A Randomized, Open-label, Two-way Crossover Study Assessing the Bioequivalence (BE) Between Single Dose of 750 mg Glucophage® XR Tablets (PT Merck Tbk, Jakarta, Indonesia-Manufactured) and 750 mg Glucophage® XR Tablets (Merck Santé, Semoy, France-Manufactured) Under Fasted State in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck KGaA, Darmstadt, Germany

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GLUCOPHAGE® XR 750 MG INDONESIA BIOEOUIVALENCE STUDY 
CV 
: intra-subject CV 
If these CVs are applied together with applicable 
bioequivalence criteria for AUG and Cmax (0.80-1.25), and the true treatment ratio 
TesVReference is allowed to vary within 0.95 and 1.05, then 44 evaluable subjects will 
provide at least 90% power to show bioequivalence. Per Indonesian guidelines, Pedoman 
Uji Bioekivalensi, Badan Pengawas Oba-t dan Makanan (BPOM), Jakarla, 2015, page 20, 
only 80% power is required at the minimum. 
For a compensation of possible drop-outs during the study, an additional four (4) subjects 
shall be included based on the site
's standard practice. Subjects will not be replaced, even 
if 
there are more than four (4) drop-outs. 
A total of forty-eight (48) healthy adult male and female subjects shall thus be included in 
this study with no reserve subjects. 48 subjects will be administered with the study drug and 
the blood will be taken at various time points of blood sampling procedures. The blood 
samples from 48 subjects will be analyzed for plasma concentrations of metformin. To 
achieve the targeted number of eligible su.b
jects, the number of potential subjects screened 
wm be around two times of the sample size. 
12 
ADVERSE EVENTS/TOXICITY 
12.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of 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 product, whether or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
Subjects will be instructed by the Investigator/study physician to report the occurrence of 
any adverse event. The Investigator 
is required to grade the severity or toxicity of each AE. 
Investigators must assess the severity of AEs according to the Qualitative Toxicity Scale, 
as follows: 
Mild: The subject is aware of the event or symptom, but the event or symptom 
is easily tolerated. 
Moderate: The subject experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity. 
 
Severe: S
'1gn
if
icant impairment of functioning: the subject is unable to carry out his 
or her usual activities. 
F
ina
l Vers
ion U
,
 22/05/2018 
Page 30 of92 
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GLUCOPHAGE® XR 750 MG INDONESIA B!OEQUIVALENGE STUDY 
APPENDIX E 
MS200084_0015 
 
Protoco
l Vers
ion 1.1, 22/05/2018 
 
Final Version 1.1. 22/05/2018 
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GLUCOPHAGE® XR 750 MG INDONESIA BIOEOUIVALENCE STUDY 
~MBER/ .. 
PAGE(S) 
-
34 
43, 53-57 
59 
72 
73 
 
·-
SECTION(S) 
12.1.3: 
Vital Signs, Physical 
Examinations, ECG and Other 
Assessments 
Appendix B 
Appendix C: 
Study Flow Chart 
Appendix E: 
 
Appendix E: 
 
 
--
-
-
·
 
INITIAL PROTOCOL 
AMENDED PROTOCOL 
WORDINGS 
WORDINGS 
Physical examination, body 
Physical examination and ecg will 
measurement (height and 
be performed during screening 
weight), and EGG will be 
and follow-up visit. 
performed during screening and 
fol!ow~up visit. 
Sponsor's Serious Adverse 
Sponsor's Ser
iot,Js Adverse 
Event(s) Report Form, Pregnancy 
Event(s) Report Form and 
Report Form, and Parent~ 
Pregnancy Report Form 
Child/Fetus Adverse Event Ret;:1ort 
Form 
-
(Adjusted) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Version 1.1, 22/0512018 
-
REASON FOR CHANGE 
Inserted body measurements-
(height and weight) during 
Follow~Up Visit-to be 
consistent with the study 
procedure described under 
section 7.4 
Inserted Parent-Child/Fetus 
Adverse Event Report Form 
template under Appendix B 
as mentioned under section 
12,1
' 1 
Inserted body height and 
weight during Follow-Up Visit 
to be consistent with the 
study procedure described 
under section 7.4 
BPOM's comment to include 
respiratory rate 
measurement during 
treatment phase to be 
consistent with study 
procedure described under 
section 7.3 
Inserted body measurements 
(height and weight) to be 
consistent with study 
procedure described under 
section 7.4 
Page 91 of 92 
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