study medication throughout the whole study period.  
Systemic retinoids (including high dose vitamin A >10,000 units per day) must be avoided 
from 180 days prior to the intake of study medication throughout the whole study period 
Furthermore, drugs interacting with minocycline and Oraycea® or affecting their absorption 
should also be avoided. Some non-drug therapies should be avoided as well. For details on 
prohibited topical drugs, systemic drugs and other therapies, see Table 3. 
Table 3: Prohibited Topical Drugs, Systemic Drugs, and Other Treatments 
Product 
Washout period 
before Baseline 
During Study 
Topical treatments on the face 
Benzoyl Peroxide (BPO) 
14 days 
Prohibited 
Antibiotics (eg. Macrolides, Clindamycin, etc. ) 
14 days 
Prohibited 
Anti-rosacea drugs (eg Metronidazole, azelaic acid, 
Brimonidine, Ivermectin) 
30 days 
 
Prohibited 
Immunomodulators (including topical calcineurin 
inhibitors) 
30 days 
Prohibited 
Corticosteroids 
30 days 
Prohibited 
Retinoids 
14 days 
Prohibited 
Astringents or abrasives (OTC scrubs, exfoliating 
cleansers and products containing salicylic acid and 
alcohol) 
7 days 
Prohibited 
Anti-microbial soaps and face wash 
Not applicable 
Prohibited 
Systemic Treatments 
Oral antibiotics ( eg Minocycline, Doxycycline, 
Metronidazole or Macrolides) 
30 days 
Prohibited 
Corticosteroids 
30 days 
Prohibited 
Immunomodulators 
30 days 
Prohibited 
Oral Ivermectin 
30 days 
Prohibited 
Non-steroidal anti-inflammatory drugs 
(except aspirin at subanalgesic doses (i.e. <325 mg once 
daily) for subjects requiring platelet aggregation 
inhibition) 
7 days 
Chronic use of NSAIDs (>14 
days) other than aspirin is 
prohibited 
Niacin at doses >500 mg /day 
7 days 
Prohibited 
Other systemic drugs used for treatment of rosacea 
30 days 
Prohibited 
Barbiturates 
30 days 
Prohibited 
Rifampicin 
30 days 
Prohibited 
Carbamazepine 
30 days 
Prohibited 
Phenytoin (Diphenylhydantoin) 
30 days 
Prohibited 
Primidone 
30 days 
Prohibited 
Cyclosporin 
30 days 
Prohibited 
Methoxyflurane 
30 days 
Prohibited 

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8.2.3.2 Dietary Aspects 
Substances which can potentially interfere with absorption of minocycline like antacids, 
multivitamins or other products containing aluminum, magnesium and calcium, oral iron 
preparations, bismuth subsalicylate and milk and other dairy products should be avoided from 
1.5 hours before to 3.0 hours after intake of DFD-29. 
8.2.3.3 Sun Exposure 
Excessive sun exposure and/or UV radiation should be avoided and protective measures 
should be taken. 
8.2.3.4 Contraceptives 
Special attention has to be paid to female subjects taking low dose oral contraceptives (35 
microgram of ethinyl estradiol or equivalent dose of other estrogens) as their effectiveness 
may be affected by the use of DFD-29. To avoid contraceptive failure, females have to use a 
second acceptable form of contraceptive from Screening up to 1 month after last dose. 
Note: ‘Acceptable’ method of contraception include double barrier methods (e.g. a 
combination of male condom with either cap, diaphragm or sponge with spermicide) in 
addition to the ‘highly effective methods of birth control that are described in Section 8.2.1, 
inclusion criterion 11. 
Male subjects are requested to be either sexually inactive, sterile or use a barrier method for 
contraception. Sperm and blood donation is prohibited from Baseline up to 1 month after last 
study drug intake. Female partners of male subjects have to adopt a highly effective method 
of contraception with a failure rate of <1 percent per year when used consistently and 
correctly. 
Please refer to inclusion criterion 11 (Section 8.2.1) for further details on contraception for 
females. 
8.3 
Study Drugs 
Study drugs include the investigational products DFD-29 (minocycline HCl) Extended 
Release Capsules (20 mg and 40 mg), matching placebo and Oraycea® (doxycycline) 
Modified Release Hard Capsules administered during the study. 
8.3.1 Investigational Product and Matching Comparators 
Dr. Reddy’s will provide DFD-29 (minocycline HCl) Extended Release Capsules (20 mg and 
40 mg) and matching placebo. DFD-29 is available for clinical trial use in the form of oral 
capsules. Placebo for DFD-29 is available as capsules matching DFD-29, formulated with the 
same excipients, but without minocycline hydrochloride. Oraycea® capsules are 
commercially available and will be purchased by ABF. In order to maintain double blinding 
of all treatments, ‘over-encapsulation’ (enclosing the original capsule within a second larger 
capsule shell) will be performed. The identity of the study drug DFD-29 is given in Table 4. 
The identity of the placebo is given in Table 5 and the identity of Oraycea® is given in Table 
6. 
 
 

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Table 4: Identity of Investigational Medical Products 
 
Test treatment 
Name: 
DFD-29 (minocycline HCl) Extended Release 
Capsules 
Active ingredient: 
minocycline HCl 
Formulation: 
Extended Release Capsules 
Dose strength: 
20 mg or 40 mg minocycline 
Dose: 
1 capsule 
Posology: 
1-0-0 (once daily, in the morning) 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
 
Table 5: Identity of Placebo 
 
Test treatment 
Name: 
Placebo for DFD-29 
Active ingredient: 
Not applicable 
Formulation: 
Capsules 
Dose strength: 
Not applicable 
Dose: 
1 capsule 
Posology: 
1-0-0 (once daily, in the morning) 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
 
Table 6: Identity of Oraycea® 
 
Test treatment 
Name: 
Oraycea® 
Active ingredient: 
Doxycycline monohydrate  
Formulation: 
Capsule with 30 mg immediate release and 10 mg 
delayed release beads 
Dose strength: 
40 mg doxycycline 
Dose: 
1 capsule 
Posology: 
1-0-0 (once daily, in the morning) 
Mode of administration: 
Oral administration with approx. 240 mL water 
Administration condition: 
Fasting state preferred, but not mandatory 
Duration of administration: 
16 weeks 
Batch number & Expiry date: 
Will be given in the TMF ***. 
*** The documentation allowing traceability will be provided in the TMF. 
 

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8.3.2 Study Drug Supply and Packaging  
DFD-29 (minocycline HCl) Extended Release Capsules and placebo for DFD-29 will be 
supplied by Dr. Reddy´s Laboratories as 25 count in HDPE bottle. The study drug will be 
imported by QPS and further managed by ABF. 
The study drugs will be supplied to ABF where over-encapsulation, re-packaging and the 
clinical labeling will be performed. Over-encapsulation will be performed with DFD-29, 
placebo and Oraycea® capsules in order to achieve double blinding of formulations. 
Subsequently, the capsules will be re-packed into new HDPE bottles (of specifications 
identical to the one in which stability of DFD-29 capsules has been evaluated) containing 25 
capsules. The medication bottles will be labeled according to ABF’s procedure as stated in 
Section 8.3.3 See sample label Figure 8-2. 
The clinical labelled study drug will be supplied to the investigational sites in HDPE bottle 
packs of 25 units. Boxes containing 6 bottles of each strength of DFD-29 (minocycline HCl) 
Extended Release Capsules (20 mg and 40 mg), Oraycea® (doxycycline) Modified Release 
Hard Capsules and placebo will be provided as individual subject kits. The six bottles in each 
individual subject kit are numbered consecutively. From the kit, two consecutively numbered 
bottles will be provided to the subjects during visits 2-5, starting with the lowest number 
available. Subjects will be instructed to always take the capsules from the bottle with the 
lowest number, until the same is empty and then start with the other bottle. Both bottles 
received by a subject during a visit, whether unused, partially used or empty, must be 
returned to the study staff at the successive visit. The study staff will verify the accountability 
of the IMPs. Partially used bottles will be re-dispensed at the successive visit, while emptied 
bottles will be replaced with the next bottle from the kit bearing the lowest available number 
(see Figure 8-1). 

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2 
6 
5 
1 
4 
3 
Visit 
Returned Medication 
Dispensed Medication  
Visit 5 
Week 12 
Visit 3 
Week 4 
Visit 2  
Baseline 
Visit 4 
Week 8 
Visit 6 
Week 16 
Visit 1 
Screening 
1 
2 
1 
3 
2 
2 
4 
4 
3 
5 
3 
4 
5 
Bottle Number 6 is a reserve bottle! 
Figure 8-1: Flowchart for dispensing and returning of study medication 

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8.3.3 Study Drug Labeling 
The labeling complies with the applicable (local) laws and regulations. The labels will be in 
German language. An English version will be available for review purposes. At the 
minimum, the following information will be provided on the label: 
 Study number (DFD-29-CD-002) 
 Study drug (25x DFD-29, 20 mg / 40 mg / placebo / Oraycea® Capsules) 
 Name, address and telephone number of sponsor or CRO 
 Batch number 
 Subject identification/treatment number 
 Bottle number 
 Quantity of dosage units 
 Route of administration (e.g., oral) 
 Directions for use 
 Storage conditions 
 Retest or expiry date 
 “For clinical trial use only” or similar cautionary statement 
 “Keep out of reach of children” or similar cautionary statement 
 
Study drugs might be relabeled during the trial. A possible reason for relabeling might be an 
extension of the expiry period which is stated on the clinical label. Any relabeling activities 
will be coordinated by QPS. Relabeling activities will be done according to a re-labeling 
protocol and will be documented accordingly. A Qualified Person (QP) will be responsible 
for final release of the investigational medicinal products for use in the trial. Final labeling 
activities including the stated re-test date on the products are part of the approval by the QP. 
 

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Figure 8-2: Sample Label 
 
 
 

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8.3.4 Study Drug Administration 
The Investigational product will be taken at a fixed time of the day once a day (± 2 hours), for 
16 consecutive weeks. The preferred time of administration of the study drug will be in the 
morning, after an overnight fast. One capsule of the assigned study drug will be swallowed 
with 240 mL (1 glass) of still water on an empty stomach. For dietary aspects upon study 
drug administration please refer to Section 8.2.3.2. 
8.3.5 Drug Accountability 
The study drug bottles will have to be returned at each scheduled visit. The investigator will 
count the number of capsules remaining in the returned bottles and document it in the drug 
accountability form. 
At the initiation visit of the study the site will receive drug accountability forms to document 
dispensing and returning of study medication. These forms will be made available to the 
authorized persons (e.g. Clinical Monitor, Auditor) and will include the following 
information: study number, dates, quantities, batch number and subject randomization 
number. A drug supply inspection for inventory purposes and to ensure proper storage will be 
conducted at regular intervals throughout the study. 
8.3.6 Storage and Return of Study Drug 
Upon receipt of the study drugs at the site, all study drugs will be inspected for completeness. 
Subsequently, the recipient must immediately return the enclosed acknowledgement of 
receipt form duly completed and signed (the date of receipt must be noted). 
The Investigator or delegate is responsible for storage of the study drug at the study site in an 
appropriate lockable room at the correct storage conditions which will be described in the 
pharmacy manual.  
All unused investigational material (drugs and packaging) must be returned to ABF on 
termination of the study and after a drug accountability check by the monitor where it will be 
destroyed. 
The Investigator or delegate of each site will be responsible for the inventory and 
accountability of the clinical supplies provided to that site, exercising accepted 
pharmaceutical practices. An accurate, timely record of the clinical study supply will be 
maintained. The original Drug Accountability Record is considered as source data and will be 
archived at the site. 
8.4 
Study Drug Discontinuation and Study Withdrawal 
8.4.1 Study Drug Interruption or Discontinuation 
The investigator must temporally interrupt or permanently discontinue the study drug if 
continued administration of the study drug is believed to be contrary to the best interests of 
the subject. The interruption or premature discontinuation of study drug might be triggered 
by:  
 
An adverse event 
 
A diagnostic or therapeutic procedure 
 
An abnormal assessment (e.g. vital signs or laboratory abnormalities) 

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 
Administrative reasons, in particular withdrawal of the subject’s consent, or subject 
becomes uncooperative. 
The reason for study drug interruption or premature discontinuation must be documented in 
the eCRF and the sponsor must be informed. If the reason for discontinuation from study 
drug is an abnormal result on a laboratory test or vital sign this information will be recorded 
as an AE in the eCRF. The subject will remain under the supervision of the investigator until 
satisfactory health has returned. 
Subjects with protocol deviations should not be withdrawn automatically unless there is a 
safety concern. The protocol deviation should be recorded in the subject’s case record form 
and Sponsor Consultation Form and included in the study report. 
Violations of in- /exclusion criteria lead to discontinuation unless agreed upon otherwise by 
the sponsor and the investigator, if there is no safety concern.  
As far as is possible, Investigators must advise subjects to refrain from consuming the 
prohibited medication (as specified in Table 3). In case subject consumes a prohibited 
concomitant medication or needs to take one, a joint decision will be taken by the medical 
monitor and Sponsor medical monitor on whether or not the subject should continue in the 
study or be withdrawn, depending upon the potential for harmful drug-drug interaction and 
influence on study efficacy assessments. The Investigator must communicate information 
about the study drug taken/ required by subject, including its generic name, dose and duration 
of treatment and reason for subject taking/ being advised to take the drug, as soon as it comes 
to his/her knowledge, to QPS clinical study coordinator, who in turn should forward the 
information to QPS and Sponsor medical monitors for a decision on continuation of the 
subject to be taken. 
Subjects who experience an AE resulting in or requiring discontinuation of study product use 
should be encouraged to be followed up in the study until the AE is resolved or stabilized. 
Subjects whose treatment randomization is unblinded at the study site should stop the study 
treatment immediately and be withdrawn from the study after follow-up. 
If a female subject becomes pregnant during the study, the study product will be discontinued 
immediately and she will be followed through the pregnancy and delivery. Details of the 
pregnancy, delivery and health of the infant should be recorded on the Pregnancy Report 
Form and the sponsor should be notified immediately. 
8.4.2 Study Discontinuation 
Subjects may prematurely discontinue the study at any time. However, subjects are requested 
to come back for an EOS examination for safety reasons. 
Premature discontinuation from the study is to be understood as: 
 Subject did not undergo the EOS examination 
and/or 
 Subject is missing pivotal efficacy assessments 
Generally, subjects will be withdrawn from the study if any of the following occurs during 
the study period, i.e. from Screening Visit to end of study (EOS): 
 Screening failure 
 Lost to follow-up 

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 Subject who decides to withdraw their informed consent 
 Subject has used prohibited treatments as listed in the Section 8.2.3 as confirmed by 
QPS and Sponsor medical monitor. 
 Any pathological event, clinical adverse event, or any change in the subject’s status 
giving indication to the investigator that further participation in the study may not be 
the best interest of the subject 
 Subject develops an exclusion criterion and is no longer eligible to continue in the 
study 
 Subject is lacking the interest, understanding, desired compliance and willingness to 
adhere to follow study procedures or adhere to restrictions to continue with the trial 
 Administrative Reasons 
 If a female subject becomes pregnant during the study, study product will be 
discontinued immediately and she will be followed through the pregnancy and 
delivery. Details of the pregnancy, delivery and health of the infant should be 
recorded on the Pregnancy Report Form and the sponsor notified immediately. 
A subject will be considered as ‘lost to Follow-up’ if, and only if, he/she cannot be reached 
after exhausting all means of contact. Every attempt should be made to contact subjects who 
are lost-to-follow-up for a final safety assessment. At least three attempts must be 
documented in the subject’s source document including the use of at least 1 certified letter. 
Any contact, either direct or indirect, should be made with the purpose to document the final 
status of the subject with regard to safety. 
Subjects who are withdrawn due to adverse event(s) or serious adverse event(s) should be 
followed until resolution or until the event is considered stable. 
The reasons for premature discontinuation of the study must be documented in the eCRF and 
the sponsor must be informed. 
Drop-outs will not be replaced. 
8.4.3 Subject’s Follow-up after Study Discontinuation 
Included subjects can leave the study at any time for any reason if they wish to do so, without 
any consequences. 
In the case of premature discontinuation after study drug intake, the assessments scheduled 
for the EOS examination will be performed as soon as possible.  
For terms and conditions of early termination of this study please refer to Section 11.1.9. 
8.5 
Treatment Exposure and Compliance 
Study drug accountability is performed at each scheduled visit by the study staff and checked 
by the monitor during site visits and at the completion of the study.  
Concerning missed doses: In case 6 or less consecutive doses are missed, subjects may 
continue with the study medication. If 7 or more consecutive doses are missed withdrawal 
from the study has to be considered by the investigator in agreement with the sponsor. The 
subject has to be at least 80% to 120% drug compliant (overall) to be analyzed per protocol 
(e.g. the subject should have received between 90 to 135 single doses of the assigned IP over 
16 weeks). 

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8.6 
Treatment Assignment and Blinding 
8.6.1 Assignment of Subject Numbers 
Subjects will receive a number on Day 1 before start of procedures/assessments. The 
assignment of number and code for subject identification is based on the obligation for 
anonymity.  
During Screening, the sites will assign three-digit sequential subject numbers preceded by a 
site number (e.g. 01-001). Upon inclusion into the study, the subjects will receive a four-digit 
randomization number (kit code) which does not contain site identification. 
8.6.2 Treatment Assignment 
Subjects will be randomized to any of the treatments assigned in a 1:1:1:1 fashion. Block size 
will be determined by the statistician of QPS Netherlands. Randomization will be stratified 
per site. The first randomizations (approximately 40% of the patients) were also stratified per 
IGA score. This stratification resulted in a high amount of study medication kits to be stored 
at the site, limiting the overall availability of unexpired kits in the study. Therefore 
stratification per IGA score is dropped and randomization is only stratified per site at 
Baseline. In order to achieve a patient population in the study with adequate representation of 
patients with moderate to severe illness (IGA score above 2) not more than 20 % of 
enrollments in the study will be of IGA grade 2 at Baseline. 
The randomization code will be generated by a computer program (OpenClinica) and is 
stored securely. It is accessible only to authorized persons who are not involved in the 
conduct and analysis of the study, until time of un-blinding. 
Randomization is controlled by the study drug packaging. The number on the subject kit 
equals the randomization number. The kits will be allocated to the sites. 
Randomization will be performed by the validated randomization module of OpenClinica. 
This module uses the randomization from Sealed Envelope™. Subjects will be assigned to a 
kit code (matching the randomization number). 
The randomization number will be un-blinded and made available for data analysis only after 
study closure, i.e., when the study has been completed, the protocol deviations determined 
and the clinical database declared complete, accurate, and locked. 
8.6.3 Double-blinding 
The study is performed in a double-blind fashion. The investigator and study staff (including 
lab personnel), the subjects, the monitors, medical monitors, the CRO personnel involved in 
clinical operations and the sponsor’s staff will remain blinded to the treatment until study 
closure. The investigational product and its matching placebo and active comparator 
(Oraycea®) are indistinguishable after over-encapsulation, and all subject bottles will be 
packaged and labelled in the same way. 
The randomization code will be kept strictly confidential. It is accessible only to authorized 
personnel, who are not involved in the conduct and analysis of the study, and will keep the 
randomization scheme strictly confidential. 

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8.6.4 Emergency Procedure for Unblinding 
The investigator has access to emergency envelopes for each subject containing the identity 
of the study drug dispensed. The investigator and the study staff must remain blinded to the 
subject's treatment assignment, even if the subject refuses to participate in any study 
procedures or experiences an AE. The identity of the study drug may be revealed only if the 
subject experiences a medical emergency whose management would be improved by the 
knowledge of the blinded treatment assignment. Subjects who have thus been unblinded 
prematurely will be discontinued from the study. 
The occurrence of any code break during the study must be clearly justified and explained by 
the investigator. Before accessing the emergency envelope, every attempt must be made by 
the investigator to discuss the intended code break with the study monitor and Dr. Reddy’s. 
In all cases, the sponsor must be informed as soon as possible before or after the code break. 
Every code break must be documented. 
8.7 
Study Parameters 
8.7.1 Efficacy Endpoints 
The following parameters have been defined as parameters regarding efficacy. Treatment 
success is achieved only if both primary endpoints are met. Baseline is defined as the last 
value measured prior to the first intake of assigned study drug. 
Co-Primary endpoints: 
 Proportion of subjects with IGA (modified scale without erythema) ‘treatment success’ – 
Grade 0 or 1 at the end of study with at least 2 grade reduction from Baseline to Week 
16. 
 
Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Week 16. 
 
Secondary endpoints 
 Proportion of subjects with at least a 2 grade reduction in IGA (modified scale without 
erythema) score from Baseline to Week 16 
 Median change in total RosaQoL score from Baseline to Week 16. 
 
Exploratory endpoints 
 Proportion of subjects with IGA (modified scale without erythema) ‘treatment success’ 
from Baseline to Weeks 4, 8 and 12. 
 Total inflammatory lesion count (sum of papules, pustules, and nodules) reduction from 
Baseline to Weeks 4, 8 and 12. 
 Proportion of subjects with at least a 2 grade reduction in IGA (modified scale without 
erythema) score from Baseline to Week 4, 8 and 12. 
 Median change in total RosaQoL score from Baseline to Weeks 4, 8 and 12. 
 Mean change in high sensitivity C-reactive protein (hs-CRP) levels from Baseline 
compared to Week 16. 
 Change in Telangiectasia score from Baseline compared to Week 16. 
 Proportion of subjects meeting CEA ‘treatment success’ criteria (i.e. a two grade 
improvement in the CEA scale) at Weeks 4, 8, 12 and 16 

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8.7.2 Safety and Tolerability Endpoints 
Baseline is defined as the last value measured prior to the first DFD-29 intake (vital signs, 
laboratory parameters). Please refer to Sections 8.1.2 and 8.1.3 for activities performed 
during individual, study visits. 
 
The following parameters have been defined as parameters regarding safety and tolerability: 
 Change from Baseline to each scheduled time point up to EOS for vital signs. 
 Change from Screening up to EOS for physical examination. 
 Change from Screening up to EOS for clinical laboratory tests. 
 Treatment-emergent AEs up to EOS. 
 Treatment-emergent AEs leading to premature discontinuation of study drug. 
 Treatment-emergent SAEs up to EOS. 
 
For pre-existing conditions, any event that worsens during treatment will be considered 
treatment-emergent. 

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9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 
Adverse Events 
9.1.1 Definitions of Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (see the ICH guidance for Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
A treatment-emergent AE is any AE temporally associated with the use of a study drug, 
whether or not considered related to the study drug. 
Adverse events will be collected by spontaneous reports from subjects, either verbal or 
recorded in the subject’s diary, by directed question of subjects, and by observation. All AEs 
from the time of signing of the ICF up to the EOS visit will be recorded. 
 
Adverse events include: 
 Exacerbation of a pre-existing disease. 
 Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
 Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
 Continuous persistent disease or symptoms present at Baseline that worsen following 
the start of the study. 
 Events considered by the investigator to be related to study-mandated procedures.  
 Abnormal assessments, e.g. vital signs or physical examination findings, must be 
reported as AEs if they represent a clinically significant finding that was not present at 
Baseline or worsened during the course of the study. 
 Laboratory test abnormalities must be reported as AEs if they represent a clinically 
significant finding, symptomatic or not, which was not present at Baseline or 
worsened during the course of the study or led to dose reduction, interruption or 
permanent discontinuation of study drug. 
 
Adverse events do not include: 
 Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure must be described in the SAE narrative. 
 Pre-existing disease or medical condition that does not worsen. 
 Situations in which an adverse change has not occurred, e.g., hospitalizations for 
cosmetic elective surgery or for social and/or convenience reasons. 
 Overdose of either study drug or concomitant medication without any signs or 
symptoms. However, overdose must be mentioned in the Study Drug Log. 

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9.1.2 Intensity of Adverse Events 
The intensity of clinical AEs is graded on a three-point scale: mild, moderate, severe, and 
reported on specific AE pages of the eCRF.  
If the intensity of an AE worsens during study drug administration, the AE will be closed and 
a new AE with enhanced severity will be generated in the eCRF. If the AE lessens in 
intensity, no change in the severity is required. 
If an AE occurs during a washout or placebo run-in phase and afterwards worsens during the 
treatment phase, a new AE page must be filled in with the intensity observed during study 
drug administration. 
 
Mild: Event may be noticeable to subject; does not influence daily activities; usually does not 
require intervention. 
 
Moderate: Event may make subject uncomfortable; performance of daily activities may be 
influenced; intervention may be needed. 
 
Severe: Event may cause noticeable discomfort; usually interferes with daily activities; 
subject may not be able to continue in the study; treatment or intervention is usually needed. 
 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe 
the intensity of a specific event (as in mild, moderate, or severe myocardial infarction). 
However, a severe event may be of relatively minor medical significance (such as severe 
headache) and is not necessarily serious. For example, nausea lasting several hours may be 
rated as severe, but may not be clinically serious. Fever of 39 °C that is not considered severe 
may become serious if it prolongs hospital discharge by a day (see Section 9.2.1.2). 
Seriousness rather than severity serves as a guide for defining regulatory reporting 
obligations. 
These definitions do not apply to clinically significant and asymptomatic laboratory test 
abnormalities or abnormal assessments considered as AEs. The investigator should tick non-
applicable on the AE page of the eCRF to qualify the intensity of the AE. 
9.1.3 Relationship to Study Drug 
Adverse events should be assessed by the investigators as to whether or not there is a 
reasonable possibility of causal relationship to the study drug and reported as either definite, 
probable, possible, , not related, as defined below: 
 
1. Not Related: The event is clearly due to extraneous causes (e.g., diseases, 
environment, etc.). Specify if known. Or, the event is most probably produced by 
other factors such as the subject’s clinical state, therapeutic interventions, or 
concomitant therapy and does not follow a known response pattern to the study 
product. 
 
2. Possibly Related: The event is temporally related to study product use but can be 
explained by another etiology. Information on the effect of study product withdrawal 
may be lacking. 
 

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3. Probably Related: The event is temporally related to study product use and is 
consistent with known effects of the study product and/or improves upon withdrawal 
of the study product.  
 
4. Definitely Related: The event follows a reasonable temporal sequence from the time 
of study product administration and/or follows a known response pattern to the study 
product, and could not have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention, or concomitant therapy, and either occurs 
immediately following study product administration or improves on stopping the 
product, or there is a positive reaction at the application site. 
9.1.4 Reporting of Adverse Events 
All AEs occurring after signing the informed consent form and until EOS must be recorded 
on specific AE pages of the eCRF. If the investigator becomes aware of a new AE up to 30 
days after EOS visit, it is within his discretion to follow up the AE and document 
appropriately. 
9.1.5 Follow-up of Adverse Events 
All subjects experiencing AEs (whether considered associated with the use of the study drug 
or not) must be monitored until: 
 resolution of AE  
 stabilization of AE  
 subject is lost to follow up  
 death of subject 
 or until the investigator considers it medically justifiable to terminate the follow-up 
9.2 
Serious Adverse Events 
9.2.1 Definitions 
9.2.1.1 Serious Adverse Events 
A Serious Adverse Event (SAE) is defined by the International Conference on Harmonization 
(ICH) guidelines as any AE fulfilling at least one of the following criteria: 
 Fatal. 
 Life-threatening. 
 Requiring subject's hospitalization or prolongation of existing hospitalization. 
 Resulting in persistent or significant disability or incapacity. 
 Congenital anomaly or birth defect. 
 Medically significant or requires intervention to prevent at least one of the outcomes 
listed above. 
 Life-threatening refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
 Important medical events that may not immediately result in death, be life-
threatening, or require hospitalization may be considered as SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 

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medical or surgical intervention to prevent one of the outcomes listed in the 
definitions above.  
 
The reference safety document to assess whether or not an SAE should be reported by the 
sponsor to Health Authorities, ECs/IRBs and investigators in an expedited fashion is the 
Investigator's Brochure. 
9.2.1.2 Hospitalization - Prolongation of Existing Hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. 
An additional overnight stay defines a prolongation of existing hospitalization. 
The following is not considered an SAE and should be reported as an AE only: 
 Treatment on an emergency or outsubject basis for an event not fulfilling the 
definition of seriousness given above and not resulting in hospitalization. 
 
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs:  
 Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
 Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for coronary angiography in a subject with stable angina 
pectoris. 
 Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for chemotherapy for cancer, elective hip replacement for 
arthritis. 
9.2.1.3 Serious Adverse Events Related to Study-mandated Procedures  
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal 
relationship (i.e., a relationship cannot be ruled out) to study-mandated procedures (excluding 
administration of study drug) such as discontinuation of subject's previous treatment during a 
washout period, or complication of a mandated invasive procedure (e.g., blood sampling, 
heart catheterization), or car accident on the way to the hospital for a study visit, etc. 
9.2.2 Reporting of Serious Adverse Events  
Detailed reporting procedures will be described in a separate Safety Management Plan, and 
are shortly outlined below. 
9.2.2.1 Before Study Drug Initiation 
Serious adverse events occurring after signature of the Informed Consent and up to study 
drug initiation must be reported to Dr. Reddy’s Laboratories Ltd, Clinical Pharmacovigilance 
only if they are considered by the investigator to be related to study-mandated procedures. 
9.2.2.2 During Study Drug Administration 
All SAEs regardless of causal relationship must be reported, including those related to study-
mandated procedures. These SAEs occurring during study drug administration, i.e., between 
study drug initiation and EOS after study drug discontinuation, are defined as treatment 
emergent SAEs. 
These SAEs are reported on SAE forms and also on AE pages in the eCRF. Therefore, they 
are entered both in the drug safety and clinical databases, and must be reconciled before study 
closure. 

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9.2.2.3 After Study Drug Discontinuation 
New SAEs, including those related to study-mandated procedures, occurring during study 
drug administration, i.e., between study drug initiation and EOS, must be reported. 
All SAEs occurring up to 30 days after study drug discontinuation must be recorded on an 
SAE form and as AEs in the eCRF. Therefore, these treatment-emergent SAEs are entered 
both in the drug safety and clinical databases, and must be reconciled before study closure.  
9.2.2.4 Reporting Procedures 
All SAEs must be reported by the investigator to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance, the Sponsor Medical Monitor, and the QPS Medical Monitor within 
24 hours of the investigator's knowledge of the event. 
 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the 
subject, whether or not this event is considered by the investigator to be related to study drug. 
 
These SAE forms must be faxed or send via E-mail to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance and the QPS Medical Monitor. The investigator must complete the SAE 
form in English (unless otherwise specified) and assess the relationship to study drug. 
 
 
 

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Contact details are provided below: 
 
Dr. Reddy’s Laboratories Ltd, Clinical Pharmacovigilance: 
Shahida Hasan, MD  
Associate Director 
Fax: +1 908-450-1510 / +1 877-445-3741 
Email: sae@drreddys.com 
 
Dr. Reddy’s Laboratories Ltd, Medical Monitor: 
Dr. Srinivas Shenoy B., MBBS, MD  
Principal Scientist- Clinical Studies 
Tel No.: +91-40-4434 6126 (Direct)  
E-mail: srinivasshenoyb@drreddys.com 
 
QPS, Medical Monitor: 
Antón Alvarez, MD, PhD 
Country and Clinical Research Director QPS Holdings, LLC 
Phone +34 981 236718 
Mobile +34 629014472 
Fax +34 881 090633 
Email: anton.alvarez@qps.com  
 
Such preliminary reports will be followed by detailed descriptions that should include copies 
of hospital case reports, autopsy reports, hospital discharge summaries and other documents 
when requested and applicable. Follow-up information about a previously reported SAE must 
also be reported within 24 hours of receiving it. The Sponsor’s Pharmacovigilance 
department may contact the investigator to obtain further information.  
 
Suspected (considered related to the study drug) and Unexpected (not previously described in 
the reference safety document), Serious Adverse Reactions (SUSARs) will be expedited by 
the Sponsor’s Pharmacovigilance department to Health Authorities, ECs/IRBs, as 
appropriate. All SAEs judged to be SUSARs and reportable will be unblinded. SUSAR 
related unblinding will be performed by the Sponsor’s Pharmacovigilance department as 
outlined within the Safety Management Plan. QPS will be responsible for sending blinded 
reports to the Investigators. 
9.2.1 Follow-up of Serious Adverse Events  
Serious adverse events still ongoing at the End-of-Study visit must be followed until 
resolution or stabilization or until the event is otherwise explained.  
 
New SAEs occurring at any time after the 30-day follow-up period after study drug 
discontinuation (whichever comes first) may be reported to Dr. Reddy’s Laboratories Ltd, 
Clinical Pharmacovigilance within 24 hours of the investigator's knowledge of the event, if 
felt appropriate by the investigators. 
 
Such information will only be entered into the drug safety database and hence will not affect 
study closure. 

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9.3 
Pregnancies 
All subjects will be instructed to use adequate contraceptive precautions. When pregnancy of 
a subject or a subject’s spouse has been discovered, the pregnancy must be recorded on a 
pregnancy reporting form and reported to Dr. Reddy’s Laboratories Ltd, Clinical 
Pharmacovigilance and the QPS Medical Monitor. The pregnancy outcomes, including 
spontaneous or voluntary termination, details of the pregnancy and birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications, will be followed. The infant’s medical record should be followed up to 1 year 
after birth. 

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10 STATISTICAL METHODOLOGY AND ANALYSES 
10.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written and finalized by QPS before the study 
closure, i.e., database closure and unblinding of the randomization code of the study. The 
SAP will provide full details of the analyses, level of significance to be used, the data 
displays and the algorithms to be used for data derivations. Furthermore, the number of 
subjects planned to be enrolled is given in the SAP. The SAP will include the definition of 
major and minor protocol deviations/violations and the link of major protocol 
deviations/violations to the analysis sets. 
10.2 
Analysis Populations 
Four different analysis sets are defined. Subjects who withdraw from the study, or who have 
missing data, will be included in the statistical analyses provided that they are eligible for 
inclusion in the analysis population as described below. 
 
Full analysis set (FAS): This analysis population includes all subjects who have been 
randomized and had at least one post baseline efficacy assessment. The FAS population will 
be the primary population for the efficacy analyses. 
 
Intention to treat population (ITT): This analysis population includes all subjects who have 
been randomized and dispensed the study drug. 
 
Safety population: This analysis population includes subjects who had at least one safety 
assessment post-baseline. The safety population will be employed in the analysis of 
tolerability and safety variables.  
 
Per-protocol population (PP): This analysis population comprises all subjects who did not 
violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) 
on the primary endpoint, i.e., without major protocol violations or deviations. 
10.2.1 Sample Size 
On the basis of comparable pharmacokinetic parameters of orally administered minocycline 
hydrochloride to doxycycline, it is assumed that DFD-29 (minocycline hydrochloride) will 
demonstrate an efficacy either similar or better than that reported with ORACEA® 
(doxycycline) 40 mg in the treatment of inflammatory lesions of papulopustular rosacea. The 
sizes of the treatment effect of doxycycline 40 mg in comparison to placebo that were 
reported from the two pivotal efficacy and safety clinical trials, that formed the basis of 
approval of ORACEA® (by USFDA, see review) for the treatment of only inflammatory 
lesions of rosacea, in terms of the two co-primary endpoints in this study, are presented in 
brief in the Table 7 below.  
 
 

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Table 7: Efficacy of Oracea®* 40 mg/day as shown in two phase 3 trials 
 
Study 1 
Study 2 
 
Oracea®  
N=127 
Placebo 
N=124 
Oracea® 
N=142 
Placebo 
N=144 
Mean change in lesion counts from Baseline 
-11.82 
±9.78 
-5.94 ± 
13.91 
-9.48 ± 
9.63 
-4.31 ± 
11.57 
Proportion of subjects with IGA of ‘0’ or ‘1’ 
at the end of study 
 39 
(30.7%) 
24 
(19.4%) 
21 
(14.8%) 
9  
(6.3%) 
*US American trade name 
Using the more conservative estimate of the difference in the treatment means of 5.17 lesions 
(from Study 2) and the estimated population variance of 112, the sample size required is 
calculated to be 44 subjects per group to achieve 70% power in the study. By accounting for 
an expected subject discontinuation rate of 10%, the required sample size is rounded of to 50 
subjects per group. 
 
The above determined sample size of 44 subjects per treatment group was also seen to ensure 
an adequately powered analysis (87%) for demonstrating non-inferiority of DFD-29 40 mg 
and DFD-29 20 mg treatments against the active comparator Oraycea® while assuming the 
lower limit of the 90% CI for concluding non-inferiority to be≤3 for the absolute change in 
total inflammatory lesion count from Baseline at Week 16 for the individual DFD-29 
treatment arms versus Oraycea® arm, a common standard deviation of 5 lesion counts, the 
expected difference of treatment means to be 0 and alpha of 0.05 (one sided). Similarly, this 
sample size will also achieve 91% power to detect a non-inferiority margin difference of 0.5 
points on the RosaQoL, assuming a common standard deviation of 0.77 points. 
10.2.2 Handling of Missing Data 
All safety analyses will be performed on data available at the time point considered. In 
summary tables, the number of subjects with missing data will be presented unless otherwise 
specified. In calculation of percentages, subjects with missing data will not be considered in 
numerator or denominator unless otherwise specified. 
For the efficacy data; in case of missing measurements, multiple imputation (MI) will be used 
to impute the missing values. For the MI of the inflammatory lesion count test and CRP, a 
MIXED model will be used, with visit as a factor and subject as random variable. For success 
rate, a logistic model will be used.  
10.3 
Efficacy Parameters 
10.3.1 Statistical Analysis of Efficacy Parameters 
Efficacy 
For all endpoints, the comparison of oral DFD-29 (40 mg capsule) versus placebo will be the 
primary objective of the study. All other comparisons viz, between oral DFD-29 (20 mg 
capsule) and placebo, between oral DFD-29 (40 and 20 mg capsules) and Oraycea® and 
between oral DFD-29 40 mg capsules and DFD-29 20 mg capsules, will be treated as 
secondary.  
 

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Co-Primary Endpoints 
 The proportion of subjects with IGA (modified scale without erythema) ‘treatment 
success’ – will be investigated with a Chi-square test. ‘Treatment success’ is described as 
having at least 2 grade reduction from Baseline with grade 0 or 1 at Week 16. 
 The difference between the treatments in terms of the change from Baseline in the total 
inflammatory lesion count at Week 16 will be tested using MIXED Model, with the 
investigator as a random factor. 
 
Secondary Endpoints: 
  The proportion of subjects with at least a 2 grade reduction in IGA (modified scale 
without erythema) score from Baseline to Week 16, will be investigated with a Chi-
square test. 
 Median change in total RosaQoL score from Baseline to Week 16 will be analyzed using 
ANOVA. 
 
For secondary and exploratory endpoints we assume that non-inferiority would be established 
if the mean change in inflammatory lesion count in the DFD-29 (40 mg capsule) group would 
be within 3 less than in the Oraycea® group for the lower limit of the 90% Confidence 
Intervals. 
10.4 
Safety and Tolerability Parameters  
Definitions of the safety and tolerability parameters are described in Section 8.7.1. 
 
The safety population is used to perform all safety analyses.  
 
The medical history is coded using the most recent Medical Dictionary for Regulatory 
Activities (MedDRA) version and listed. 
 
All AEs and SAEs are coded using the most recent MedDRA version at the study start. 
The treatment-emergent AEs are tabulated by system organ class (SOC), and individual 
preferred terms within each SOC by treatment group. The number and percentage of subjects 
who experienced AEs coded with the same preferred term and SOC will be summarized by 
treatment group (in descending order according to the incidence in the investigational study 
drug group). Adverse events will also be tabulated by severity and by relationship to study 
drug. Summary tables will be accompanied by individual subject listings broken down by 
treatment group, including pre-dose events.  
SAEs will be listed and summarized similarly to AEs.  
 
Reasons for death will only be listed. 
 
Reasons for premature discontinuation of study drug will be listed and summarized by 
frequency tables. 
 
Individual subject listings of vital signs data and laboratory measurements will be provided. 
Vital sign measurements and laboratory measurements will be summarized at each time point 
using mean, median, standard deviation, min, max, number of available observations, and 
change from Screening or Baseline for the following parameters: 

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 Change from Baseline to each scheduled time point up to EOS for vital signs 
compared between DFD-29, Oraycea® and placebo. 
 Change from Screening up to EOS for physical examination compared between DFD-
29, Oraycea®and placebo.  
 Change from Screening up to EOS for clinical laboratory tests compared between 
DFD-29, Oraycea® and placebo. 
 Treatment-emergent AEs up to EOS compared between DFD-29, Oraycea® and 
placebo. 
 Treatment-emergent AEs leading to premature discontinuation of study drug 
compared between DFD-29, Oraycea® and placebo. 
 Treatment-emergent SAEs up to EOS compared between DFD-29, Oraycea® and 
placebo. 
Standard numeric laboratory parameters are presented in the units supplied. If needed, a 
conversion will be made to standard units. 
10.5 
Exposure to Study Drugs 
A listing with information about the drug administration will be provided. 
10.6 
Baseline Parameters and Concomitant Medications 
Summary statistics (mean, median, standard deviation, min, max, number of available 
observations) will be provided for continuous demographic variables (e.g., age, height, 
weight). Individual subject listings of demographic data will be provided. 
 
Qualitative demographic characteristics (gender, race) will be summarized by counts and 
percentages. Other Baseline subject characteristics (medical history, physical examination 
clinical findings, previous medications, inclusion/exclusion checklist) will only be listed.  
 
Distributions of these parameters will be compared between the treatment groups only 
descriptively. No statistical inference will be performed. 
 
Previous and concomitant medications will be coded by the sponsor according to the World 
Health Organisation (WHO) drug code and the ATC (Anatomical Therapeutic Chemical) 
class code. Previous medications will be summarized by tabulating the number and 
percentages of subjects treated. 
10.7 
Exploratory Analyses 
Exploratory data-driven analyses can be performed with the caveat that any statistical 
inference will not have any confirmatory value. 
 
Exploratory Endpoints: 
 Proportion of subjects with at least a two grade improvement of IGA (modified scale 
without erythema) grade from Baseline to Weeks 4, 8 and 12 will be investigated with a 
Chi-square test. 

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 The difference between treatments in terms of the change from Baseline in the total 
inflammatory lesion count at Weeks 4, 8 and 12 will be tested using MIXED Model with 
the investigator as a random factor. 
 The proportion of subjects with at least a 2 grade reduction in IGA (modified scale 
without erythema) score from Baseline to Week 4, 8 and 12, will be investigated with a 
Chi-square test. 
 Median change in total RosaQoL score from Baseline to Weeks 4, 8 and 12 will be 
investigated using ANOVA. 
 The difference between treatments will be tested for the mean change in high sensitivity 
C-reactive protein (hs-CRP) levels from Baseline to Week 16 using ANOVA 
 Change in Telangiectasia score from Baseline to Week 16 will be investigated using 
ANOVA. 
 Proportion of subjects meeting CEA ‘treatment success’ criteria (i.e. a two grade 
improvement in the CEA scale) in the treatment groups at Weeks 4, 8, 12 and 16 will be 
investigated using ANOVA. 
 
Exploratory analyses for the following subgroups will be performed: 
 Male versus female. 
 Mild (score 2), moderate (score 3) and severe (score 4) IGA score. 
 Normal hs-CRP versus abnormal hs-CRP at Baseline 
10.8 
Clinical Study Report 
Safety and tolerability parameters as well as efficacy parameters will be evaluated and the 
study outcome presented in a Clinical Study Report. 
 
 

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11 PROCEDURES AND GOOD CLINICAL PRACTICE  
11.1 
Procedures 
11.1.1 Protocol Amendments 
Any substantial change to a protocol has to be considered as an amendment as soon as these 
documents have been submitted to ECs/IRBs or Health Authorities. Therefore, an 
amendment could occur before or after the approval of these documents by ECs/IRBs or 
Health Authorities. Each amendment must be documented in writing and approved by Dr. 
Reddy’s. It should be reviewed by the Principal Investigator(s) or Steering Committee, as 
appropriate. 
Adaptations of the core subject Information and Informed Consent requested by ECs/IRBs 
are not considered as amendments, as long as they do not significantly change the core 
document or affect the protocol. 
11.1.1.1 Non-substantial Amendment 
Administrative or logistical minor changes require a non-substantial amendment. Such 
changes include but are not limited to changes in study staff or contact details (e.g., Dr. 
Reddy’s instead of CRO monitors) or minor changes in the packaging or labeling of study 
drug.  
The implementation of a non-substantial amendment could be done with or without 
(according to national regulations) notification to the appropriate ECs/IRBs and Health 
Authorities. It does not require their approval or to be signed by the investigators.  
11.1.1.2 Substantial Amendment 
Significant changes require a substantial amendment. Significant changes include but are not 
limited to: new data affecting the safety of subjects, change of the objectives/ parameters of 
the study, eligibility criteria, dose regimen, study assessments/procedures, treatment or study 
duration, with or without the need to modify the core Subject Information and Informed 
Consent. 
Substantial amendments are to be approved by the appropriate ECs and in some countries by 
the Health Authorities. The implementation of a substantial amendment can only occur after 
formal approval by the appropriate ECs/IRBs and/or Health Authorities and must be signed 
by the investigators. 
11.1.1.3 Urgent Amendment 
An urgent amendment might become necessary to preserve the safety of the subjects included 
in the study. The requirements for approval should in no way prevent any immediate action 
being taken by the investigators or Dr. Reddy’s in the best interests of the subjects. Therefore, 
if deemed necessary, an investigator can implement an immediate change to the protocol for 
safety reasons. This means that, exceptionally, the implementation of urgent amendments will 
occur before submission to and approval by ECs/IRBs and Health Authorities.  
In such cases, the investigator must notify Dr. Reddy’s within 24 hours. A related substantial 
amendment will be written within 10 working days by QPS on behalf of Dr. Reddy’s and 
submitted to the appropriate ECs/IRBs and Health Authorities. 

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11.1.2 Monitoring 
The monitor will contact and visit the investigator regularly and will be allowed, on request, 
to have access to all source documents needed to verify the entries on the eCRF and other 
protocol related documents; provided that subject confidentiality is maintained in agreement 
with local regulations. It will be the monitor's responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered on them. Dr. Reddy’s monitoring 
standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs and the recording of the main efficacy, 
safety and tolerability parameters. Additional checks of the consistency of the source data 
with the eCRFs are performed according to the study-specific monitoring plan. 
The investigator must ensure that subjects' anonymity will be maintained. On eCRFs or other 
documents submitted to Dr. Reddy’s, subjects should not be identified by their names, but by 
the subject number. The investigator must keep a subject identification code list showing the 
randomization number, the subject's name, date of birth and address or any other locally 
accepted identifiers. Documents identifying the subjects (e.g., subjects' signed informed 
consent forms) should not be sent to Dr. Reddy’s and must be kept by the investigator in 
strict confidence. 
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure that 
any issue detected in the course of these monitoring visits is resolved. If the subject is 
hospitalized or dies in a hospital other than the study center, the investigator is in charge of 
contacting this hospital in order to document this SAE. 
The investigator will supply Dr. Reddy’s on request with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems and/or 
governmental queries, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 
An initiation visit will be performed before the first subject is included. Monitoring visits and 
contacts will occur at regular intervals thereafter, according to a frequency defined in the 
study-specific monitoring plan. A close-out visit will be performed after study closure. 
11.1.3 Data management 
11.1.3.1 Data Collection 
A Subject Screening and Enrollment Log will be completed for all eligible or non-eligible 
subjects with the reasons for exclusion. 
For each subject enrolled, regardless of study drug initiation, an eCRF must be completed and 
signed by the principal investigator or co-investigator. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted on 
the eCRF. Case report forms are to be completed on an ongoing basis.  
Designated investigator staff will enter the data required by the protocol into the electronic 
Case Report Forms. Designated investigator site staff will not be given access to the EDC 
system until they have been trained. The Investigator must certify that the data entered into 
the electronic Case Report Forms are complete and accurate. 

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11.1.3.2 Database Management and Quality Control 
All data from the source documents will be entered into the eCRF if not otherwise stated in 
this protocol. 
The CRA will perform source data verification according to the monitoring plan and the 
SOPs of the CRS department. The CRA will use the eCRF system to track the monitoring 
queries and their resolution by the site. 
The entered data is systematically checked by Data Management of the CRS department, 
QPS Netherlands, according to the data validation plan and the applicable SOPs.  
After the eCRF has been declared complete and accurate, the eCRF will be locked, after 
written approval of the Sponsor. Any changes to the eCRF after that time can only be made 
after receipt of written approval of the Sponsor. 
Quality assurance (QA) performs process audits based on their annual audit plan (results are 
not shared with sponsors). On request of the sponsor, QA may perform a study audit 
including the data management process. 
11.1.4 Recording of Data and Retention of Documents 
The investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents will be classified into two different categories: investigator's file, and subject 
clinical source documents. 
The investigator's file will contain the protocol/amendments, a copy of the eCRFs and data 
clarification and query forms (after database lock), EC/IRB and Health Authority approval 
with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization 
forms, 
screening 
and 
enrollment 
logs, 
and 
other 
appropriate 
documents/correspondence as per ICH/Good Clinical Practice (GCP) and local regulations. 
Subject clinical source documents include, but are not limited to subject hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory reports, 
pathology and special assessment reports, consultant letters, etc. 
These two categories of documents must be kept on file by the investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). No study document 
should be destroyed without prior written approval from Dr. Reddy’s. Should the investigator 
wish to assign the study records to another party, or move them to another location, Dr. 
Reddy’s must be notified in advance. 
When source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
11.1.5 Audit 
The Dr. Reddy’s Quality team may conduct audits of clinical research activities in 
accordance with internal standard operating procedures (SOPs) to evaluate compliance with 
the principles of GCP and ICH related guidelines.  

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Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by Health Authorities, the investigator must 
inform Dr. Reddy’s immediately that such request has been made. 
The investigator will permit such audits by Dr. Reddy’s or Health Authorities and facilitate 
them by providing access to the relevant source documents. 
11.1.6 Handling of Study Drugs 
ABF will supply all study drug to the site according to local regulations. Drug supplies must 
be kept in an appropriate, secure area and stored according to the conditions specified on the 
drug labels. The site must maintain an accurate record of the shipment and dispensing of 
study drug on an accountability form, which must be given to the monitor at the end of the 
study. An accurate record of the date and amount of study drug dispensed to each subject 
must be available for inspection at any time. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
responsible person must not destroy any drug labels, or unused drug supply. Upon 
termination of the study, the monitor will collect used and unused drug subject bottles. They 
will be sent to the warehouse, where the sponsor or its deputy will check drug accountability. 
In certain circumstances, used and unused drug containers can be destroyed at the site once 
drug accountability is final and checked by the sponsor or its deputy and written permission 
for destruction has been obtained from Dr. Reddy’s. 
11.1.7 Publication of Study Results 
In accordance with standard editorial and ethical practice, Dr. Reddy’s will support 
publication of the data. This will be done under the responsibility of Dr. Reddy’s. 
11.1.8 Disclosure and Confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by Dr. 
Reddy’s in strict confidence and to request similar confidentiality from his/her staff and the 
EC/IRB. Study documents provided by Dr. Reddy’s (investigators' brochures, protocols, 
eCRFs and other protocol-related documents) will be stored appropriately to ensure their 
confidentiality. The information provided by Dr. Reddy’s to the investigator may not be 
disclosed to others without direct written authorization from Dr. Reddy’s, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the trial.  
11.1.9 Premature Termination or Suspension of the Study 
Both Dr. Reddy’s and the investigator reserve the right to terminate the study at any time.  
If a study is prematurely terminated or suspended, Dr. Reddy’s will promptly inform the 
investigators, the ECs/IRBs and Health Authorities, as appropriate, and provide the reason(s) 
for the termination or suspension.  
If the study is prematurely terminated or suspended for any reason, the investigator in 
agreement with Dr. Reddy’s should promptly inform the enrolled subjects and ensure their 
appropriate treatment and follow-up. 
In addition, if the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should promptly inform Dr. Reddy’s and the EC/IRB, and should 

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provide the sponsor and the EC/IRB with a detailed written explanation of the termination or 
suspension. 
If the EC/IRB terminates or suspends its approval/favorable opinion of a study, the 
investigator should promptly notify Dr. Reddy’s and provide Dr. Reddy’s with a detailed 
written explanation of the termination or suspension. 
11.2 
Good Clinical Practice 
11.2.1 Ethics and Good Clinical Practice 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the "Declaration of Helsinki" (as amended in Tokyo, Venice, Hong Kong, 
Somerset-West, Edinburgh, Washington DC, Tokyo, Seoul and Fortaleza) and with the laws 
and regulations of the country in which the clinical research is conducted. A copy of the most 
recent version of the Declaration of Helsinki will be provided in the investigator site file.  
All studies must follow the ICH GCP Guidelines and, if applicable, the Code of Federal 
Regulations. In other countries in which GCP Guidelines exist, the investigators will strictly 
ensure adherence to the stated provisions. 
11.2.2 Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the subject 
(such as subject information used to obtain informed consent) to an Ethics Committee (EC) 
or Institutional Review Board (IRB). Approval from the committee must be obtained before 
starting the study, and should be documented in a dated letter to the investigator, clearly 
identifying the trial, the documents reviewed and the date of approval. A list of members 
participating in the meeting must be provided, including the functions of these members. If 
study staff were present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the EC/IRB approval must also be 
submitted as amendments by the investigator to the EC/IRB in accordance with local 
procedures and regulations (see Section 11.1.1). 
11.2.3 Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, and 
objectives of the study and potential hazards of the study drug. The investigator must also 
explain to the subjects that they are completely free to refuse to enter the study or to 
withdraw from it at any time for any reason. Appropriate forms for documenting written 
informed consent will be provided to the sites prior to the study. The Informed Consent and 
Subject Information will be provided in the local language. 
11.2.4 Compensation to Subjects and Investigators 
Dr. 
Reddy’s 
is 
providing 
insurance 
in 
study 
related 
bodily 
injury 
to 
the 
investigator/center/Subject against claims arising from the study, except for claims that arise 
from malpractice and/or negligence due to QPS (CRO) and Investigator. 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
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12 STRUCTURED RISK ANALYSIS 
A risk-benefit analysis was made by Dr. Reddy´s Laboratories and part of the submission 
package. 

QPS: 160382 
Clinical Study Protocol 
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02 October 2018, Amendment IV 
 
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13 REFERENCES 
 
Abram K, Silm H, Oona M. Prevalence of rosacea in an Estonian working population using a 
standard classification. Acta Derm Venereol. 2010; 90:269–73. 
 
Bewley A, Fowler J, Schöfer H, Kerrouche N, Rives V. Erythema of Rosacea Impairs 
Health-Related Quality of Life: Results of a Meta-analysis. Dermatol Ther (Heidelb). 2016 
Mar 16. [Epub ahead of print] 
 
Dean OM, Maes M, Ashton M, Berk L, Kanchanatawan B, Sughondhabirom A, 
Tangwongchai S, Ng C, Dowling N, Malhi GS, Berk M. Protocol and rationale-the efficacy 
of minocycline as an adjunctive treatment for major depressive disorder: a double blind, 
randomised, placebo controlled trial. Clin Psychopharmacol Neurosci. 2014;12(3):180-8. 
 
Del Rosso JQ. Oral Doxycycline in the Management of Acne Vulgaris: Current Perspectives 
on Clinical Use and Recent Findings with a New Double-scored Small Tablet Formulation. J 
Clin Aesthet Dermatol. 2015;8(5):19-26. 
 
Dosal JR, Rodriguez GL, Pezon CF, Li H, Keri JE. Effect of tetracyclines on the 
development of vascular disease in veterans with acne or rosacea: a retrospective cohort 
study. J Invest Dermatol. 2014;134(8):2267-9. 
 
Duman N, Ersoy Evans S, Atakan N. Rosacea and cardiovascular risk factors: a case control 
study. J Eur Acad Dermatol Venereol. 2014;28(9):1165-9. 
 
Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Clustering of autoimmune diseases in 
subjects with rosacea. J Am Acad Dermatol. 2016a;74(4):667-672.e1. 
 
Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Subjects with Rosacea Have Increased 
Risk of Depression and Anxiety Disorders: A Danish Nationwide Cohort Study. 
Dermatology. 2016b;232(2):208-13. 
 
Feldman SR, Huang WW, Huynh TT. Current drug therapies for rosacea: a chronic vascular 
and inflammatory skin disease. J Manag Care Spec Pharm. 2014;20(6):623-9. 
 
Garrido-Mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J 
Pharmacol. 2013;169(2):337-52. 
 
Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic family of 
compounds with promising therapeutic properties. Review of the literature. Am J Physiol 
Cell Physiol. 2010;299(3):C539-48. 
 
Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an 
analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory 
Care Survey--Outsubject Department data collected by the U.S. National Center for Health 
Statistics from 1995 to 2002. Br J Dermatol. 2005;153(6):1176-81.  

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 103 of 107 
Version 01. Eff. Template date 21-Sep-2012 
 
Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical 
presentation, and new therapeutics. Exp Dermatol. 2016 Jul 4. doi:10.1111/exd.13143. [Epub 
ahead of print] 
 
Hua TC, Chung PI, Chen YJ, Wu LC, Chen YD, Hwang CY, Chu SY, Chen CC, Lee DD, 
Chang YT, Liu HN. Cardiovascular comorbidities in subjects with rosacea: A nationwide 
case-control study from Taiwan. J Am Acad Dermatol. 2015;73(2):249-54. 
 
Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral minocycline and 
extended-release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne 
rosacea. J Drugs Dermatol. 2013;12(3):292-8. 
 
Kanai M, Shimizu H. [A case of hypertrophic pachymeningitis treated successfully with 
antibiotics: the remarkable effect of minocycline hydrochloride in reducing the serum C-
reactive protein value]. No Shinkei Geka. 2009;37(7):673-9. 
 
Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study on the epidemiology of rosacea in the 
U.K. Br J Dermatol. 2012 Sep;167(3):598-605. 
 
Spoendlin J, Voegel JJ, Jick SS, Meier CR. Migraine, triptans, and the risk of developing 
rosacea: a population-based study within the United Kingdom. J Am Acad Dermatol. 
2013;69(3):399-406. 
 
Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, Mess C, Cevikbas F, 
Rivier M, Carlavan I, Déret S, Rosignoli C, Metze D, Luger TA, Voegel JJ. Clinical, cellular, 
and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 
2011;15(1):2-11. 
 
Tan J, Schöfer H, Araviiskaia E, Audibert F, Kerrouche N, Berg M; RISE study group. 
Prevalence of rosacea in the general population of Germany and Russia -The RISE study. J 
Eur Acad Dermatol Venereol. 2016 Mar;30(3):428-34. 
 
van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for 
rosacea. Cochrane Database Syst Rev. 2015;(4):CD003262. 
 
Vemuri RC, Gundamaraju R, Sekaran SD, Manikam R. Major pathophysiological 
correlations of rosacea: a complete clinical appraisal. Int J Med Sci. 2015;12(5):387-96. 
 
Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, Powell F. Standard 
classification of rosacea: Report of the National Rosacea Society Expert Committee on the 
Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584-7. 
 
Wilkin J, Dahl M, Detmar M, Drake L, Liang MH, Odom R, Powell F; National Rosacea 
Society Expert Committee. Standard grading system for rosacea: report of the National 
Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad 
Dermatol. 2004;50(6):907-12. 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
Confidential 
Page 104 of 107 
Version 01. Eff. Template date 21-Sep-2012 
Wollina U. Recent advances in the understanding and management of rosacea. F1000Prime 
Rep. 2014;6:50. 
 
Review NDA 50-805, ORACEATM (doxycycline, USP) Capsules 40 mg 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/050805lbl.pdf 
 
‘Recommendations related to contraception and pregnancy testing in clinical trials’ available 
as http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf  
Accessed on 16 November, 2016 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
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14 APPENDICES 
14.1 
IGA 
Table 8: IGA Scale 
Score 
Definition 
0 = Clear 
No signs or symptoms present 
1 = Near clear 
1 or 2 papules 
2 = Mild 
Some papules and pustules 
3 = Moderate 
Moderate number of papules and 
pustules 
4 = Severe 
Numerous papules and pustules, 
nodules 
 
14.2 
CEA 
Table 9: CEA Scale 
Score 
Definition 
0 = None 
No redness present 
1 = Mild 
Slight pinkness 
2 = Moderate 
Definite redness 
3 = Significant 
Marked erythema 
4 = Severe 
Fiery redness 
 
14.3 
Telangiectasia Score 
Table 10: Telangiectasia Score 
Score 
Number of Telangiectasias visible 
0 = Clear 
No telangiectasias 
1 = Mild 
≤4 telangiectasias 
2 = Moderate 
5-9 telangiectasias 
3 = Severe 
≥10 telangiectasias 
 
 
 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
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14.4 
Diagram of the Face 
 
 
 
A 
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C 
D 
 
 
 
Each pustule to be marked by ‘X’ at its approximate location. 
Each papule to be marked by ‘□’ at its approximate location. 
Each nodule/cyst to be marked by ‘O’ at its approximate location 
 
Figure 14-1: Diagram of the Face 

QPS: 160382 
Clinical Study Protocol 
Sponsor: DFD-29-CD-002 
02 October 2018, Amendment IV 
 
CSP, Template code: TSP820.01 
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14.5 
Example of the Rosacea Quality of Life Instrument 
 
Figure 14-2: Example of the Rosacea Quality of Life Instrument